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10 11 12 13 14 15 10 9 8 7 6 5 4 3 2 1
 How small the cosmos (a kangaroo’s pouch
would hold it), how paltry and puny in comparison
to human consciousness, to a single individual
recollection, and its expression in words!
Vladimir Nabokov—from Speak, Memory
 This book is dedicated to the memory of my mother,
Evelyn Ruth Sweatt. Through some miracle, despite
spending the last years of her life suffering the ravages of
Alzheimer’s disease, she always maintained her cheerful
outlook and sweet disposition.
 Foreword to the
First Edition

In 1967, the neuroscientist E. Roy John published the field has been revolutionized. Consider the range
Mechanisms of Memory, a substantial 468-page survey of discoveries, tools, and ideas that are part of con-
of how the brain learns and remembers. Now, in 2003, temporary memory research, but which were absent
the neuroscientist J. David Sweatt has written a book altogether in the 1960s: the development of Drosophila
about memory under the same title. A consideration and Aplysia as model systems for studying the genet-
of the differences between the two books provides a ics and the synaptic changes underlying behavioral
dramatic picture of the progress that has been made memory, the discovery of LTP, the concept of multiple
in recent years. Indeed, it is striking how dissimilar memory systems, and an entire new discipline that is
the two books are, beyond the title. Building from the delineating the biochemistry and molecular biology
techniques and tools available at the time, Roy John of short-term and long-term neural plasticity. As one
emphasized work at a global, structural level of anal- of the very few books available that surveys learning
ysis: for example, the problem of localization of func- and memory from molecules to behavior, Mechanisms
tion, representation of information in assemblies of of Memory (vintage 2003) provides a welcome and
neurons, and electrophysiological correlates of learn- readable treatment of these extraordinary develop-
ing and memory. One chapter discussed how macro- ments. Progress in the neuroscience of behavior fol-
molecules might be important for memory storage, lows a slower, more gradual course than molecular
but the first studies of protein synthesis inhibition and biology or biochemistry, but across the time spanned
memory had been done only a few years earlier, and by these two books about the mechanisms of memory,
molecular techniques were not available to take the the progress is breathtaking.
problem further.
David Sweatt’s comprehensive book shows not Larry R. Squire
only that much has happened since the 1960s, but that March, 2003

xi
 Preface to the
First Edition

This book is primarily intended for advanced into our thinking about memory. I note that building
undergraduates, graduate students, and researchers these models is at a relatively early stage, but one
interested in learning and memory. After a brief intro- thing the reader hopefully will take from the book is
duction to the basics of learning and memory at the some perspective on where we stand at present and
psychological level, the book will describe current where the future may lie.
understanding of memory at the molecular and cel- Most of us have seen the large and complex sche-
lular level. Particular emphasis will be on the hippo- matic diagrams summarizing intermediary metabo-
campus and its role in declarative and spatial learning, lism. Hundreds of discrete and highly regulated
although examples from other anatomical and behav- enzymatic steps are necessary for the relatively basic
ioral systems will also be used. As the book overall function of converting glucose into ATP. How can
progresses from chapter to chapter, I will deliberately memory be any less complex than that at the molecu-
move from well-established facts and background, to lar level? Human learning and memory is likely the
a description of current work and thinking in the area, most highly evolved and sophisticated biological
to at last what should be clearly labeled speculation. process in existence. In my view, the ultimate molecu-
In my opinion, this book is appropriate for use in lar understanding of learning and memory will make
advanced undergraduate and graduate-level learn- processes such as intermediary metabolism seem sim-
ing and memory courses, courses that typically are ple in comparison. This book represents one first step
based in Psychology, Biology, and Neuroscience at beginning to put together the complex puzzle of the
Departments at the University and Medical School molecular basis of memory.
levels. I hope that it provides a nice foundation for While a strong case can be made that the molecular
thinking about the molecular underpinnings of synap- basis of memory will of necessity be quite complex at
tic plasticity and information storage. However, the the biochemical level, a more difficult argument arises
book is primarily targeted to active researchers (at as to whether understanding these processes is even
all stages of their career development) in the learning really important. Is it molecular stamp collecting? If
and memory fields. all the nervous system really cares about is the firing
One goal of the book is to begin to embrace the of action potentials, isn’t the underlying biochemistry
complexity of mechanisms of learning and memory really just housekeeping? A second point that I want
at the molecular level. Some who work on the cellu- to try to make with this book is that understanding
lar processes of learning and memory seem to want the underlying molecular basis is important. Where
to ignore this complexity, deny its existence, or throw possible, I will try to utilize examples illustrating that
up their hands in frustration and imply that the prob- various molecular processes are being used for infor-
lem is insoluble. I share none of these viewpoints. My mation processing; information processing that occurs
hope in this book is to begin to organize a framework at a level independent of patterns of action potential
of thinking about synaptic plasticity and memory at firing. Also, I want to highlight that action potentials
the molecular level—one which recognizes and begins and neurons per se are incapable of storing information.
to incorporate this extreme biochemical complexity That is because all biological processes are subserved

xiii
xiv Preface to the first edition

by biochemical phenomena. This book is written from a more scholarly tone and gives appropriate credit to X
the perspective that, in the limit, neurons are bags of et al., etc. However, it rapidly leads to bloated verbiage
chemicals and the fundamental unit of information that is much more difficult to read. Taking all this into
storage is the molecule. consideration, I decided to handle the citations in the
This book seeks to take the reader from a basic following way. At the end of each chapter is a section
background of learning theory and synaptic physiol- titled “References” which is a little different from the
ogy, to a detailed discussion of the biochemical mech- typical list of references in terms of its content. It is not
anisms of long-term changes in synaptic function and exhaustive. “References” is the short list of papers that
information storage, to a discussion of the molecular were the principal papers I used in preparing the chap-
basis of learning and memory disorders. Themes that ter, and there is a distinct bias toward citing reviews
are highlighted include: that I feel are particularly lucid and informative. In a
real sense, the references are my list of recommended
l Genes and gene regulation in memory formation.
readings for further information. The cited reviews are
l The role of long-term changes in synaptic function
a place where readers looking for more detailed refer-
in memory.
ences can find citations to the extensive list of primary
l Does Long Term Potentiation  Memory?
literature. I apologize in advance to the many research-
l Multimodal signal integration at the molecular
ers whose primary papers I have not cited directly.
level and its role in cognition as related to memory.
I strongly encourage anyone with any complaint,
l Learning disorders with a focus on mental
correction, criticism or suggested addition to e-mail
retardation syndromes.
me (david@cns. neusc.bcm.tmc.edu). Constructive
l Memory disorders with a focus on Alzheimer’s
criticism is the only means by which the content of
Disease.
the book may be improved in the future. So, when
l The biochemical basis of cellular information
John Lisman wants to fire off a scathing critique of
processing.
my inadequate representation of his work, I encour-
l Biochemical mechanisms for information storage.
age him to send me an e-mail so that I can take his
A few comments concerning references are in order. comments into consideration in future writing efforts.
There have been many thousands of publications in I want to emphasize that I encourage everyone to do
the fields that are covered by this book. The chapters this. I want the post-doc who spent two years opti-
covering LTP biochemistry, which is the area that the mizing assays for measuring protein kinase activa-
book covers in the greatest detail, are drawn from tion, so that they could measure an LTP-associated
about 900 primary publications. Some single para- increase in CaMKII, to be able to e-mail me and get
graphs in these sections summarize work from about at least some recognition for their effort. In cases like
50 different research papers. In writing the book, I this it is likely to be helpful to send me the relevant
had to make a decision—I could write sentences like citation and a few sentences describing its significance
“Postsynaptic calcium is known to be involved in LTP and relevance. The overall goal of encouraging this
induction: blocking a rise in postsynaptic calcium sort of interaction is to allow a means for dynamically
blocks LTP induction, elevating postsynaptic calcium correcting and updating the book content.
elicits synaptic potentiation, and a rise in postsynap- Finally, I am more than happy to share Powerpoint
tic calcium has been shown to occur with LTP-induc- files containing the figures from the book with anyone
ing stimulation.” Or I could write sentences like “X who would like to use them for teaching purposes,
et al, Y et al, and Z et al. showed that injecting calcium etc. An e-mail to the above address will suffice to get
chelators postsynaptically blocked LTP induction, P that particular ball rolling.
et al., Q et al, and Z et al. showed that.…” The latter
type of sentence, the historical narrative, obviously has David Sweatt
 Preface to the
Second Edition

In the six years since the publication of the first edi- I have also kept the teachers in mind in prepar-
tion of Mechanisms of Memory, I have had many stu- ing the second edition, and this has manifested itself
dents tell me how much they appreciated the easy in several ways. As has always been the case, all the
readability and relatively informal writing style that figures (plus some) for the book are available on my
I used in writing the first edition of the book. For book website (http://www.neurobiology.uab.edu/
the second edition, I have striven to maintain that sweatt_lab) freely available for download. (If anyone
approach to the writing. I also have maintained a nar- has any problems accessing them, just send me an e-
rative approach to writing the second edition, try- mail at: [email protected].) I have also added some
ing to tell stories about the overall development of new types of references. First, there is now a list of
the field of memory research, and providing various further reading at the end of each chapter that pro-
anecdotal descriptions of specific seminal experiments vides good sources of basic background information
in this area. These two aspects of the first edition, the and additional specific topic-related information. I
story-telling approach and the informal writing style, also have added recommended “Journal Club” arti-
were likely the most appealing aspects of the book cles that students can be assigned for outside reading.
from the “student perspective,” based on the feed- These articles are chosen to be representative of classic
back I received. As with the first edition, I apologize papers in the field, as examples of modern approaches
in advance to all the many memory scientists whose to studying memory, or as representing particularly
specific work is not cited in detail, citations sacrificed hot topics in the memory area. All of these papers will
on the altar of readability. serve as good case studies for further detailed reading
I have also tried to make this edition more student- for students participating in any class based on this
friendly in new ways. For one thing, there is greater textbook.
breadth to this edition, including new sections on Finally, I know that in many cases specific indi-
human memory and cognition, working memory, neu- vidual instructors will want to address particular
roimaging, and “simple” invertebrate model systems. topics in more detail than is presented in this book.
I feel these additions make the text more useful as an Fortunately, there is now a comprehensive series of
introductory volume. I have also included an appen- books available, comprising up-to-date chapters writ-
dix on hypothesis testing and experimental design ten by leading experts in specific areas of the mem-
that I hope will be very useful to aspiring young sci- ory field. The series is published by Elsevier and is
entists, to help give them a framework for thinking titled Learning and Memory, a Comprehensive Reference
about designing research projects. Finally, based on (Jack Byrne, Series Editor, specific volumes edited by
feedback that I have had from other instructors, I have Howard Eichenbaum, Roddy Roediger, Randolph
diminished the level of detail of the multitudinous Menzel, and David Sweatt). The recent reviews pub-
molecular mechanisms that contribute to memory lished in this series are excellent, detailed reviews on
formation, so that the text is at least somewhat more specific topics that are touched on in the chapters in
tractable for students not as well-versed in molecular this book. I feel that many instructors (or advanced
biology and biochemistry. students) may wish to delve more deeply into the

xv
xvi Preface to the second edition

details of particular areas of memory research, or beginning to put together the complex puzzle of the
instructors may wish to assign advanced topics for molecular basis of memory.
term papers, etc. For this reason at the end of each This book seeks to take the reader from a basic
chapter I have cross-referenced specific chapters from background of learning theory and basic studies of
the Learning and Memory, a Comprehensive Reference human memory, to the level of synaptic physiology,
series that relate to topics covered in the chapter. I and thence to a more detailed discussion of the bio-
feel that the combination of Mechanisms of Memory as chemical mechanisms of long-term changes in syn-
a launching point for further reading, coupled with aptic function and information storage. The book
the detailed up-to-date information available in the finishes with a discussion of the molecular basis of
Learning and Memory, a Comprehensive Reference series, learning and memory disorders, discussing clinical
provides an unparalleled resource for instruction in syndromes that are associated with human memory
the area of memory mechanisms. Additional informa- malfunction.
tion for accessing reviews in the Learning and Memory, Themes that are highlighted include:
a Comprehensive Reference series is also available on my l Multiple memory systems in human cognition.
book website. l Genes and epigenetic regulation in memory formation.
One overall goal of the book is to begin to embrace l The role of long-term changes in synaptic function
the complexity of mechanisms of learning and memory
in memory.
at the molecular level. My hope in this book is to begin l The NMDA receptor as an information processing
to organize a framework of thinking about synaptic
nexus.
plasticity and memory at the molecular level—one l Multimodal signal integration at the cellular and
which recognizes and begins to incorporate the known
molecular level and its role in cognition as related
biochemical complexity into our thinking about mem-
to memory.
ory. I note that building these models is at a relatively l Learning disorders with a focus on mental
early stage, but one thing the reader will hopefully
retardation syndromes.
take from the book is some perspective on where we l Memory disorders with a focus on Alzheimer’s
stand at present, and where the future may lie.
disease.
Most of us have seen the large and complex sche- l Invertebrate model systems for studying memory
matic diagrams summarizing intermediary metabo-
mechanisms.
lism. Hundreds of discrete and highly regulated l Biochemical mechanisms for perpetual information
enzymatic steps are necessary for the relatively basic
storage.
function of converting glucose into ATP. How can
memory be any less complex than that at the molecular Finally, I strongly encourage anyone with any com-
level? Human learning and memory is likely the most plaint, correction, criticism or suggested addition to e-
highly evolved and sophisticated biological process in mail me at: [email protected].
existence. In my view, the ultimate molecular under-
standing of learning and memory will make proc- David Sweatt
esses such as intermediary metabolism seem simple Memory Lane
in comparison. This book represents one first step at Trussville Alabama
 Acknowledgements

I want to begin by profusely thanking Felecia Hester received over the years from the NIH, in particular
for all the great work she did in putting together the from the NIMH, NIA, and NINDS.
second edition of Mechanisms of Memory. Felecia was I thank my many colleagues and collaborators,
my collaborator in all aspects of preparing the book from whom I have learned much over the years.
for publication, she read every sentence with an edito- I especially thank my former and current students
rial eye, and prepared many of the figures in the book. and post-docs, from whom I have learned much more
Preparing the book literally would not have been pos- than I ever taught.
sible without her, and I thank her deeply and sincerely. I also would like to thank my editor, Johannes
I also wish to thank my wife, Kim Strifert, to whom Menzel, for his infectious enthusiasm for the book
the first edition was dedicated. I am fortunate beyond project and numerous suggestions to help improve
belief to be married to such an interesting, encourag- the book, as well as his associate Clare Caruana for
ing, deep-thinking, and beautiful woman. her help and input on many aspects of the book. The
I have received tremendous support from the anonymous reviewers of the book proposal and the
University of Alabama at Birmingham, and I thank my anonymous readers of the first edition who provided
many colleagues here for their support, encourage- feedback also deserve recognition for their contribu-
ment, and helpful discussions. I also thank the Evelyn tions in making the book better—they made many
F. McKnight Brain Research Foundation for their useful suggestions that I incorporated into the text.
strong support in making so many great things pos- Finally, I would like to specifically thank the many
sible here at the Evelyn F. McKnight Brain Institute. scientists who allowed me to use figures illustrating
I gratefully acknowledge the research support I have their research results and important concepts.

xvii
MECHANISMS
OF MEMORY
 Multiple Memory Systems
J. David Sweatt, acrylic on canvas, 2008–2009
 C ha p t er

1
Introduction
The Basics of Psychological Learning
and Memory Theory

I. Introduction
A. Categories of Learning and Memory
B. Memory Exhibits Long-Term and Short-Term Forms
II. Short-Term Memory
A. Sensory Memory and Short-Term Storage
B. Working Memory
C. The Prefrontal Cortex and Working Memory
D. Reverberating Circuit Mechanisms Contrast with Molecular Storage Mechanisms for Long-Term Memory
III. Unconscious Learning
A. Simple Forms of Learning
B. Unconscious Learning and Unconscious Recall
C. Unconscious Learning and Subject to Conscious Recall
D. Operant Conditioning
E. Currently Popular Associative Learning Paradigms
IV. Conscious Learning—Subject to Conscious and Unconscious Recall
A. Declarative Learning
B. Spatial Learning
V. Summary
Further Readings
Journal Club Articles
References

I. Introduction An understanding of the cellular and molecular

basis of learning and memory of course requires a firm
Knowledge is power and learning is the tool we foundation in understanding the behavioral processes
use to get it. For that reason humans have evolved these mechanisms subserve. This first chapter serves
extremely sophisticated mechanisms for learning as an introduction to the basics of learning and mem-
new information and storing it for subsequent recall. ory, its theory and terminology. This will provide you
This book will be a description of recent laboratory with the fundamental terms most psychologists use to
discoveries that have begun to scratch the surface of describe the types and forms of learning and memory
the amazingly complex phenomenon of learning and that we will be discussing throughout the book.
memory, focusing on their cellular and molecular What is learning? Before we can begin to effectively
bases. discuss categorizing types of learning and memory, it


 1. Introduction

is useful to define both of the terms we will be using output on the part of the person involved. For exam-
extensively throughout this book: “learning” and ple, an experimenter would have to have them
“memory.” Both of these terms are so widely used respond with “David” instead of “I don’t know”
and implicitly understood that there is a great temp- when they showed them my picture. Nevertheless, it
tation to say “learning is when you learn something is important to remember that this definition is based
and memory is when you remember it.” This type of in experimentation, not theory.
definition obviously is not going to take us very far. At the other end of the spectrum is the criticism
Upon serious reflection it becomes clear that nei- that the definition is too broad. It certainly covers
ther “learning” nor “memory” is easy to define, and many types of alterations in behavior, such as sim-
indeed learning and memory psychologists con- ple sensitization and habituation, which most people
tinue to debate these definitions to this day. In this would not consider as “real” learning (this is illus-
book we will define learning as: the acquisition of an trated in Box 1, for example). Nevertheless, a consid-
altered behavioral response due to an environmental erable body of literature is available indicating that
stimulus. In other words, learning is when an animal many simple forms of behavioral modification qualify
changes its behavior pattern in response to an experi- as learned responses, and most researchers in the field
ence. Note that what is defined is a change in a behav- agree with this. These forms of simple, non-associative
ior from a pre-existing baseline. Don’t get confused: learning are described in Section III of this chapter,
learning is not a response to an environmental stimu- and in more detail in Chapter 3 of this book.
lus, but rather is an alteration in that response due to
an environmental stimulus. An animal has a baseline
response, experiences an environmental signal, and
A. Categories of Learning and Memory
then has an altered response different from its previ-
ous response. This is learning (see Figure 1). This broad, umbrella-like definition of learning
Memory is defined as the storage of the learned covers so many different types of behavioral modi-
item, which of course must be subject to recall by fications that some sort of organizing principle and
some mechanism. attendant nomenclature are called for. We will use
These definitions are functional definitions that an organizational framework developed and pro-
lend themselves to experimental application. An mulgated by Larry Squire and Eric Kandel (1–3). As
experimentalist has to be able to observe something a starting point we will use their system, and I would
(and ideally measure it) in order to be able to test a be remiss if I did not credit their many significant and
hypothesis. The definitions of learning and memory influential contributions in this area.
that are used in this book derive directly from the In this scheme human memory is typically divided
experimentalist mindset. This practical orientation is into declarative and non-declarative types, also
both a strength and a weakness for the definitions— known respectively as explicit and implicit memory
their ready application in practice leads to limitations (see Figure 2). This type of system, subdividing mem-
for their use in theory. ory into several separately identified components, dis-
For example, one criticism of this definition of tills the modern concept of multiple memory systems.
learning is that it is too narrow. If someone learns my It is now clear that different anatomical structures in
name and stores it as a perfectly legitimate memory, the brain are involved in different types of memory
that learned item may never be manifest as an altered formation. Moreover, the different systems can oper-
behavioral output on their part. This is a completely ate as parallel processors, operating independently.
valid theoretical criticism and a limitation to the defi- This allows multi-tasking, with conscious and uncon-
nition. The rebuttal to this argument is that in order scious memory systems operating simultaneously and
for one to ever prove that such a memory exists, one increasing the overall “memory throughput” of the
would have to demonstrate an altered behavioral CNS. Figure 2 briefly summarizes the major subdivi-
sions of human memory, along with the associated
known areas of the CNS that are involved in those
Learning: The acquisition of an altered behavioral specific types of memory. We will discuss most of the
response due to an environmental stimulus. major subdivisions listed in Figure 2 in greater detail
later in this chapter, and in Chapter 3 of this book.
Memory: The processes through which learned information is
stored.
The multiple memory systems concept is impor-
tant and soundly based on functional neuroanatomy.
Recall: The conscious or unconscious retrieval process However, a different, cognitively based framework is
through which this altered behavior is manifest.
also useful to consider. This additional system is based
Figure 1 Definitions of learning, memory, and recall. on whether different types of learning and memory are
 I. Introduction 

Box 1

Learning in a plant? “sensitization”

in the venus’ flytrap

Our functional definition of learning is: a change in has evolved a mechanism whereby stimulation of a
an animal’s behavioral responses as a result of a unique single trigger hair is insufficient to cause closure of the
environmental stimulus. This broad definition is useful trap. Two hairs must be stimulated in succession (or
in that it encompasses various non-associative forms simultaneously) to trigger a trapping response. Thus,
of learning such as sensitization and habituation, but in one circumstance stimulating a particular trigger hair
the breadth of the definition can be criticized. This can will give no response, whereas depending on recent his-
be illustrated by consideration of “sensitization” in the tory stimulating the same trigger hair will in another
Venus’ flytrap plant. instance give trap closure. This is clearly an example
Although plants are not thought of expressing of an altered response that depends on a prior environ-
behavior in the same sense as animals, plants can and mental stimulus. In a sense, the mechanical stimulation
do respond to environmental stimuli. We are all famil- of the first trigger hair could be viewed as analogous to
iar with the phototactic responses of plants as they turn “sensitizing” the plant, in order that it respond to the
to follow the sun, foliage changes in response to cool- mechanical stimulation of the second hair. Venus’ flytrap
ing weather, and the nocturnal closing of certain flow- photograph by Muriel Weinerman.
ers, just to name a few simple examples. However, these
types of responses are really more akin to reflexive, non-
learned behaviors in animals.
One intriguingly complex, multi-component response
of a plant to an environmental stimulus is exhibited by
Dionaea muscipula, commonly known as the Venus’ fly-
trap. This carnivorous plant, indigenous to the peat
bogs of the Carolinas in the southeastern United States,
supplements its nutrition by capturing and digesting
insects. Insects are trapped by Dionaea when they land
in one of the plant’s V-shaped leaves, which closes on
the hapless victim like a miniature steel bear trap.
It is the triggering mechanism for closure of the trap
that warrants our attention. Each half of the V-shaped
trap has on its inward facing surface three trigger hairs.
Mechanical stimulation of these hairs is what elicits
closure of the trap. To eliminate “false alarms,” Dionaea

consciously or unconsciously processed. Thus, using illustrative purposes, and for the rest of this chapter
this system one can divide learning into two broad and in Chapters 2 through 6 we will cover many spe-
classes—unconscious learning and conscious learning. cific examples in each category.
For the purposes of this framework we also introduce The nomenclature summarized in Figure 3 empha-
a “recall” term (see Figure 3), and apply conscious and sizes that any given memory event is comprised of
unconscious to it as well. Thus, any type of memory three components: learning; storage; and recall. An
(with one exception, see below) falls into one of four item or event is learned, stored for some period of time,
categories: unconscious learning with unconscious and recalled. Highlighting these three components is
recall; unconscious learning subject to conscious recall; necessary, because each corresponds to a distinct mole-
conscious learning subject to unconscious recall; and cular and cellular set of events.
conscious learning subject to conscious recall. Specific It is also important to note that the category for
examples of each category are listed in Figure 3 for the learning, memory, and recall of a specific bit of
 1. Introduction

HUMAN MEMORY

DECLARATIVE NON-DECLARATIVE
(EXPLICIT) (IMPLICIT)

FACTS EVENTS

PROCEDURAL PRIMING SIMPLE NON-ASSOCIATIVE

(SKILLS AND CLASSICAL LEARNING
HABITS) CONDITIONING

EMOTIONAL SKELETAL
RESPONSES MUSCULATURE

MEDIAL STRIATUM NEOCORTEX AMYGDALA CEREBELLUM

TEMPORAL REFLEX
LOBE PATHWAYS

Figure 2 Subdivisions of human memory and associated brain regions. Human memory is typically divided into declarative and non-
declarative types, also known as explicit and implicit memory, respectively. In addition to various types of memory described in the text,
priming is also listed. Priming is unconscious memory formation. An example of priming is if one hears or reads a word, for a period of time
afterward one is more likely to use that word in conversation or in a word completion task. This occurs even if no conscious memory for
having heard the word is formed. Chart adapted from Milner, Squire, and Kandel (13).

Hierarchical Organization of Memory

Unconscious learning Conscious learning Working memory

Storage Storage
(unconscious) (unconscious)
Conscious
storage and
conscious recall
Subject to conscious
Subject to conscious Unconscious recall
recall recall

• Declarative learning
• Spatial learning
• Trace conditioning • Conscious associative
• Operant conditioning conditioning
• Hippocampus-
dependent
contextual fear
conditioning
• Taste learning
• Conditioned taste Non-associative learning Associative learning Motor learning
aversion • Habituation • Pavlovian
• Sensitization conditioning
• Dishabituation • Delay Eye-blink
conditioning
• Cued Fear
conditioning

Figure 3 Hierarchical organization of memory. Short-term and long-term memory is subject to being learned by either conscious or
unconscious processes. Similarly, memory can be recalled either consciously or unconsciously. Many forms of simple learning such as motor
learning, simple associative conditioning, and non-associative learning can be learned and recalled unconsciously. More complex forms of
learning typically involve conscious processes. Short-term working memory is listed as a separate category because it is essentially entirely
conscious and not stored for more than a few seconds.
 I. Introduction 

information is not static over time, but subject to either short-lasting or long-lasting. With only a few
change. This can be illustrated by considering the exceptions (see Box 2), the duration of the memory for
learning and recollection of a phone number that a learned event depends on the number of times an
becomes familiar with repetition. One first looks animal experiences a behavior-modifying stimulus.
up the number and consciously stores and recalls For example, a single repetition (or “training trial”)
the number. Over time one repetitively punches in may elicit a memory that lasts only a few minutes,
the number and it is subject to being learned uncon- whereas repeated stimulations will likely result in
sciously as a motor pattern, and recalled uncon- memory lasting hours to days. Repeated presentations
sciously in the same way. This is one example of how of multiple training trials can elicit memory lasting for
the same bit of information, over time, can be subject even more prolonged periods, up to the lifetime of the
to conscious learning, unconscious learning, conscious animal. Thus, the acquisition of memory is a graded
recall, and unconscious recall. phenomenon (see Figure 4).
Finally, note that storage is unconscious in this One exciting area of contemporary learning research
model. This emphasizes the underlying nature of is to try to understand the basis for this attribute. It is
the storage mechanisms—they do not require ongo- intriguing to wonder how repeated presentations of the
ing conscious rehearsal. This has critically important identical environmental stimulus can uniquely elicit a
implications concerning the cellular and molecular long-lasting behavioral alteration, especially when one
processes that underlie memory storage. They must be considers that the behavioral output (e.g., enhanced
stable and capable of self-perpetuation in the absence responsiveness) is identical in the short- and long-lasting
of ongoing conscious input. forms. This is still fairly mysterious at present for the
This is not to say that all forms of memory are various mammalian systems that we will be discussing;
stored unconsciously—clearly several forms of short- however, significant progress has been made address-
term “working” memory are conscious. A good exam- ing this issue in the Aplysia invertebrate model system
ple of this is short-term storage of a phone number, that will be discussed in Chapter 3.
where one can store information over time essen- Long-term memory also has the general attribute
tially by conscious repetition over a given time span. that it undergoes a period of consolidation. Decades
However, this form of memory is in a separate cate- ago it was discovered that, for a period of time after
gory from longer-term forms of memory from a cellu- the training period, generally on the order of hours,
lar and molecular perspective (see Figure 3). Working memories that were normally destined to become
memory can be stored as a short-term change in fir- long-term memories were susceptible to disruption.
ing pattern in cortical neurons, for example in a Disruption of nascent long-term memories can be
reverberating circuit. As such, it does not require any brought about by trauma, for example, or in a more
persisting biochemical modification for its mainte- refined manipulation application of inhibitors of
nance. Indeed, at the molecular level this seems likely protein synthesis can block memory consolidation
to be the distinguishing characteristic of working (Figure 5). Thus it is clear that some set of molecular
memory. It is memory that cannot sustain itself in the processes is occurring for some period of time after
absence of continuing neuronal firing. the training trial, which are necessary for memory to
These categories of learning and memory roughly be established as truly long-lasting. Once the critical
correspond to the typically used “non-declarative time window has passed, the same disruptive manip-
memory” and “declarative memory” nomencla- ulations have no effect on memory storage. Studies
ture popularized by Squire and Kandel (Figure 2), of the cellular and molecular mechanisms contribut-
and widely accepted and utilized. I also emphasize ing to the consolidation of long-term memory will be
the conscious/unconscious terminology because it an area of emphasis in Chapters 2, 3, 6, and 10 of this
highlights the cognitive differences between the two book.
forms. Most importantly, this terminology semanti- There has been a resurgence of interest in the
cally separates the learning from the memory storage consolidation phenomenon lately because several
from the recall—an important mindset to adapt as we groups have reported that previously stored memo-
seek to understand learning and memory events in ries are subject to disruption in certain circumstances.
molecular terms. Specifically, for some types of memory an event
already learned and stored in long-term memory is
B. Memory Exhibits Long-Term and selectively subject to disruption when it is recalled.
The basic experimental observation is that while pro-
Short-Term Forms
tein synthesis inhibitors do not wipe out stored mem-
Emphasized by Eric Kandel, Jim McGaugh, and ory, the same protein synthesis inhibitor treatment
many others (4), almost all forms of memory can be will disrupt memory if the subject is simultaneously
 1. Introduction

Box 2

Non-graded acquisition of memory—food aversion

and imprinting

Generally, if an animal consumes a novel foodstuff that

subsequently causes sickness, even after a single such
experience the animal will exhibit a life-long aversion
to that particular food. While for animals in the wild
the survival value of this type of learning is obvious,
the phenomenon can have unintended consequences.
For example, I once got food poisoning after eating a
bowl of New England clam chowder; to this day even
the sight of a can of New England clam chowder on
the grocery store shelf is enough to send me scurrying
to the next aisle. This is a textbook case of conditioned
food avoidance—being from Alabama, I had never had
clam anything until that day. I certainly will fastidiously
avoid future clam encounters of any kind.
While I have not personally experienced it, hatchling
chicks exhibit a robust form of learning termed imprint-
ing. A newborn bird will develop a strong, long-lasting
affinity for whatever it sees in the first hour after hatch-
ing. In one famous example, a group of young geese
imprinted on the experimental ethologist Konrad Lorenz.
In experimental situations chicks will even imprint on
inanimate objects, such as red boxes or dolls. Of course,
While most forms of long-term memory exhibit in the wild this type of learning serves a useful purpose,
graded acquisition, some types of learning are so criti- as hatchlings will almost always first see their mother
cal to an animal’s survival that extremely robust learn- and imprint upon her. The chicks will then stick close by
ing mechanisms have evolved to subserve them. One the mother as she guides and protects them through the
striking example of this is conditioned food avoidance. perilous fledgling period.

required to recall the information (5–6). Thus, pair- (the engram), changing them at least transiently and
ing protein synthesis inhibitors with a behavioral task triggering a new process of memory reconsolidation.
requiring information recall can lead to a selective Finally, to round out our terminology we need to
loss of a previously stored memory from long-term introduce three terms related to the loss or suppres-
stores. This intriguing process is referred to as recon- sion of memories: extinction; forgetting; and latent
solidation of memory. The necessity for a process of inhibition. Forgetting is woefully familiar to most of
memory reconsolidation highlights the fact that previ- us, and its basis is essentially unexplored. At a min-
ously formed, apparently stable, memories are labile imum it can be defined as a failure over time of the
after recall, and must be restabilized for continued storage or recall processes.
storage. Extinction is the specific erasure of a previous
The process of memory reconsolidation also illus- memory in response to a new environmental stimu-
trates that recall is its own unique process; recall is lus. Extinction has largely been studied in the context
not simply a passive process that does not impact the of reversal of learning. For example, if your cafeteria
underlying memory storage mechanism. Rather, recall, serves hamburgers every Monday you will learn over
in at least some instances, directly impacts the molecu- time that the cafeteria always serves hamburgers
lar and cellular processes underlying memory storage on Monday. If at some later point they stop serving
 I. Introduction 

1000 Training Testing at 24 Hrs.

4 trains / day 100
for 4 days

latency to step-down (s)

80
Duration of withdrawal (% of control)

60

40

500 20
*
0
4 single shocks
Control Inhibitor Control Inhibitor

Single Figure 5  Protein synthesis inhibitors block consolidation of

tail shock long-term memory. Inhibitors of protein synthesis typically block
the ability of learned information to be consolidated into a long-
100 lasting form. In this experiment rats were trained in a step-down
Control avoidance paradigm (see Chapter 4). Animals are placed on an
0 elevated platform in the middle of an electric grid and receive a
0 1 4 7 mild foot shock when they step down from the platform. On the
Days after training training day animals that received a saline infusion (CONTROL)
or the protein synthesis inhibitor anisomycin (INHIBITOR) both
Figure 4  Graded acquisition of memory. Multiple training trials quickly step down from the platform (latency to step-down, Y-axis).
typically result in more robust and long-lasting memory formation.
Twenty-four hours later the control animals exhibit a much longer
In this case sensitization of the gill-withdrawal reflex in Aplysia califor-
latency to step down, indicating that they have learned to avoid
nica was measured by quantitating the duration of gill withdrawal in
the electrified floor. Animals treated with protein synthesis inhibi-
response to a slight touch (duration of withdrawal, Y-axis). Delivery
tor have not consolidated their memory for the step-down training,
of a tail shock to the animal elicits sensitization, and an increase in
and exhibit a short latency to step down just as they did on the first
the magnitude of the protective gill withdrawal reflex (see Box 3 and
day. Additional experiments (not shown) have demonstrated that
text). Increasing numbers of training trials (tail shocks) increases both
anisomycin treatment immediately after training is also effective at
the duration of the memory (days of duration) and the magnitude of
blocking memory consolidation, indicating that consolidation is a
the learned response. Adapted from Kandel (14).
post-training phenomenon (5).
A few words about the particulars of the Aplysia model system
are appropriate at this point, although we will discuss this system
in much greater detail in later parts of the book. Much (but by no
means all) of the work in Aplysia has been geared toward under-
standing the basis of sensitization in this animal. Aplysia has on is an example of extinguishing a previously learned
its dorsum a respiratory gill-and-siphon complex, which is nor- response. This is an extinction of a memory that
mally extended when the animal is in the resting state. If the gill Monday means hamburgers. Similar to forgetting, the
or siphon is lightly touched (or experimentally, squirted with a
unique mechanisms underlying extinction have not
Water-Pic), this elicits a defensive withdrawal reflex in order to
protect the gill from potential damage. This defensive withdrawal been extensively studied. One intriguing speculation is
reflex can undergo both habituation (by repeated light stimuli) that the reconsolidation mechanism may be involved
and sensitization. Sensitization occurs when the animal receives in some cases, the thinking being that perhaps recon-
an aversive stimulus, for example a modest tail-shock experimen- solidation is the process that has evolved to allow spe-
tally or a predatory nip in the wild (see Box 3). After sensitizing
cific erasure of previously learned material, by opening
stimulation, the animal exhibits a more robust, longer-lasting gill-
withdrawal in response to the identical light touch or water squirt. up a period of susceptibility on recall (5–6).
Acquisition of this sensitization response is graded; repetitive Latent inhibition is the mirror image of extinction.
sensitizing stimuli can give sensitization lasting minutes to hours Latent inhibition refers to the capacity of prior experi-
(one to a few shocks), or weeks (repeated training trials over a few ence to suppress (“inhibit”) new learning. The “latent”
days). We will return to the Aplysia system in later chapters of the
in latent inhibition refers to the attribute that the pro-
book, where we will discuss several of the biochemical mechanisms
underlying the short- and long-term modification of this behavioral cess is passive and not generally recognizable until
response. one observes a failure of learning. Latent inhibition can
be illustrated by the following example. Over a life-
time of food consumption you passively and uncon-
hamburgers on Monday it will take a while to relearn sciously learn a wide variety of tastes. Familiar tastes
that contingency. Over time, you will no longer from foods that you have repeatedly consumed are
assume that if it’s Monday that means hamburgers, not subject to conditioned food avoidance (see Box 2)
and similarly will no longer infer that if they are serv- if they are paired with a nausea-inducing agent. The
ing hamburgers then it is Monday. This disassociation prior experience with the familiar taste leads to latent
10 1. Introduction

inhibition of subsequent aversive conditioning; having Short-term storage refers to retention of information
a latent memory that the taste has not been previously in the short-term system after the information has been
associated with malaise leads to an inhibition of the processed and has reached consciousness. The “process-
formation of a new, different association. ing” may have been either the processing of new sen-
sory input, or processing in the sense of recalling a
previously stored memory, hence short-term storage
operates on both new and old information (Figure 6A).
II. Short-term memory In the case of handling new information, short-term
storage may operate as a step in the sequence of events
The quickest, earliest stages of memory of necessity leading to long-term storage of that information.
deal with processing transient sensory and perceptual If a person is distracted, information is rapidly lost
stimuli. The buffers for holding onto sensory informa- from short-term storage. One commonly-used tech-
tion for seconds or a few minutes after their termina- nique to counteract this fact (in humans at least) is
tion in the environment are referred to as short-term ongoing repetition or rehearsal of the information held
memory. The short-term memory system is divided into in short-term storage (Figure 6A). As a first approxi-
three basic components: sensory memory; short-term mation, the information in your short-term stor-
storage; and working memory, each with different age is the information of which you are consciously
functions. aware.
It is important to realize that short-term memory is
bidirectional. It is clear that short-term memory deals
with sensory perceptions as already mentioned, but B. Working Memory
short-term memory also handles information that is It is possible to hold a fact in short-term storage
recently recalled from long-term stores. Thus, short- without doing anything with it. However, if the infor-
term memory is both an input device and an output mation is manipulated and further processed in any
device. It not only handles new information freshly way, it is referred to as being held in working memory.
perceived, it also handles old information freshly Thus, the term working memory refers specifically to
recalled. Old information must be brought forward the type of memory system used to hold information
into a short-term memory store for utilization, and for short periods of time while it is being utilized. A
this is also a component of short-term memory. simple example is doing arithmetic calculations using
remembered numbers (what is 4  56?). Mentally
multiplying 4  56 is clearly a different memory task
A. Sensory Memory and Short-Term Storage
than simply remembering the number 224 for a few
The first component of the short-term memory sys- seconds.
tem deals exclusively with freshly perceived informa- Alan Baddeley has presented a refined model of the
tion, for example the face of someone you have just working memory component of short-term memory
met. The sensory input (visual in this example) begins that is a significant addition to the simpler multi-store
its journey into memory by passing into the first stage model presented in the previous section and in Figure
of the short-term memory system. This initial, tran- 6A. In the Baddeley model, the passive sensory reg-
sient stage of sensory information storage is referred isters and short-term stores (Figure 6A) are also aug-
to as sensory memory, or the sensory register (Figure mented by a working memory module (Figure 6B).
6A). While it is difficult to define exactly when per- In the Baddeley module, three different storage sys-
ception ceases and short-term memory takes over, it tems contribute to the working memory component of
is clear that sensory input, be it touch, taste, smell, short-term memory. The phonological loop is respon-
sight or sound, must pass into a short-term store sible for short-term storage of auditory and spoken
in order to be further processed as part of a lasting language information. Limitations to the capacity of
memory. the phonological loop are responsible for the familiar
The sensory register is the first stage of processing limits on digit-span memory capacity, for example.
new information into a memory. Presumably, each The visuospatial sketchpad is conceptually similar to
different sensory system has dedicated components the phonological loop, except that it deals with visual
of the sensory register that contribute to passing its and spatial information. The episodic buffer is the
unique information along to memory. However, two component that deals with holding and manipulating
sensory registers have been widely studied, and have information recently recalled from long-term storage.
been poetically named. Echoic memory refers to the These three components are regulated by a central
auditory sensory store, while iconic memory refers to executive system that coordinates and integrates their
the visual store. functions.
 II. Short-term memory 11

RESPONSE RESPONSE
OUTPUT GENERATOR

LONG-TERM
REHEARSAL STORE
S BUFFER
E
N
S SHORT-TERM
O STORE
R
STIMULUS Y R
INPUT Self-addressable memory bank
E
G not subject to decay
Memory bank subject
I
to rapid decay
S
T
E
R CONTROL PROCESSES
• Stimulus analyzer programs
• Alter biases of sensory channels
• Activate rehearsal mechanism
• Modify information flow from SR to STS
• Code and transfer information from STS to LTS
• Initiate or modify search of LTS
• Heuristic operations on stored information
• Set decision criteria
• Initiate response generator

Figure 6A The multi-store memory model. Memory can be broadly categorized as having a few basic components, delineated by the
timing of their participation. Sensory input impinges upon sensory organs (eyes, ears, etc.) and is held very briefly as a perception in a
sensory register. Information then traverses to a short-term store where it is held (and potentially rehearsed and processed) for seconds
to minutes. From the short-term store the information may be passed on for long-term storage for minutes to years. Higher-order control
mechanism and processes such as attention-related systems orchestrate the overall process. (SR  sensory register; STS  short-term store;
LTS  long-term store). Adapted, with permission, from the work of Shiffrin and Atkinson (1969). “Storage and retrieval processes in long-
term memory.” Psychological Review 76:179–193. Copyright 1969 by the American Psychological Association.

C. The Prefrontal Cortex and Working Memory

Central
executive What brain region does the work in working mem-
ory? There is very strong experimental support that
the prefrontal cortex (PFC) is one anatomical site sub-
serving working memory. The PFC in humans is large,
is located in the rostral part of the frontal lobes, and
Visuospatial Episodic Phonological occupies about one-third of the cerebral cortex. The
sketchpad buffer loop PFC is immediately rostral to the premotor and motor
cortices, and is extensively interconnected with other
parts of the cerebral cortex and the hippocampus.
The laboratory of the late Patricia Goldman-Rakic
Visual Episodic pioneered studies in non-human primates that dem-
Language
semantics LTM
onstrated a role for the PFC in working memory.
These elegant studies combined discrete anatomical
lesioning approaches, pharmacologic studies, and
Fluid systems Crystallized systems
direct recordings in vivo from the PFC during work-
Figure 6B Baddeley’s working memory module. An executive ing memory tasks. More recently, these studies have
control system regulates the integration of three basic components been reinforced by studies in humans using functional
of the working memory system. The system overall coordinates the magnetic resonance imaging (fMRI).
processing of visual sensory information, verbal language, and infor- Altogether, a convincing case has been made that
mation recalled from long-term episodic memory stores. (LTM  long-
term memory). Adapted with permission from Baddeley (2001). “Is
the PFC contributes to working memory, and indeed
working memory still working?” Am. Psychol. 56:849–864. Copyright Goldman-Rakic and colleagues have proposed that
2001 by the American Psychological Association. different PFC subregions contribute to different
12 1. Introduction

Prefrontal cortex
Working memory

Response
Ventrolateral PFC Dorsolateral PFC
Non-spatial memory Spatial memory
(color, shape, etc.)

Figure 7  Anatomical subdomains of working memory. This

model is based on work by Goldman-Rakic and co-workers.

Ha Dis Se
bitu hab nsi
atio itua tiza
n tion tion
Short-term memory Long-term memory
Working memory Figure 9  Some simple non-associative forms of learning.
Habituation, dishabituation and sensitization are illustrated. Each
circle represents a hypothetical response to an environmental stim-
ulus. Habituation is a decrease in response (arbitrarily defined in
this schematic example) with repeated presentation of the stimulus.
Action potential firing Persisting molecular and Dishabituation is a recovery to normal baseline response when the
sustained neural circuit cellular changes animal receives a different environmental stimulus. Sensitization
activity changes in synaptic
is an increase in the magnitude of the response above the original
structure
baseline.
anatomical circuit alterations

Figure 8  Mechanisms for storing short-term memory are dis-

tinct from those underlying long-term memory.
III. Unconscious learning

components of the working memory system. A. Simple Forms of Learning

Specifically, they have proposed that persisting neuro- In this section we will explore several “simple,”
nal activity in the ventrolateral PFC contributes to non- i.e., non-associative, forms of learning. Keep in mind
spatial short-term memory (the color and shape of an that even those forms of learning that exhibit them-
object, for example) while the dorsolateral PFC contrib- selves in a fairly straightforward manner at the
utes to spatial short-term memory (see Figure 7). behavioral level involve elaborate underlying cellu-
lar and molecular machinery. In this section we will
D. Reverberating Circuit Mechanisms Contrast emphasize that several forms of non-associative learn-
with Molecular Storage Mechanisms for ing are exhibited by animals, including: habituation;
dishabituation; and sensitization (see Figure 9). These
Long-Term Memory
forms of learning involve altered responses to a single
The mechanisms underlying short-term memory stimulus, and do not necessitate the animal forming
and working memory involve persistent firing of neu- any association between one environmental stimulus
rons within the PFC and elsewhere in the CNS. Thus, and another—that is, these forms of learning are non-
the memory trace for short-term memory is based in a associative. They also can occur unconsciously (see
repetitively firing neural circuit actively encoding and Figure 3), generally requiring neither conscious per-
holding information. It is important to emphasize that ception of environmental stimuli nor conscious recall
this mechanism contrasts with the mechanisms under- of information.
lying long-term memory, which do not rely on persist- Perhaps the simplest form of learning in exist-
ent or reverberating neuronal action potential firing ence is habituation; for example when an animal is
for their persistence (see Figure 8). Thus, short-term repeatedly presented with an innocuous environmen-
memory storage and long-term memory storage man- tal stimulus, the animal’s response to that stimulus
ifest a fundamental mechanistic difference. Moreover, decreases over time. For example, if someone moves
the fact that long-term memories can be maintained in from a small, quiet town to a street-level apartment
the absence of ongoing action potential firing (at least in Manhattan, typically at first the street noises in
for long periods of time) means that the fundamental the city are disturbing. However, over time, the new-
unit of information storage, the engram, must reside comer becomes accustomed to the new environment,
wholly or in part at the molecular and cell structural and the street noise is no longer so bothersome. This
level in the case of long-term memory. type of phenomenon is referred to as habituation. The
 III. Unconscious learning 13

Box 3

Aplysia in its natural habitat

Given the popularity of Aplysia as an experimen-

tal system, one might be tempted to think of Aplysia as
being indigenous to the aquaria of neurobiology labo-
ratories. However, the most widely studied Aplysia spe-
cies, californica, lives in the cool Pacific waters off the
California coast. Aplysia spends its time in the tidal and
near-coastal zones, where it feeds on a diet of seaweed.
Except for the buffeting of the ocean waves and currents
(and, one must assume, the occasional curious scuba
diver), Aplysia lead a fairly peaceful existence. They are
unsavory to fish and have very few natural predators;
however, Aplysia can serve as prey to certain types of
sea anemones. When an Aplysia is seriously perturbed,
it exhibits its most dramatic behavioral response; inking.
Aplysia possess an ink gland and can release a cloud of
viscous purple ink, similar to the well known octopus.
Although the precise function of the inking is unknown,
two popular ideas are that the ink may contain noxious
compounds to help ward off predators, or may serve
to camouflage the animal from potential attackers. A
strong aversive stimulus such as one that elicits inking
by Aplysia also results in sensitization of the animal. For
some period of time after inking an animal will exhibit
enhancement of its baseline defensive withdrawal
responses. This ethologically relevant form of behavior
modification is the basis for laboratory study of sensiti-
zation in Aplysia.

teleologic explanation for habituation is that over time at their doorstep, street noises may once again become
animals learn to ignore environmental stimuli that noticeable. It is worth noting that dishabituation is
carry no unique informational content. a useful tool to distinguish habituation from fatigue.
Habituation is a very robust behavioral phenom- A habituated response can be overcome by a dishabit-
enon that exhibits itself in many forms—essentially all uating stimulus; however, a decreased response due
baseline behavioral responses more complex than the to fatigue cannot.
purest reflex responses habituate. Some of the more Animals can also learn to become hyper-responsive
well studied habituation phenomena experimentally to an environmental stimulus, a phenomenon known
are habituation of the Aplysia californica gill-and- as sensitization. Sensitization is defined as an increased
siphon defensive withdrawal response and habitua- response over and above the normal baseline response
tion of reflexive leg-lifting in Drosophila. Habituation which occurs in response to an environmental signal.
is also frequently encountered outside the labora- Sensitizing stimuli typically can elicit an augmentation
tory setting; in particular it is frequently observed by in response from either a non-habituated or a habitu-
teachers in the classroom lecture environment. ated starting point. In the second scenario a component
After a response is habituated, if you present of the increased responsiveness must, by definition,
another, unique, stimulus, dishabituation can occur. then be described as dishabituation (see Figure 9).
For example, even after becoming habituated to street Keep in mind that in some ways the definitions
noises, if one is expecting a visitor to be dropped off of habituation, dishabituation, and sensitization are
14 1. Introduction

Box 4

Hermissenda—the good-looking one in the family

While even a dedicated neurobiologist would be

hard-pressed to describe Aplysia as aesthetically attrac-
tive, another popular invertebrate species used in stud-
ies of learning and memory is a clear winner in any
molluscan beauty contest. With its bright coloration
and striking profile, Hermissenda is the closest thing to
a poster child available among the invertebrate species
commonly studied by neurobiologists. Hermissenda is
not just all looks and no brains, however. This system
has been used to study the cellular and molecular basis
of a particular form of associative learning exhibited by
the animal. Hermissenda are normally phototactic; that
is, they will move toward a lighted area. However, if the
animal is trained that light predicts an upcoming aver-
sive stimulus, in this case turbulence in the water sur-
rounding the animal, the normal phototactic response
is suppressed. The laboratories of Dan Alkon and Terry
Crow have been instrumental in discovering the neuro-
nal circuitry, cellular physiology, and molecular mecha-
nisms underlying this form of associative conditioning.

arbitrary. In the natural setting animals are constantly on easily studied, simple forms of learning in special
modifying their behaviors in response to the ongoing preparations that lent themselves to experimental
barrage of environmental signals. Thus, it is difficult investigation at the cellular level. In particular, the
to determine what a “baseline” response is outside of work of Eric Kandel (Figure 10) and his colleagues
a stringently controlled experimental setting. allowed enormous progress in our understanding of
All of these non-associative forms of learning can the cellular basis of behavior in general, and learning
exhibit themselves in either short-term or long-term and memory specifically. Kandel and his colleagues
forms. The duration of the memory for a learned event Tom Carew, Jack Byrne, and Bob Hawkins, along with
depends on the number of times an animal experi- many others, have used the simple marine mollusk
ences a behavior-modifying stimulus. For example, Aplysia californica (Figure 11) to great effect to study
a single sensitizing stimulation may elicit sensitiza- the behavioral attributes and cellular and molecular
tion that lasts only a few minutes, whereas repeated mechanisms of learning and memory.
stimulations will likely result in sensitization lasting
hours to days (see Figure 4, for example). Repeated
presentations of multiple training trials can elicit sen- B. Unconscious Learning and Unconscious Recall
sitization lasting for weeks.
One exciting area of contemporary neurobiologi- Motor Learning
cal research is to try to understand the basis for short- Motor learning, skills, and habits are the classic exam-
term and long-term non-associative learning. Starting ples of unconsciously learned and unconsciously recalled
in the 1960s the mechanisms underlying habituation memories. Walking is a good example. Walking is an
and sensitization began to be worked out at the cel- extremely complex task involving intricate motor move-
lular and biochemical level. Part of this watershed ments, which we generally perform automatically and
of new understanding of the basis of learning and mem- with great facility. We learned to walk unconsciously as
ory came about as a result of the insight to capitalize small children and, if anything, trying to exert conscious
 III. Unconscious learning 15

contractions and hand movements are taking place com-

pletely below the level of conscious thought.
While complex unconscious processes go into the
initial establishment of learned motor patterns, in
some cases such as speech and walking, there is prob-
ably also a complicated interaction of developmental
processes with signals generated in response to envi-
ronmental stimuli. As mentioned above, in the early
stages of many types of motor learning there is con-
scious involvement, the need for which disappears
over time as part of the learning process. The circuitry
and cellular mechanisms underlying motor learning
are quite complex, involving the motor cortex, basal
ganglia including the neostriatum, and cerebellum.
The site of memory storage for most types of motor
memory involve or have access to the principal cir-
Figure 10 Dr Eric Kandel. Dr Kandel is a University Professor cuits which mediate the behavioral motor pattern,
at Columbia University and Nobel Prize-winner who led pioneer- such as the motor cortex, basal ganglia, and spinal
ing studies on the cellular basis of learning and memory. cord motor neurons. A discussion of these systems
is presented in Chapter 2 as part of the discussion of
human memory systems.
Some motor memories are subject to limited con-
scious recall, but in most cases trying to replay a
motor memory with too much conscious control sim-
ply messes things up. This is likely a component of the
common “choking” component of sports, although
stress-induced release of modulatory neurotransmit-
ters which affect performance is also certainly a factor.
It is interesting that the unconscious aspect of motor
recall has made it into popular sports lingo. When an
athlete is at the top of his or her game they are typi-
cally referred to as being “unconscious.”

C. Unconscious Learning and Subject

Figure 11 Aplysia Californica. Aplysia, a nudibranch mollusk
to Conscious Recall
found in the cool waters off the coast of California, popularized for
its use in studies of simple forms of learning and memory. The forms of learning we have talked about so far
are non-associative. In habituation, sensitization, etc.,
nothing is learned about the relationship or associa-
control over our walking as adults likely leads to an tion of one event with another. We next move on to
awkward gait. a more complex form of learning where a predictive
Another example of unconscious learning is learning relationship is learned—an animal learns that one
to play an instrument such as the guitar or piano, at least environmental stimulus reliably predicts another.
as concerns the motor components. Repetition allows An important set of nomenclature in this area arose
the development of finely tuned motor patterns that can out of the pioneering work of Ivan Pavlov (Figure 12).
be recalled without conscious thought. Learning of the Pavlov and his co-workers studied associative con-
motor components also occurs without much conscious ditioning of the salivary response of dogs—studies
control, although certainly there is conscious involve- indeed so classic that the terms classical condition-
ment when the initial motor patterns are beginning to ing and Pavlovian conditioning are now used syn-
be laid down. Even in this case, though, one does not onymously with associative conditioning. Pavlov
consciously work out the pattern of firing of individual knew, as does anyone that has ever owned a dog,
muscles—indeed we by-and-large don’t have very much that when a dog is presented with a food stimulus a
control over the contraction of single muscles and are not strong salivatory response is elicited (see Figure 13).
really conscious of them as single units. When we learn This is a natural response, of course, and this saliva-
to play an instrument, a multitude of complex muscle tion is referred to as the unconditioned response, and
16 1. Introduction

correspondingly the food stimulus is referred to as the example the reliability of a tone for predicting a sub-
unconditioned stimulus. Pavlov’s breakthrough reali- sequent food presentation. This type of learning is
zation, which he subsequently rigorously documented profoundly important for survival in any natural envi-
and studied, was that he could train dogs to associate ronment, and for this reason has been robustly selected
a neutral stimulus, such as the ringing of a bell, with for in animal evolution. Stated another way, associa-
the food stimulus. Over time the dog would form an tive learning allows the neural encoding of cause-and-
association between the bell and the food, and Pavlov effect relationships. The stable formation of a memory
found that the bell alone would ultimately cause a trace, such that an accurate record of cause-and-effect
salivatory response just like the food did. The bell- relationships is available for future reference, provides
elicited salivation was termed the conditioned res- such a pronounced competitive advantage that this
ponse, and correspondingly the bell tone was termed form of learning is typically quite vigorous.
the conditioned stimulus (Figure 13). The importance of this last point cannot be over-
In associative learning an animal learns the pre- stated! Nature has selected for a robust capacity of
dictive value of one stimulus for another, in Pavlov’s nervous systems to accurately reflect one of the prin-
cipal physical laws that govern the real world: cause
and effect. Thus, nervous systems of all sorts have
evolved to the best of their capacity sophisticated and
robust circuit, cellular, and molecular mechanisms to
encode these types of information.
Generally associative learning is quite reliable—
obviously the accuracy of storing cause-and-effect rela-
tionships is of paramount importance and has been
selected for evolutionarily. This is one significant fac-
tor in the popularity of studying associative learning
experimentally—the learned behaviors are observable,
relatively rapidly acquired, and reliably expressed.
However, this is not to say that associative learning
is flawless. Numerous examples exist in the literature
and anecdotally of animals having mislearned associ-
ations. For example, one of my colleagues who works
Figure 12 Ivan Pavlov pioneered the study of associative con- with Macaque monkeys had a monkey who learned
ditioning, studying modification of reflex responses in dogs. that certain visual stimuli predicted the subsequent

Conditioned
stimulus

Unconditioned
stimulus
Unconditioned
response

Conditioned
stimulus

Conditioned
response
Figure 13 Pavlovian associative conditioning of the canine salivary response. Repeated pairings of an auditory cue with food causes the
animal to learn the predictive value of one for the other. See text for details.
 III. Unconscious learning 17

arrival of a food reward. However, the animal also Delay conditioning US

“learned” that it was necessary to wave his hand in CS
an idiosyncratic way in order for the food reward to
be delivered. Of course, in reality the hand movement
was entirely superfluous to the task and the reward Time
delivery. B. F. Skinner recorded several similar cir-
cumstances in training pigeons in associative learning
tasks, where in some cases elaborate but unneces- Trace conditioning
US
sary motor patterns were executed before the animal CS
pecked an object to receive a food reward. Skinner
termed these behaviors “superstitious” behaviors,
a somewhat loaded term that is anthropomorphic, Time
but not without appeal. Regardless of the terminol- Figure 14  Delay and trace conditioning. Associative condition-
ogy, it is clear that these are examples of associative ing falls into two broad categories—delay conditioning, and trace
learning gone awry. Presumably what has happened conditioning. In trace conditioning an intervening time interval is
is that early on in the training, the animal has errone- introduced between the termination of the CS and the onset of the
US. Trace conditioning involves the hippocampus.
ously associated some movement on their part with
the food reward, and formed a lasting but inaccurate
memory that executing the movement is necessary
to receive the reward. I bring up these examples as simultaneously with a CS after the CS has been pre-
indications of the robustness of associative mem- sented continuously for some delay period.
ory, but with the interesting twist that as with all Trace conditioning refers to a conditioning proto-
robust systems there is an attendant possibility of col where the CS is presented, terminated, and fol-
error-proneness. lowed after some intervening period by the US. The
Against this backdrop it is then interesting to CS and US never overlap in time, and are temporally
consider that associative learning depends on two contiguous in the sense that they are presented closely
attributes of the environmental stimuli—contigu- in time, but never simultaneously. The term “trace”
ity and contingency. Contiguity refers to the property arises from the fact that some memory trace for the
of the stimuli occurring coincidentally, that is over- CS must be preserved over time so that it can subse-
lapping in time or one immediately after the other in quently be associated with the US.
time. This captures Nature’s rule of cause and effect. The distinct use of the two terms “delay condi-
Environmental stimuli are generally perceived simulta- tioning” and “trace conditioning” may seem like
neously with or immediately after the events that cause scientific hyper-semanticism, because the two proto-
them. Contingency refers to the ordering of the stim- cols seem so similar. However, the reasonably subtle
uli—that one stimulus consistently precedes the other alteration of introducing a brief intervening time span
in onset. This captures the predictive value of one event between CS and US brings entirely new neuronal cir-
for the other; that is, in nature the cause will always cuits to bear on the cognitive processing involved.
precede the effect. In the examples of mislearning in the Indeed, trace conditioning requires the hippocampus,
previous paragraph the animals presumably misrepre- whereas delay conditioning does not. This hippo-
sented contiguous stimuli as also being contingent. campus-dependence of trace associative learning has
The issue of contiguity in associative conditioning been largely studied in rodents, but elegant studies
raises the consideration of two basic types of classi- in Larry Squire’s laboratory have demonstrated that
cal associative conditioning: delay conditioning and humans with hippocampal lesions also have defi-
trace conditioning (see Figure 14). The type of classi- cits in trace associative conditioning (7). Thus, delay
cal associative conditioning we have discussed so far and trace conditioning differ fundamentally in their
is referred to as delay conditioning. This term derives underlying anatomy and relevant circuitry, so much
from the typical timing of this type of associative con- so that they indeed are quite different forms of learn-
ditioning protocol experimentally. For example, if one ing. It is for this reason that making the reasonably
is training an animal to learn that a tone predicts a small move from delay conditioning to trace condi-
food reward using a delay conditioning protocol, the tioning progresses us from one category of learning to
tone is started and maintained continuously until the another entirely.
food reward is presented. Thus, the onset of the CS is The recall of trace conditioning has mapped onto
followed by a delay before the onset of the US. With it a temporal component as well. Re-experiencing the
delay conditioning the CS and US are contiguous and CS after trace conditioning has occurred allows for
overlapping—in other words the animal receives a US conscious recollection of the US, during the “trace”
18 1. Introduction

period. For example, let’s say that I am trained that One specific example of fear conditioning involves
a tone preceeds a foot shock by five seconds. During the delivery of an innocuous acoustic cue (CS) paired
testing, when I hear the tone I have five seconds dur- with a mild foot shock (US) within a novel environment
ing which I am expecting the foot shock to be deliv- (see Figure 15). When tested 24 hours after training,
ered. Because of this aspect of the possibility of rats, mice, and other rodents exhibit marked fear,
conscious anticipation, trace conditioning is our first measured by freezing behavior or other reflex fear
example of learning that can occur unconsciously but responses, in response to representation of either the
can be subject to conscious recall (see Figure 3). context (contextual fear conditioning) or the auditory CS
delivered in a different context (cued fear conditioning).
Both cued and contextual fear conditioning have been
D. Operant Conditioning shown to be dependent upon the amygdala, whereas
contextual fear conditioning also involves the hippo-
Pavlov’s dogs were passive participants in their
campus. We will return to these two forms of learning
learning experience. They did not have to do any-
in Chapter 4, where we discuss rodent behavioral mod-
thing beyond perceiving the environmental stimulus,
els of learning in more detail.
after which natural reflexes took over and an uncon-
Conditioned taste aversion is another form of
scious salivatory response occurred. This type of
associative learning; in this case, an animal learns to
learning is distinct from learning paradigms where
associate the novel taste of a new foodstuff (CS) with
a voluntary motor response is elicited. Conditioning
subsequent illness (US) resulting from ingestion of
where the animal is required to execute a voluntary
some toxic agent (see Figure 16). The adaptiveness
motor response is referred to as operant conditioning.
of this form of learning should be apparent; by pre-
It is important to bear in mind that the distinction is
venting subsequent ingestion of poisonous foods sur-
a practical one, based in experimentation. Operant
vival is greatly enhanced. This is obviously a form of
conditioning simply refers to the fact that the experi-
learning that is not very forgiving of multiple train-
menter is quantitating a voluntary movement (not a
ing trials; not surprisingly, animals learn after a single
reflex) as the behavioral output indicating that learn-
pairing of novel taste and toxin to avoid that taste in
ing has occurred. The examples I used above where
future encounters.
monkeys or pigeons were required to push a lever or
One interesting aspect of conditioned taste aver-
peck a button are examples of operant conditioning.
sion learning is the long CS-US interval. Unlike other
Over the years there has been debate over whether
operant conditioning will use different mechanisms associative conditioning paradigms, such as fear con-
from classical associative conditioning, and whether ditioning or eye-blink conditioning where the CS-
operant and classical conditioning should really be US interval is typically on the order of seconds, with
considered as distinct categories. We don’t have the conditioned taste aversion the system can tolerate
final answer to this question, but suffice it to say that delays of hours between the CS taste and US toxin.
it appears that operant conditioning will not require This suggests that there are cellular and biochemical
unique cellular or molecular mechanisms—likely the events initiated by the taste stimulus alone that are
mechanistic differences will be confined to the types likely to be long-lasting. Indeed, novel tastes alone
of neuronal circuitry involved. trigger memory formation automatically, as can be
measured by increased food consumption upon repre-
sentation of a foodstuff (Figure 16). This phenomenon
E. Currently Popular Associative Learning is referred to as attenuation of neophobia (11).
Finally, comparing and contrasting fear condition-
Paradigms
ing with conditioned taste aversion raises a final gen-
Two associative learning paradigms that are used eral attribute of associative conditioning, referred to
extensively in the modern laboratory for studying as salience. We discussed above that contingency and
learning are conditioned fear (8–9) and conditioned contiguity are two hallmarks of associative condition-
taste aversion (10). In both paradigms, animals learn ing, and salience is a term used to refer to the third
an association between a neutral conditioned stimulus general property. Salience refers to the fact that ani-
and an aversive unconditioned stimulus. Both serve as mals do not in general learn to associate conditioned
powerful examples of classical Pavlovian condition- stimuli and unconditioned stimuli that are not typi-
ing, and both result in robust, long-lasting memory cally paired in their natural environment. For exam-
after even a single CS-US pairing. These two behavio- ple, nausea-inducing stimuli are by far much more
ral paradigms are also accommodating to researchers robust producers of taste aversion than are generic
because the neuroanatomical pathways underlying painful stimuli that may robustly support other types
the learning are fairly well-established. of aversive conditioning. Similarly, pairing nausea
 III. Unconscious learning 19

TRAINING

• Animal is placed in novel context

• Hears a tone
• Receives foot shock

CONTEXTUAL TEST CUED TEST

• Animal is returned to same context • Animal is placed in modified context

• Test for freezing behavior • Hears a tone
• Test for freezing behavior
Figure 15  Fear conditioning. Fear conditioning is a form of associative conditioning in which an aversive, fear-evoking stimulus is
paired with a novel environmental cue. A wide variety of environmental stimuli can be used for fear conditioning, such as places (contexts),
auditory cues, visual cues, odors, etc.

Behavioral procedures used to assess novel taste learning

NEOPHOBIA TASTE AVERSION

?
DAY 1 10’

DAY 1 10’
LiCl

DAY 2 10’ DAY 2 10’

Measure increased consumption Measure decreased consumption

as index of long-term memory as index of long-term memory
of novel taste of novel taste

Figure 16  Taste learning. Taste learning is a robust and automatic form of learning in animals. Two types of assessments generally used
to evaluate taste learning are attenuation of neophobia, in which an animal learns that a taste is not dangerous, and conditioned taste aver-
sion, in which an animal learns that a given taste is dangerous. These can be measured experimentally by giving a single exposure to a novel
food on Day 1 (ten minutes of Nutri-grain bar in this case) and monitoring the animal’s response to representation of that same stimulus 24
hours later (Day 2). If the animal finds the new food to be non-aversive, consumption of the food will be increased—attenuation of neopho-
bia. If an aversive stimulus is paired with the novel food (e.g., a lithium chloride injection), then the animal will exhibit a decreased con-
sumption of the food on Day 2—conditioned taste aversion. See Chapter 4 for additional details.

with visual stimuli or auditory cues is not very effec- and a term that is used to describe this is that the
tive at aversive conditioning to these stimuli. Clearly, stimulus is salient to the animal, in other words, the
evolution has operated to select for robust learning of stimulus is likely to be pertinent to the animal under
associations that can occur in the natural environment, the given condition.
20 1. Introduction

Thus, in general, it is not the case that unconscious this book will also depend on a large number of other
associative learning operates such that any two envi- factors, such as motivation, attention, level of arousal,
ronmental signals can be associated. This likely arises etc. Thus, human declarative learning, and likely most
from a combination of factors. First, there is a degree analogous forms of learning in animals, is subject to a
of anatomical specialization in the CNS such that par- wide variety of modulatory factors.
ticular functions are parsed out into particular areas. For example, particularly robust memory for single
Thus, as a practical matter, the central processing of events is typically referred to as “flashbulb” memory
two environmental stimuli may never “touch” each in humans. There are several examples of this type
other in the brain, and therefore can never be asso- of memory that many Americans have shared, the
ciated. In this instance the stimuli “touching” each most recent example being the terrorist destruction
other can be taken quite literally in that some ana- of the Twin Towers in New York City. Like most peo-
tomical cross-connection must be made. Conversely, ple, I remember vividly how I learned of the attacks,
for any association to take place the underlying neu- and I am sure I will never forget seeing live on televi-
ral circuits processing the environmental informa- sion the second tower collapse. Flashbulb memories
tion must be able to connect anatomically. It is only are usually associated with a high state of arousal
possible to draw an associative learning circuit if the or a high level of emotional valence—an example
two stimuli being paired impinge upon each other at of the strong modulatory influences that learning is
some point. subject to.
This probably seems like a statement of something As are the other types of conscious learning we will
that is intuitively obvious. However, if associative discuss in this section, declarative learning is depend-
learning requires that two information-processing cir- ent on the hippocampus—in later sections of the book
cuits connect with each other, this must of necessity we will return to the importance of modulatory influ-
utilize molecular and chemical processes. A descrip- ences on hippocampus-dependent learning, and dis-
tion of these types of processes, in particular molecular cuss some likely molecular mechanisms underlying
mechanisms that can contribute to associative events, this effect.
is a central theme of later chapters of this book. It is difficult to model declarative learning in non-
Overall, we have seen in this section that various human animals, because the behavioral output for
models of associative conditioning have transitioned these types of memories is actually quite subtle and in
us from unconscious processes to conscious processes. most cases it is not even clear what are relevant type
Many associations can be learned unconsciously and of learning might be in lower animals (see Box 5).
expressed unconsciously. However, various types of Partly for this reason most of what we know about
associative learning also begin to recruit conscious declarative learning comes from human studies,
processes. While learned unconsciously they can be in particular studies of patients with hippocampal
recalled consciously. As a generalization, the transi- lesions. These studies will be described in more detail
tion involves recruitment of the hippocampus into the in Chapter 2 (see also references 12–13). Suffice it to
learning process. In the following section we will tran- say for our purposes that a number of classic studies
sition to even more complex forms of learning that of humans with hippocampal lesions led to the dis-
also depend on the hippocampus. sociation of declarative from non-declarative forms of
memory in humans.
Declarative memory is that type of memory that is
IV. Conscious learning—subject lost when a human suffers hippocampal damage—
to conscious and unconscious this includes the capacity to form memories for facts,
names, places, and personal experiences (Figure 3).
recall
Hippocampal damage results in anterograde amnesia for
these types of memories—that is, there is a loss of the
A. Declarative Learning
capacity to form new memories. Old memories (more
Human declarative learning is what we typically than about one year) are largely spared, i.e., there is rel-
think of when we think of “learning.” This is the con- atively little retrograde amnesia. Non-declarative forms
scious acquisition of new facts, or the formation of of memory such as sensitization, motor learning, delay
memories for events that occur in our lives, which are classical conditioning, etc., are spared in humans with
available for subsequent recall at will. The extent to hippocampal lesions.
which you remember what you read in this book will A final comment on declarative learning is that it is
depend upon the processes of conscious declarative generally associative, although not in the sense of clas-
learning. Of course, the extent to which you remember sical associative conditioning where a cause-and-effect
 V. Summary 21

Box 5

A rodent model of declarative memory?

It is difficult to imagine a rodent model for declara- This is readily demonstrated in the laboratory: when rats
tive memory, but there is one potentially parallel type of or mice are presented with highly palatable solutions
learning in rodents that I will mention briefly. Because of novel tastes, such as saccharin or sucrose, they will
toxic plants and other poisonous foodstuffs coexist with consume small amounts on the first exposure; on subse-
most animals, as described above conditioned taste aver- quent exposures, the animals consume more (see Figure
sion evolved to protect animals from being poisoned out 16). This attenuation of neophobia is a behavioral meas-
of the gene pool. However, avoidance of something that ure of memory for the novel taste, and is part of a proc-
is toxic is not possible if it has been ingested in lethal ess of familiarization to the formerly novel taste. There
quantities, so a supplementary behavior has also evolved is a fairly clear consensus that the insular cortex is the
to protect animals from toxic foods. Neophobia is the char- primary site of learning and memory for novel tastes, so
acteristic fear of novel foods, and ensures that animals this form of learning is clearly not strictly analogous to
ingest only small quantities, as if to sample the food to human declarative learning. However, it does depend
determine if it is safe to eat. If the animal develops illness, on the cerebral cortex as its storage site, as is likely in
a conditioned taste aversion results, and this foodstuff human declarative memory. Furthermore, it is reason-
will be avoided on future encounters. If no illness results ably analogous to a human learning a “fact,” in this case
and assuming the food is reasonably palatable, animals what something tastes like, and having that information
will increase their intake on subsequent exposures. available for conscious recall.

relationship is learned. Most declarative learning B. Spatial Learning

does not take place in a cognitive vacuum, but items
A final example of hippocampus-dependent learn-
are typically learned in the context of other related
ing in both humans and lower animals is spatial
facts or objects. A good example of this for illustra-
learning. Obviously animals must learn to navigate
tive purposes is learning someone’s name. Learning
their environment, and learn to associate particular
a name is certainly a declarative learning event, and
places with particular items or events. This type of
you can list off the names of all the people you know
learning has been the classically defined learning sys-
well as a reiteration of a list of “facts.” However, each
tem in which involves the hippocampus. A wide vari-
name also serves as a descriptor of an individual and
ety of different studies have shown that molecular or
is associated with that person, their face, their house,
anatomical lesions of the hippocampus lead to spa-
etc. This type of multiple association for learned
tial learning deficits, in both humans and lower ani-
facts (i.e., declarative learning) is the rule rather than
mals. Also, direct measurements of a wide variety of
the exception. It is likely that most declarative learn-
molecular and physiologic changes have been shown
ing occurs as learning something within a variety of
to correlate with spatial learning. These topics will be
contexts: other facts or places with which the fact is
discussed in greater detail in the next chapter.
associated. This point is important to keep in mind as
we begin to explore the molecular basis for declara-
tive learning. It is certainly possible that many of
the molecular mechanisms that are discovered as V. Summary
subserving what we have defined as associative con-
ditioning may translate directly as mechanisms This chapter has described a number of basic
contributing to declarative learning. Stated more attributes of learning and memory, based largely on
strongly, at this point it is appropriate to hypoth- the psychological study of these phenomena. We also
esize that associative molecular mechanisms will be have introduced and discussed a number of terms
part of the molecular infrastructure of declarative related to memory and its study. Mastery of these
learning. basic terms and an understanding of their utilization
22 1. Introduction

will be critical for your comprehension of the remain- Squire, L. R. (2004). “Memory systems of the brain: a brief history
der of this textbook. and current perspective”. Neurobiol. Learn. Mem. 82(3):171–177.
Squire, L. R., and Kandel, E. R. (2008). Memory: From Mind to
There are a number of basic take-home messages Molecules, 2nd ed. New York: Roberts and Company.
for this chapter. Tronson, N. C., and Taylor, J. R. (2007). “Molecular mechanisms
of memory reconsolidation”. Nature Reviews Neuroscience
1. Memory is not monolithic—there are many 8:262–275.
different types of learning and memory, most of
which are subserved by different anatomical areas
of the nervous system. This principle is distilled in Journal Club Articles
the multiple memory systems concept. Bechara, A., Tranel, D., Damasio, H., Adolphs, R., Rockland, C., and
2. Almost all forms of memory have both short-term Damasio, A. R. (1995). “Double dissociation of conditioning and
and long-term forms. declarative knowledge relative to the amygdala and hippocam-
3. The mechanisms underlying short-term memory pus in humans”. Science 269(5227):1115–1118.
Knowlton, B. J., Mangels, J. A., and Squire, L. R. (1996). “A neo-
are distinct from those underlying long-term
striatal habit learning system in humans”. Science 273(5280):
memory. In general, brief forms of short- 1399–1402.
term memory are sustained by repetitive or Packard, M. G., and McGaugh, J. L. (1996). “Inactivation of hippoc-
reverberating action potential firing, while long- ampus or caudate nucleus with lidocaine differentially affects
term forms of memory are sustained by persisting expression of place and response learning”. Neurobiol. Learn.
Mem. 65(1):65–72.
molecular and cellular modifications.
For more information—relevant topic chapters from: John H. Byrne
4. Memory can be broadly subdivided into non- (Editor-in-Chief) (2008). Learning and Memory: A Comprehensive
declarative and declarative forms, and similarly Reference. Oxford: Academic Press (ISBN 978-0-12-370509-9).
into unconscious and conscious forms. (1.02 Roediger, H. L. III, Zaromb, F. M., and Goode, M. K. A
5. Both unconscious and conscious forms of Typology of Memory Terms. pp. 11–24; 1.03 Capaldi, E. J., and
Martins, A. History of Behavioral Learning Theories. pp. 25–39; 1.04
learning can be manifest in many different
Nadel, L. Multiple Memory Systems: A New View. pp. 41–52; 3.01
ways, for example associative and non-associative Eichenbaum, H. Introduction and Overview. pp. 1–8; 3.02 White,
forms, operant forms, etc. These subtypes N. M. Multiple Memory Systems in the Brain: Cooperation and
vary depending on the particular sensory Competition. pp. 9–46.)
inputs that trigger the learning, and depending
on the behavioral output that manifests the
memory. References
1. Squire, L. R., and Kandel, E. R. (1999). Memory: From Mind to
Molecules (distributed by W. H. Freeman and Co.). New York:
Scientific American Library.
Further Reading 2. Eichenbaum, H. (2001). “The hippocampus and declarative
Baddeley, A. (2001). “Is working memory still working?” Am. memory: cognitive mechanisms and neural codes”. Behav. Brain
Psychol. 56:849–864. Res. 127:199–207.
Eichenbaum, H. (2002). The Cognitive Neuroscience of Memory. New 3. Kandel, E. R., and Squire, L. R. (2000). “Neuroscience: breaking
York: Oxford University Press. down scientific barriers to the study of brain and mind”. Science
Eichenbaum, H., Yonelinas, A. P., and Ranganath, C. (2007). “The 290:1113–1120.
medial temporal lobe and recognition memory”. Annu. Rev. 4. Eichenbaum, H., and Cohen, N. J. (2001). From Conditioning to
Neurosci. 30:123–152. Conscious Recollection: Memory Systems of the Brain. Upper Saddle
Gold, P. E. (2004). “Coordination of multiple memory systems”. River, NJ: Oxford University Press.
Neurobiol. Learn. Mem. 82(3):230–242. 5. Vianna, M. R., Szapiro, G., McGaugh, J. L., Medina, J. H., and
LeDoux, J. E. (2001). Synaptic Self: How Our Brains Become Who We Izquierdo, I. (2001). “Retrieval of memory for fear-motivated
Are. New York: Viking. training initiates extinction requiring protein synthesis in the
McDonald, R. J., Devan, B. D., and Hong, N. S. (2004). “Multiple rat hippocampus”. Proc. Natl Acad. Sci. USA 98:12251–12254.
memory systems: the power of interactions”. Neurobiol. Learn. 6. Nader, K., Schafe, G. E., and LeDoux, J. E. (2000). “The labile
Mem. 82(3):333–346. nature of consolidation theory”. Nat. Rev. Neurosci. 1:216–219.
McDonald, R. J., and White, N. M. (1993). “A triple dissociation of 7. Clark, R. E., and Squire, L. R. (1998). “Classical conditioning
memory systems: hippocampus, amygdala, and dorsal stria- and brain systems: the role of awareness”. Science 280:77–81.
tum”. Behav. Neurosci. 107(1):3–22. 8. LeDoux, J. E. (2001). Synaptic Self: How Our Brains Become Who
McNaughton, B. L., Battaglia, F. P., Jensen, O., Moser, E. I., and We Are. New York: Viking.
Moser, M. B. (2006). “Path integration and the neural basis of the 9. Quirk, G. J., Repa, C., and LeDoux, J. E. (1995). “Fear conditioning
‘cognitive map’”. Nat. Rev. Neurosci. 7(8):663–678. enhances short-latency auditory responses of lateral amygdala
Milner, B., Squire, L. R., and Kandel, E. R. (1998). “Cognitive neuro- neurons: parallel recordings in the freely behaving rat”. Neuron
science and the study of memory”. Neuron 20(3):445–468. 15:1029–1039.
Shiffrin, R. M., and Atkinson, R. C. (1969). “Storage and retrieval 10. Berman, D. E., and Dudai, Y. (2001). “Memory extinction, learn-
processes in long-term memory”. Psychological Review ing anew, and learning the new: dissociations in the molecular
76:179–193. machinery of learning in cortex”. Science 291:2417–2419.
 References 23

11. Swank, M. W., and Sweatt, J. D. (2001). “Increased histone 13. Milner, B., Squire, L. R., and Kandel, E. R. (1998). “Cognitive
acetyltransferase and lysine acetyltransferase activity and neuroscience and the study of memory”. Neuron 20:445–468.
biphasic activation of the ERK/RSK cascade in insular cortex 14. Kandel, E. R. (2001). “The molecular biology of memory
during novel taste learning”. J. Neurosci. 21:3383–3391. storage: a dialogue between genes and synapses”. Science 294:
12. Eichenbaum, H. (1999). “The hippocampus and mechanisms of 1030–1038.
declarative memory”. Behav. Brain Res. 103:123–133.
 Medium Spiny Neuron
J. David Sweatt, acrylic on canvas, 2008–2009
 C h a p t e r

2
Studies of Human Learning and Memory

I. Introduction—historical precedents with studies of human subjects

A. Amnesias
B. Memory Consolidation
II. The hippocampus in human declarative, Episodic, and Spatial Memory
A. Anatomy of the Hippocampal Formation
B. Lesion Studies in Human Memory Formation
C. Imaging Studies
III. Motor Learning
A. Anatomy
B. Habits
C. Stereotyped Movements
D. Sequence Learning
IV. Prodigious Memory
A. Mnemonists
B. Savant Syndrome
C. You are a Prodigy
V. Summary
Further Reading
Journal Club Articles
References

I. Introduction—historical systems. These two concepts will be discussed in

precedents with studies of human this chapter. The important historical precedence
subjects of human studies of basic memory mechanisms as a
prelude to later understanding using animal stud-
In the history of memory studies it is likely that rats ies is why this chapter on human studies is near the
have been the subjects most often experimented on. beginning of this book on memory mechanisms. This
This contrasts with humans, who have been the most arrangement of the book content is by design—this
studied but not the most experimented on. The dis- order of presentation is historically accurate and the
tinction here is that a scientist has freedom to manip- remaining chapters of the book focusing on animal
ulate a rat for many types of experimental designs, studies owe a great debt to the pioneering work done
while ethical and moral considerations largely limit using observations of human patients. In a sense, the
scientists to studying (i.e., simply observing) humans animal studies provide the continuing narrative of the
without much freedom to lesion, drug, dissect, or oth- story of scientists’ pursuit of understanding memory.
erwise manipulate them. Against this backdrop it is
striking, then, that two of the most profound concep-
A. Amnesias
tual advances in the history of the memory field have
initially come from studies of human subjects. Amnesia is both frightening and fascinating to con-
These two conceptual advances are the idea of mem- template, so much so that Hollywood has turned to
ory consolidation, and the idea of multiple memory amnesia as a plot device on many occasions (see Table 1).

25
26 2. Studies of Human Learning and Memory

Table 1 Movies Using Amnesia as a Plot Device were formed before the memory-damaging insult. The
term retrograde amnesia is reserved for profound loss
Movie Director (plus notable actors) Year
of memory, and is distinct from normal forgetting.
Anterograde amnesia Retrograde amnesia is the classic plot device wherein
Memento Christopher Nolan (Guy Pearce) 2001 the character wakes up and can’t remember who
Finding Nemo Andrew Stanton (Animated—Ellen 2003 or where he is. Retrograde amnesia can result from
DeGeneris as Dory) injury, disease, or profound psychological trauma.
50 First Dates Peter Segal (Adam Sandler) 2004 As a practical matter, it is extremely difficult to
Retrograde amnesia distinguish whether retrograde amnesia results from
The Bourne Identity Doug Liman (Matt Damon) 2002 a loss of memory storage or a loss of the capacity for
Total Recall Paul Verhoeven (Arnold 1990 memory recall. We will return to this issue later on in
Schwarzenegger, Sharon Stone)
Chapters 4 and 5 where we will discuss experimen-
Spellbound Alfred Hitchcock (Ingrid Bergman, 1945
Gregory Peck) tally-induced amnesias.
Eternal Sunshine of Michel Gondry (Jim Carrey, Kate 2004 Anterograde amnesia is a loss of the capacity to
the Spotless Mind Winslet) form new memories. Anterograde amnesia results
The Forgotten Joseph Ruben (Julianne Moore) 2004 from a lesion or deficit in the anatomical, cellular, or
Men in Black Barry Sonnenfeld (Tommy Lee 1997
molecular mechanisms necessary to acquire and store
Jones, Will Smith)
information in the nervous system. In its purest form,
Not sure
anterograde amnesia leaves every previously formed
Mulholland Drive David Lynch (Michael J. Anderson, 2001
memory still intact and available for recall. Individuals
Diane Baker)
with anterograde amnesia typically have intact short-
Here are some personal comments, for what they are worth. term memory, but lack the capacity to form long-term
Memento and Finding Nemo: outstanding movies that, without a doubt,
are the most scientifically accurate movies ever made involving a memories. Sadly, these individuals live a moment-
character with a memory disorder. 50 First Dates: I have to admit I to-moment existence because they are unable to
couldn’t stand to watch more than about 10 minutes of this—a chick- remember anything that has happened to them for
flick all the way. The Bourne Identity, Total Recall, Spellbound: pretty good
action-type films. The disclaimer here is that these are probably the more than a few minutes.
male equivalent of a chick-flick, whatever that’s called. Eternal Sunshine
of the Spotless Mind: pretty creepy sci-fi for something that basically is a
chick-flick. The Forgotten: the amnestic angry-mother variant of a chick- B. Memory Consolidation
flick. Men in Black: OK, not much amnesia really, but at least it’s not a
chick-flick. Mulholland Drive: Classic David Lynch, and if any movie Studies with amnestic human subjects have iden-
qualifies as the antithesis of a chick-flick, this is it—seriously. If anybody tified a process that we now refer to as memory
understands what the heck was going on in this movie, please tell
me. Product Liability Warning—never, ever try to watch Memento and consolidation. Briefly stated, the idea of memory con-
Mulholland Drive in the same night—your brain will probably explode. solidation is captured in the theory that memory for-
mation and stabilization proceeds as a time-dependent
process, and that with time memories get stronger, i.e.,
less susceptible to disruption. The theory of memory
The term amnesia is derived from mnemos, which is consolidation is now ancient by modern scientific
the Greek root for memory. Mnemos is derived from standards. One of the first observations to suggest
Greek mythology—Mnemosyne was one of the mytho- memories need be consolidated came over a hundred
logical Titans, and she was the goddess of recollection years ago, using human subjects, where distraction
or remembrance—it was she who gifted humans the and interference immediately after a training session
capacity for memory. Mnemosyne was one of Zeus’ could disrupt long-term memory formation, whereas
lovers, and she gave birth to the nine muses. The muses the same distractions long after a training session had
are the source of inspiration for music, poetry, and sto- limited effects (1).
ries. They also invented the combining of letters, i.e., Physicians also had noted that patients that had
writing, arguably the most useful technological devel- an epileptic seizure could often experience a loss of
opment in the history of information storage.1 memory for events immediately preceding the sei-
Thus, based on its Greek language roots, amnesia zure, or that head trauma cases might experience the
literally means “no memory.” As a clinical syndrome, same effect. In a more recent and systematic study of
amnesia is referred to as being either retrograde or this effect, Larry Squire and his colleagues studied ret-
anterograde. Retrograde amnesia is a loss of previously rograde memory effects (amnesia) in patients that had
formed memory. Thus, it is the loss of memories that been given electroconvulsive shock, which triggers
epileptic seizures. Note that the seizures in this case
1
I am not considering language a technology, because its use does are triggered specifically, safely, and therapeutically—
not require an implement. electroconvulsive therapy (ECT) is used clinically in
 I. Introduction—historical precedents with studies of human subjects 27

Perceptual memory Working memory

Cortical “association” areas

Temporal Parietal Cingulate Olfactory Prefrontal

Cerebellum Parahippocampal region

Neostriatum Amygdala
Hippocampus

Brainstem and spinal Hypothalamus, autonomic

motor outlets and hormonal outputs

Motor memory Emotional memory Declarative memory

Habits Conditioned Episodic and
Skills preferences semantic
Sensori- and aversions Conscious
motor adaptations Memory recollection
modulation Flexible expression
Copyright © 2002, Elsevier Science (USA). All rights reserved.
Figure 1 A current conception of the major memory systems in the brain. Adapted from Fundamental Neuroscience, Learning and Memory:
Brain Systems, Howard Eichenbaum. Copyright Elsevier 2003.

cases of severe intractable depression. This iatrogeni- Multiple Memory Systems

cally-induced type of seizure allowed a unique oppor- The modern conceptualization of memory in humans
tunity to study retrograde amnesia in humans in a is that memory is subserved by multiple memory sys-
prospective and controlled memory study. Because tems. We now think of human memory not as a single
the patients had the seizures at a predefined time, and monolithic process, but rather as a complex multi-com-
were available both before and after the ECT treat- ponent, multi-output process. The multiple components
ment, this allowed Squire and his colleagues to sys- are, in most cases, at least partially interacting and in
tematically evaluate the retrograde amnestic effects some instances can be completely independent. The
of seizure (2). Their finding was that memories less multiple components largely map onto discrete anatom-
than two years old were much more susceptible to ical subregions of the central nervous system (CNS)—
seizure-associated transient loss than older memories. these subregions and their associated memory systems
These findings were particularly compelling because are summarized in Figure 1 and Table 2.
the investigators were able to test memory in the same Most of the human neuroanatomical regions that
individual both before and after seizure. These findings are associated with specific memory systems have
and many others like them provide a compelling case been identified using clinical approaches (see Figure 2).
that memories are differentially susceptible to disrup- Historically, most of the relevant brain regions were
tion, depending on how old they are. The mechanistic first identified by studying patients who had identifi-
implications of this are critically important—the find- able brain lesions restricted to particular subregions,
ing implies that older memories are stored or recalled or in some cases diseases that exerted their effects
using different cellular/molecular mechanisms than in a brain subregion-selective manner. For exam-
newer memories. There is no other way they could be ple, the cytopathological effects of Parkinson’s and
differentially susceptible to disruption. Huntington’s disease are largely limited to the basal
We will return to animal studies of memory con- ganglia, and these patients have deficits in the acquisi-
solidation as a cellular and molecular process many tion of new motor skills. In another example, patients
times in this book, but human studies were the first with lesions to the occipital cortex due to localized
to suggest the existence of the phenomenon. It should strokes can have deficits in word priming. Finally, the
not escape your attention that the human studies also classic cases that led to the paradigm shift of thinking
demonstrate the clinical relevance of understanding about humans as having multiple memory systems
amnestic mechanisms. came from studies of patients having hippocampal
28 2. Studies of Human Learning and Memory

Table 2 Multiple Memory Systems in the Human Central and temporal lobe lesions, and the associated deficits
Nervous System in declarative, episodic, and spatial memory.
Human clinically-based studies have been particu-
Memory Subtype Corresponding Central Nervous System
Subregion larly compelling in motivating the multiple memory
systems concept because there have been many
Working memory Prefrontal cortex, contributions from
instances that allowed a double dissociation of memory
caudate nucleus
systems. For example, a patient with an occipital cor-
Declarative, Medial temporal lobe system including the tex lesion may have pronounced deficits in word-stem
episodic, and hippocampus, dentate gyrus, entorhinal
priming. However, that same individual may have no
spatial memory and perirhinal cortices
deficits in declarative memory, such as memorizing
Habits, motor skills, Striatum (caudate nucleus and putamen), word lists. In contrast, a patient with a hippocampal
procedural memory globus pallidus,* and cerebellum lesion will have pronounced declarative memory defi-
cits, but their word-stem priming can be completely nor-
Priming Occipital cortex, neocortex in general
mal. Considering these findings from the two patients
Aversive associative Amygdala as one unit of evidence provides a double dissociation
conditioning between priming and declarative memory. One patient
has deficits in system A but not system B, while the
Motoric associative Cerebellum
conditioning other has deficits in system B but not system A. It is
very difficult to rationalize this double dissociation as
Olfactory and taste Olfactory bulb, insular cortex, nucleus reflecting anything other than two separate and distinct
conditioning tractus solitarius (NTS), positive and memory systems. There is evidence for these types of
negative reinforcement systems (amygdala
or nucleus accumbens)
double dissociations in human patients for almost all of
the different memory systems listed in Table 2.
Sensitization, Spinal cord, brainstem nuclei, amygdala
habituation
II. The hippocampus in human
Circadian rhythm Hypothalamus—suprachiasmatic nucleus
(SCN)
declarative, episodic, and spatial
memory
Reward, positive Nucleus accumbens, ventral tegmental area
reinforcement, (VTA) As described in the first chapter of this book, the
addiction
prototypical role of the hippocampus in humans is to
* Collectively the caudate nucleus, putamen, and globus pallidus are allow declarative, episodic, and spatial memory. We
referred to as the basal ganglia. will discuss this in more detail in this section, organized

A B
Frontal lobe Parietal lobe
Amygdala Hippocampus

Cerebellum
Temporal lobe

Copyright © 2006, American Society for Neurochemistry. All rights reserved.

Figure 2 Illustrative drawing of the major brain regions and temporal lobe system in the human brain. (A) Anatomical sites, marked
by black dots, within the temporal lobe where electrical stimulation evolved memory-like responses in human patients in experiments by
Penfield. These studies were some of the first implicating the temporal lobe system in human memory. (B) The location of the hippocam-
pus and amygdala inside the temporal lobe. Adapted from Basic Neurochemistry, Learning and Memory, Joe Tsien, Academic Press. Copyright
Elsevier 2006.
 II. The hippocampus in human declarative, episodic, and spatial memory 29

as follows. First, I will briefly review the anatomy of the entorhinal cortices; these are the cortical areas in the
hippocampal formation, as this is a necessary founda- immediate anatomical vicinity of the hippocampus near
tion for this section and many subsequent chapters in the rhinal fissure in the temporal lobe. The outputs of
the book. Then we will discuss early studies that high- the perirhinal and entorhinal cortices then project to the
lighted the necessity of proper hippocampal function dentate gyrus and the hippocampus proper (these two
for memory formation, although this section will be are referred to jointly as the hippocampal formation).
brief because this area has been covered extensively in The hippocampus proper is also known in old-
the literature already and is given adequate treatment style anatomical nomenclature as Cornu Ammonis
in a number of standard textbooks and reviews in the (Ammon’s Horn, after the ram’s horn-sporting Greek
area (see Further Reading). god) because of its shape. Hippocampus is Greek for
sea-horse, which is a term coined by anatomists to
describe the overall shape of the anatomical struc-
A. Anatomy of the Hippocampal Formation
ture. The Cornu Ammonis (CA) terminology leads
As shown in Figure 3, the hippocampus is both to four anatomical subdivisions of the hippocampus:
downstream and upstream of essentially all the cor- areas CA1; CA2; CA3; and CA4. Areas CA1 and CA3
tical association regions of the CNS (3). This fact in are the largest and most easily identified (Figure 3).
itself suggests that the hippocampus is part of a multi- The principal neurons in the CA regions are called
modal sensory integration system in the CNS. We will pyramidal neurons because of the shape of their cell
review the anatomical structure of the hippocampal body—they comprise about 90% of all the neurons
formation in the following section. This anatomical in the CA regions of the hippocampal formation (see
information will be further strengthened by a vari- Figure 4). The output neurons of the hippocampus are
ety of functional data that will be reviewed in the last the CA1 pyramidal neurons—their axons are glutama-
three parts of this section. tergic, and it is via these axons that information leaves
Figure 3 illustrates that raw sensory information the hippocampus proper. The axons of CA1 neurons
gathered by the various sensory organs procedes via project predominantly to the ipsilateral and contralat-
the thalamus to the cerebral cortex. Sensory informa- eral entorhinal cortices, but additional direct outputs
tion from the various cortical sensory areas is fun- of CA1 neurons project to the contralateral hippocam-
neled down to the hippocampus via the perirhinal and pus via the fornix (see Figure 5). Secondary efferents

Hippocampal Connectivity in the CNS

Somatosensory

Visual

Sensory regions Olfactory

of cortex

Auditory

Perirhinal/ Perirhinal cortex

entorhinal
cortex Entorhinal cortex

CA3
Hippocampal Dentate gyrus
formation CA1

Figure 3 Hippocampal connectivity in the CNS. Illustration of the pathway from sensory perceiving regions of the cortex through the
perirhinal and entorhinal cortices to the hippocampal formation. Figure adapted from Squire and Zola-Morgan (3). Copyright American
Association for the Advancement of Science.
30 2. Studies of Human Learning and Memory

noting because, although I will frequently use the term

“hippocampus-dependent,” any phenomenon thus
described might equally well be described as entorhi-
nal cortex-dependent or perirhinal cortex-dependent.
The hippocampal formation and its adjacent cortical
regions function in tandem in both memory formation
and cognitive processing (4).
Before leaving the topic of cortical inputs into the
hippocampus, it is worth emphasizing specifically that
the prefrontal cortex and hippocampus are functionally
interconnected (5). On the hippocampal input side this
connection is from the prefrontal cortex to the entorhi-
nal, perirhinal, and parahippocampal cortices, and
thence on to the hippocampus proper. The existence of
these connections has, in part, led to the general view
of the prefrontal cortex as part of a sensory–motor–lim-
bic integration system. Consistent with this view are
the reciprocal connections from the hippocampus back
to the prefrontal cortex. These fall into two broad cat-
egories. First are the projections from the CA1 pyrami-
dal neurons and subicular neurons to the entorhinal
and perirhinal cortices, which then provide efferent
innervation back to the prefrontal cortex. A second,
more direct route is a projection from CA1 pyramidal
neurons onto prefrontal cortex neurons themselves (6).
This integration of hippocampus and prefrontal
cortex is important as one considers a potential role
for the hippocampus in cognition in general, and
schizophrenia in particular, given the widely recog-
Figure 4 A hippocampal pyramidal neuron. This photo illus- nized involvement of dysfunction of the prefrontal
trates the cell body and dendritic tree of a single hippocampal cortical areas in schizophrenia (see Table 3). As the
pyramidal neuron. In this image, the neuron is filled with fluores-
hippocampus is one unit that interacts with the pre-
cent dye to allow visualization. Image courtesy of Shigeo Watanabe
and Daniel Johnston. frontal cortex, dysfunction in each area might precipi-
tate or exacerbate dysfunction in the other.
Finally, note that as is shown in Figure 5 and Table
of CA1 pyramidal neurons via the subicular neurons 4, the hippocampus receives a wide variety of extrinsic
also project to subcortical regions, including the ven- inputs of various neuromodulatory neurotransmitters.
tral striatum and mammillary bodies. These include projection fibers that are serotonergic,
We will return to the synaptic structure of the hip- dopaminergic, cholinergic, and noradrenergic. There also
pocampus in more detail in Chapters 6 and 7. For now are intrinsic interneurons in the hippocampus that are
suffice it to say that the hippocampus proper, com- GABAergic, and numerous peptide neuromodulators
prising areas CA1–CA4 plus the dentate gyrus, form including reelin, BDNF, NGF, etc., that are all present
one functional and anatomical unit involved in infor- in the hippocampus. The intrinsic connections between
mation processing and memory consolidation. Exactly pyramidal neurons in the hippocampus are glutama-
how this happens is still a mystery, but current ideas tergic. I list these neurotransmitter systems to point out
about the cellular and molecular basis of this process- the wide variety of neuromodulators hypothesized to be
ing are, of course, the focus of this textbook. involved in, and important for, hippocampal function.
Thus, we can see that information goes out of the Although there is not room to go into the function
hippocampus and ultimately back up into the cortex of these various transmitters and neuromodulators in
in its principal pathway, back-tracking its way once detail, in general these neurotransmitters and neuro-
again through the entorhinal and perirhinal cortices. modulators help optimize hippocampal function. For
I emphasize this because it is important to remember example GABA, acetylcholine, norepinephrine, and
that these cortical areas immediately adjacent to the serotonin all participate in synchronizing hippocampal
hippocampal formation are functionally an extension neuron firing patterns by various mechanisms, effects
of the hippocampus (and vice versa). This is worth which are associated with both memory formation and
 II. The hippocampus in human declarative, episodic, and spatial memory 31

Hippocampal output pathway & intrinsic circuit

A Entorhinal B CA1
cortex
CA3
Perforant
pathway

Dentate Entorhinal cortex

gyrus CA1 outputs

Mossy
fibers
C
CA3 CA1 axon
Schaffer
collaterals
GABAergic interneuron

CA1
Norepinephrine
Acetylcholine
Amygdala, Serotonin
Subiculum/
cortex
entorhinal cortex
Lateral
septum
Schaffer collaterals
Figure 5 Hippocampal intrinsic circuit and output pathways. Schematic and illustration of the principal pathway through the hippocampus.
On the left is a schematic of the structures through which the sensory signal travels within the hippocampal formation. Top right is a more realistic
drawing of these structures (1). Bottom right shows the signaling occurring in area CA1 of the hippocampus, focusing on the cellular connections.

Table 3 Memory-Associated Cognitive Dysfunction in Humans

Disease or Syndrome Type of Memory Affected or Involved* Likely Anatomical Locus

Schizophrenia Working memory Prefrontal cortex

Major depression Declarative memory ?
Aging-related dementias Long-term declarative and episodic memory Temporal lobe hippocampal
system
Korsakoff’s Syndrome (alcoholism, Long-term declarative and episodic memory Mamillary bodies, limbic
malnutrition) system, thalamus
Huntington’s Disease and Parkinson’s Disease Motor learning, habit learning Nigro-striatal system
Attention deficit Generalized or specific learning Frontal lobes?
hyperactivity disorder (ADHD) disabilities, dyslexia Basal ganglia?
Post-traumatic stress disorder* (PTSD) Aversive associative conditioning, lack of extinction Amygdala, hippocampus
This is a partial listing of human diseases or syndromes that are associated with certain types of learning and memory deficits. Please note that
not all disease characteristics and anatomical regions affected are listed. In addition, learning disabilities and Alzheimer’s disease are subjects of
entire later chapters of the book. Major depression has been found to be associated with a variety of memory deficits including declarative memory,
although the basis for this is unclear.
* PTSD is unique on this list in that it is a disorder caused by excessively robust (or inappropriate) memory, as opposed to a disorder associated
with an inability to form memories.

cognitive processing. BDNF and reelin, while typically at least two-fold. One role is to process information of
thought of as trophic factors, also have acute effects on a wide variety of sorts, which we will discuss in other
synaptic function in the adult hippocampus. Both these sections of this chapter. The second general function is
large peptides function as neuromodulators control- to download information into the cortex for storage as
ling the likelihood of triggering long-lasting changes in long-term memory, which we will discuss in the next
hippocampal synaptic function. Of course, the function section.
of glutamate receptors, including the NMDA recep-
tors integral to long-term synaptic plasticity in the
B. Lesion Studies in Human Memory Formation
­hippocampus, is necessary for proper function of the
hippocampus and attendant cognitive processing. As we have already discussed, consolidation is
As mentioned above, the general roles of the hip- the general term for the process by which memo-
pocampus and nearby associated cortices appear to be ries are rendered stable and lasting. Its existence as a
32 2. Studies of Human Learning and Memory

Table 4 Major Neurotransmitters in the Hippocampus

Neurotransmitter Abbreviation, General role

synonym

Serotonin 5HT, neuromodulation

5-hydroxytryptamine
Dopamine DA neuromodulation
Acetylcholine ACh neuromodulation
Norepinephrine NE neuromodulation
Gamma-amino GABA inhibitory
butyric acid transmission
Glutamate Glu excitatory
transmission
Principle neurotransmitter systems in the hippocampus Figure 6 (Left) Magnetic resonance imaging scan showing the
removal of medial temporal lobe structures in patient H. M. The
lesion included all of the entorhinal cortex, most of the perirhinal
cortex and amygdala, and about half of the hippocampus. (Right)
­ henomenon has been reliably demonstrated by many
p Scan of a normal control subject showing the structures removed in
investigators using many different learning paradigms H. M. A, amygdala; cs, collateral sulcus; EC, entorhinal cortex; H,
hippocampus; MMN, medial mammillary nucleus; PR, perirhinal
over a span of four decades. Despite its long history of
cortex. From Corkin et al. (9). Copyright Elsevier 2003.
investigation, however, certain aspects of the process
are quite mysterious. For example, it is not clear if
consolidation is a process whereby a short-term mem- medial temporal lobe resection on his patient, in an
ory is rendered long-lasting, i.e., a process of serial admittedly desperate attempt to control the seizures.
conversion of short-term to long-term memory, or if This procedure removed most of H. M.’s hippocampi
short-term and longer-term memories of a given event on both sides along with the adjacent cortical tissue,
are consolidated entirely separately. and the amygdala (see reference 9). Figure 6 shows an
A few things are clear, however. Consolidation MRI of patient H. M.’s CNS, illustrating his hippocam-
clearly is not a unitary process. There are consolida- pal lesions compared to a control subject. Figure 7 illus-
tion processes that subserve different types of learn- trates the analysis of the MRI of H. M., compared to the
ing (explicit versus implicit, for example), that at a original surgeon’s estimate of the extent of his lesions.
minimum utilize different brain areas. There are also This iatrogenic lesion partially treated the epilepsy,
distinct consolidation processes for short-term, inter- and essentially completely destroyed H. M.’s capac-
mediate-term, and long-term memories that probably ity for long-term memory consolidation. H. M.’s prior
are different—we will return to this in the next chapter memories were mostly intact for his lifetime up to sev-
of the book. There is also a clear distinction between eral years predating the surgery. However, after the time
the consolidation of memory versus the storage of of the surgery H. M. was essentially completely unable
memory. Brain lesions to specific areas can lead to a to form any new long-lasting declarative and episodic
selective disruption of consolidation of new memories memories. He lived a minute-to-minute existence for his
without affecting storage and recall of old memories. last 50 years. His only new memories were of facts that
The classic studies illustrating this distinction he had been exhaustively exposed and re-exposed to.
involve patient “H. M.” The story of H. M. has been Testing of H. M. unambiguously demonstrated the
told and analyzed repeatedly in the learning and existence of consolidation processes in human memory.
memory literature, so I will only briefly review the He had preservation and stability of a large number of
case here. The first studies of H. M. and his memory pre-existing memories, and a clear capacity to recall
deficits are landmarks in the field, and helped une- them consistently. What he did not have was the capac-
quivocally establish the existence of memory consoli- ity to make any new memories that lasted for more
dation as a distinct process (7–9). than a few seconds without continuous rehearsal.
H. M. was (Henry Gustav Molaison, deceased 2008) There has been a general tendency to ascribe this
an unfortunate victim of human neurosurgical experi- deficit to loss of the hippocampus, which is consist-
mentation. H. M. initially presented in the early 1950s ent with a wide variety of animal lesion studies and
with epilepsy that was effectively untreatable by any of indeed with the memory consolidation deficits of other
the drugs or procedures of the day. His seizures were patients with more selective hippocampal lesions.
profound and debilitating. His physicians hypothe- However, it is important to remember that H. M. had
sized that his seizures originated in the hippocampus, a lesions of the surrounding perihippocampal cortices
known and common locus of seizure generation. A neu- and the amygdala, which likely contribute to the par-
rosurgeon named William Scoville performed a ­bilateral ticularly pronounced nature of his deficits (Figure 7).
 II. The hippocampus in human declarative, episodic, and spatial memory 33

Surgeon’s estimate Revised estimate

of H.M.’s lesions based on MRI

A
A
5 cm B
8 cm B C
C

A B A B

Collateral sulcus Hippocampus

uncus hippocampus Entorhinal cortex Amygdala Entorhinal cortex

C D C D

hippocampal gyrus Small lesion hippocampus

hippocampus
(posterior part)

Figure 7 MRI of patient H. M.’s brain lesions. (Left) Scan showing the removal of medial temporal lobe structures in H. M. The lesion
included all the entorhinal cortex, most of the perirhinal cortex and amygdala, and about half of the hippocampus. (Right) Scan of control
subject. A, amygdala; cs, collateral sulcus; EC, Entorhinal cortex; H, hippocampus; MMN, medial mammillary nucleus; PR, perirhinal cortex.
Reproduced from Corkin et al. (9).

Also, given what we discussed earlier in this chap- of protein synthesis block memory consolidation
ter about the role of the hippocampus in multimodal when they are applied after training. Consolidation
cognitive processing, one wonders about generalized is known to be a process that requires several hours
cognitive deficits in H. M. I am not referring to a loss after training. Hippocampus-dependent long-term
of intelligence, but rather to the possibility of a general memory consolidation is also dependent on altered
inability to process information about his surround- gene expression. Activation of the NMDA subtype of
ings, correlations among items and events, etc. These glutamate receptor is involved, as are a number of sig-
problems may also have contributed to his cognitive nal transduction mechanisms and neuromodulatory
problems and his long-term memory deficits. These neurotransmitter systems. Overall, a quite wide vari-
considerations do not negate the conclusion of a defi- ety of studies using many different approaches have
cit in memory consolidation in H. M., but simply point demonstrated that involvement in memory consolida-
out that interpreting the basis of H. M.’s cognitive defi- tion is a central attribute of hippocampal function. We
cits should take into consideration modern ideas about will spend much of the rest of the book discussing the
the important role of the hippocampus in information cellular and molecular particulars of this process. In
processing as well as memory consolidation. brief, the hippocampus serves as an intermediate-term
The role of the hippocampus in memory consolida- memory store that ultimately downloads information
tion that was identified in the initial landmark stud- to the cortex for longer-term storage. The basis for this
ies of H. M. have been confirmed and extended in a process is mysterious, but one thing that is clear is
wide variety of hippocampal lesion studies in experi- that the hippocampus must be able to hold a memory
mental animals. Obviously, animal experimentation trace for some appreciable period of time—hours to
allows a much more detailed and controlled experi- days or weeks at least.
mental approach than human studies and a number In Chapter 7 we will talk about a cellular mecha-
of attributes of hippocampus-dependent memory con- nism likely to be critical to allowing the hippocam-
solidation have become clear. For example, inhibitors pus to serve as this sort of memory buffer—long-term
34 2. Studies of Human Learning and Memory

Box 1

Studies in non-human primate models

Human patient studies have provided compelling Thinking of human declarative, episodic, and spa-
evidence for multiple memory systems, and indeed tial memory as exclusively hippocampus-dependent is
have fundamentally changed scientific thinking about too great an oversimplification. Many medial lobe ana-
how memory works. Careful and ethically-conscien- tomical structures are involved in these forms of mem-
tious studies of human subjects have both improved ory, including the perirhinal, parahippocampal, and
our basic understanding of mechanisms of memory and entorhinal cortices, and likely even the amygdala and
allowed the development of new medical and behavioral its adjacent cortical areas are involved in a modulatory
approaches to improving function in patients with cogni- capacity.
tive disorders. However, studies with human subjects are, Lesions to the hippocampus provoke greater ret-
of necessity, limited by ethical and moral considerations. rograde amnesia than was initially thought, based on
Studies with non-human primates represent a power- studies of patients like H. M. Sophisticated studies
ful additional approach to understanding memory and in monkeys demonstrated that hippocampal lesions
cognitive processing in complex nervous systems that result in retrograde amnesia for items learned weeks or
closely resemble the human CNS anatomically. Studies months before. Indeed, recent studies using human sub-
in non-human primates, of course, allow different kinds jects have indicated that hippocampal damage results
of experimental approaches that are not practicable in in partial retrograde amnesia for events occurring up
humans. Many sophisticated and elegant studies of to several years previously (22). At a minimum, these
memory function in non-human primates have sup- various studies imply that the hippocampus-dependent
ported the basic models of memory systems that we memory consolidation period in primates extends much
have been discussing in this chapter, at the anatomical, longer than is apparent from most studies of simpler
functional, cellular, and behavioral levels. However, ani- animal models.
mal studies have led to significant refinements of our Detailed descriptions of the experimental basis for
thinking about the role of medial temporal lobe struc- these brief generalizations are presented in reviews by
tures in primate (including human) memory. These Mishkin et al. (1998), Cipolotti and Bird (2006), and Zola
“refinements” can be briefly summarized as: and Squire (2001), listed in Further Reading.

potentiation (LTP). Long-lasting synaptic potentiation discussed at the beginning of the chapter. Declarative
of this sort is also likely involved in the precise for- memories, facts and personal experiences, are depend-
mation and maintenance of hippocampal place cell ent on the hippocampus and medial temporal lobe
firing patterns. We also will touch on shorter-lasting for their formation. Many other types of memories,
forms of synaptic plasticity that may be involved in including motor learning and many types of associa-
short-term storage of information and information tive conditioning, are hippocampus-independent.
processing in the hippocampus; phenomena such as
post-tetanic potentiation (PTP) and short-term poten-
tiation (STP) that may be involved in the “timing” C. Imaging Studies
aspect of hippocampal processing of CS-US contin- A clear prediction of the hypothesis that the hip-
gencies over the period of a few seconds. pocampus is involved in memory formation is that
Characterization of the memory deficits in H. M. measurable hippocampal activation should be asso-
provided a turning point in the history of cognitive ciated with long-term memory formation. The avail-
neuroscience. For example, it became clear that H. ability of functional imaging technologies that allow
M. had selective deficits in certain types of memory. one to test the CNS structures that are activated with
Some memory systems were still intact, and thus hip- various tasks, using non-invasive techniques on liv-
pocampus-independent. Studies of H. M. and patients ing, breathing, thinking humans (see Box 2), has made
like him with hippocampal lesions led to a new clas- testing the hypothesis a practical possibility. Indeed,
sification system for different types of memory in the a wide variety of different in vivo imaging experi-
human—the multiple memory systems concept that we ments using human subjects have explored the idea
 II. The hippocampus in human declarative, episodic, and spatial memory 35

Box 2

MRI, fMRI, and PET

The capacity to probe the structure and function The order of this list also generally reflects their ease of
of the human CNS, non-invasively, and in an awake, use and the breadth of their availability.
behaving human is one of the most phenomenal tech- MRI was originally referred to as nuclear magnetic
nological steps forward in recent history. The three most resonance (NMR) imaging. NMR is actually a more
commonly used approaches in this area for human stud- accurate term to describe the physical basis of MRI—
ies are: magnetic resonance imaging (MRI); functional MRI is a sophisticated technology based on the capac-
MRI (fMRI); and positron emission tomography (PET). ity to detect subtle changes in the orientation of atomic

A B

a
b
c
d
e
f
g
h
i
j
0 2 4 6 8 10 12

C L hpc (-21 -21 9) R hpc (24 -24 -15) R parahpc (24 -33 -18) Precuneus (3 -69 30)
0.3
0.2 0.2
0.1 0.0
0.0
0.0 0.0 –0.3
–0.2
–0.6
–0.1 –0.2 –0.4
–0.6 –0.9
–0.2
–0.4 –1.2
pla. per. obj. wid. pla. per. obj. wid. pla. per. obj. wid. pla. per. obj. wid.

BOX 1 Functional neuroimaging of the retrieval of the spatial context of an event. (A) Areas activated in the place condition
relative to the perceptual control condition width are shown in color on a “glass brain” and include: (a) posterior parietal; (b)
precuneus; (c) parieto-occipital sulcus and retrosplenial cortex; (d) parahippocampal gyrus; (e) hippocampus; (f) midposterior
cingulate; (g) anterior cingulate; (h) dorsolateral prefrontal cortex; (i) ventrolateral prefrontal cortex; and (j) anterior prefron-
tal cortex (p  0.001 uncorrected for multiple comparisons). (B) Activations in place-width shown on the averaged normalized
structural MR images of the subjects, with threshold p  0.01 uncorrected for multiple comparisons. Coronal and saggittal slices
through the left retrosplenial cortex (above) and left hippocampus (below) are shown. (C) Level of activation in four regions
across all conditions place (pla), person (per), object (obj), and width (wid), shown as estimated percent signal change relative to
background activation (i.e., when the subject is moving between questions). The name of the regions and x, y, and z coordinate
of location (the voxel of peak response) is given above each graph. Note the strongly spatial response of right (R) hippocampal
(hpc), and parahippocampal (parahpc) areas. The left parahippocampus (not shown) shows a similarly spatial pattern, whereas
the responses estimate for that condition and the parameter estimate for the width condition. Figure adapted from Burgess et al.
(2001b). Copyright Elsevier 2002.

Continued
36 2. Studies of Human Learning and Memory

BOX 2—cont’d

MRI, fMRI, and PET

nuclei when they are placed in a powerful magnetic anatomical MRI (see Figure) to localize regions of the CNS
field and probed with electromagnetic pulses. The reso- that are activated under specific conditions, such as learn-
nance of nuclei in the atoms and molecules in tissue is ing a list of names. This is an experiment in real-time, in a
the fundamental property being measured by an MRI behaving human, which gives insights into the anatomical
machine. Due to differences in the magnetic resonance structures involved in CNS function. The principal limita-
properties of different types of tissues and fluids in the tions of fMRI are the relatively slow rate of real-time anal-
human body, highly detailed anatomical images can be ysis (minutes instead of seconds) because of the need for
generated by quantitating these differences and display- averaging signals, and the fact that fMRI is measuring a
ing them as an anatomical picture. signal (indirectly, oxygen usage) that is many mechanistic
MRI is thus a powerful tool to image anatomical struc- steps removed from neuronal activity per se. Nevertheless,
tures in living humans, without hurting the subject under fMRI is an extremely powerful approach for studying the
study. MRI is typically used to define normal anatomy, neuroanatomical basis of human cognitive function and
and lesions, pathologies, and breakages. When NMR dysfunction.
imaging began to be widely applied to human patients, PET imaging is less widely used, because it involves
the “nuclear” was dropped from the name in order to the use of radioactive materials injected into the subject.
make the process sound less frightening. The 2003 Nobel For PET, materials that can tag a tissue or cell type of
Prize in medicine was awarded to Paul Lauterbur and Sir interest are labeled with a radioactive atom and the ana-
Peter Mansfield for developing MRI for clinical use. tomical distribution of the radioactive material is deter-
Metabolic changes in brain cells of course trigger mined with tomography techniques. How does one tag
chemical changes in fluids surrounding the tissue, espe- the tissue or cell of interest? You might look for meta-
cially secondarily to the use of oxygen for metabolic pur- bolically active cells using labeled glucose derivatives,
poses. These chemical changes trigger local changes in for example, or use labeled specific ligands that bind to
blood flow in order to compensate for oxygen usage— receptors on certain cells to localize those types of cells. In
­specifically, oxygen is dumped from hemoglobin and local PET scanning, the distribution of the radioactive material
blood flow rate increases to compensate. This causes a is compared to an anatomical image produced by MRI or
change in the magnetic resonance properties of the hemo- X-ray-based methods. This allows the accurate anatomi-
globin in the blood that is detectable with MRI. Functional cal localization of the molecule of interest. The PET term
MRI measures these metabolic changes in real-time, comes from the fact that when the radioactive material
and is used as an index of functional activity. An fMRI decays it results indirectly in positron emission, and the
(blood flow) signal can be mapped onto a corresponding anatomical distribution is determined with tomography.

that hippocampal activation should be correlated in memory. Therefore, at this point in the develop-
with memory formation, using either PET or fMRI- ment of the field not many definitive statements can
type imaging. Unfortunately, so far there has not been be made concerning the role of the hippocampus in
a great deal of consistency in the results among these human memory formation, based on the approach of
types of studies, therefore it has not been unambigu- human imaging. However, I would like to make a few
ously demonstrated that hippocampal activation is general comments to indicate some of the interesting
clearly associated with memory formation. ideas that are beginning to emerge.
Part of the reason for the inconsistent results is One interesting idea that has been supported by
probably the fact that in vivo imaging technologies numerous studies is that there is lateralization of hip-
in humans are fairly new, and there likely has been pocampal function in humans. Lateralization simply
inconsistent application of the technology across stud- means that the left hippocampus does something dif-
ies. Also, new technologies, of necessity, bring with ferent from the right hippocampus. In general, the
them a period of time when the various technical right hippocampus (in humans) appears to be more
and theoretical approaches are being refined; this has involved in visual and spatial learning and mem-
certainly been the case with human imaging studies ory, while the left hippocampus appears to be more
 II. The hippocampus in human declarative, episodic, and spatial memory 37

A B

C D

E F

Figure 8 The virtual reality town used in functional neuroimaging and neurophysiological studies of topographical and episodic memory.
(A) A view from within the town, as seen by a subject. (B) Aerial view of the area used for testing navigation in neuropsychological studies.
This view was never seen by subjects. (C) Receiving an object in the episodic memory test. (D) Answering a “place” question in the episodic
memory test. (E and F) Activation of the right hippocampus correlates with accuracy of navigation in the virtual reality (VR) town. The loci of
significant correlation are shown superimposed on the structural template to which all scans were normalized (r  0.56); significant correla-
tion was also found in the right inferior parietal cortex. Adapted from Burgess et al. (2002). Neuron 35:625–642. Copyright Elsevier 2002.

involved in verbal and narrative memory. Another and reference 10). Studies of this sort, along with other
interesting finding that appears with reasonable con- studies of memory acquisition, have in many instances
sistency in the literature is that the hippocampus is supported a role for the hippocampus in memory
reliably activated with memory retrieval. This is, of acquisition, and also in spatial navigation. Along simi-
course, not a prediction that necessarily arises out of lar lines, various studies have reported hippocam-
the hypothesis that the hippocampus is involved in pal activation, using both PET and fMRI approaches,
memory consolidation. when subjects are presented with novel stimuli. The
This is not to say that the hippocampus has not been activation of the hippocampus with novel stimuli may
found to be activated with memory acquisition—that both represent the use of the hippocampus as a mem-
is also the case. For example, the hippocampus has ory comparator for identifying novel stimuli, and the
been found to be activated when human subjects learn use of the hippocampus to encode and form memories
to navigate a “virtual town.” In these studies human for new items or places.
subjects in an fMRI scanner can learn to navigate a Finally, one of the more fascinating human imaging
computer-based virtual town, and the activity of the studies investigating the function of the hippocampus
hippocampus be imaged simultaneously (see Figure 8 involved studying London taxi drivers. The layout of
38 2. Studies of Human Learning and Memory

A likelihood of survival of the species. The capability to

perform an acrobatic maneuver might mean escap-
ing a predator. The capacity to throw a round object
with great velocity and accuracy might mean putting
dinner on the table. The capacity to rapidly and pre-
cisely move your fingers on a six-stringed instrument
might mean … er …, uhm … OK, maybe my father
B was right and I wasted my time learning how to do
that. Regardless, the human capacity for motor learn-
ing is amazing.

A. Anatomy
There are two basic anatomical systems involved
Figure 9 (A) Voxel based morphometry indicates increased in human motor performance and motor learning (see
posterior hippocampal volume bilaterally in licensed London taxi Figure 11). The first is the cerebellar system, which we
drivers compared with control subjects. (B) Amount of time spent will discuss in more detail in Chapter 5 where we will
taxi driving (corrected for age) was positively correlated with vol-
ume increase in the right posterior hippocampus. Adapted from
talk about cerebellum-dependent associative memory.
Maguire et al. (2000a). Copyright Elsevier 2002. The second is the basal ganglia-dependent (striatal)
system, which I will briefly outline here.
The term “basal ganglia” refers to a collection of
the streets of London is notoriously convoluted, and interacting CNS structures and neuronal nuclei (see
experienced taxi drivers in London must of neces- Figures 12 and 13). The basal ganglia are the stria-
sity have undertaken extensive learning and memo- tum (comprising the caudate nucleus, putamen, and
rization of navigational cues and street relationships. nucleus accumbens), and the globus pallidus. The
Hence, Maguire and colleagues undertook structural striatum is the principal input nucleus for this path-
MRIs of the brains of licensed London taxi drivers, way, and it receives afferents from essentially every
analyzed their hippocampi, and compared them with cortical area, both motor and sensory. Other parts of
those of control subjects who did not drive taxis. They the basal ganglia are the subthalamic nucleus, which
found that the posterior hippocampus (bilaterally) of interacts with the globus pallidus, and the substantia
taxi drivers was significantly larger relative to that nigra, which contains dopaminergic neuron cell bod-
of control subjects (see Figure 9 and reference 11). In ies and modulates striatal function. The output of the
addition, hippocampal volume correlated with the basal ganglia is principally to the ventral anterior and
amount of time they had spent as a taxi driver. These ventrolateral nuclei of the thalamus. There is very lit-
findings suggest the interesting idea that the posterior tle output of these thalamic nuclei to the brain stem
hippocampus is involved in storing a spatial repre- or spinal cord motor nuclei—instead they project back
sentation of the environment, and that this particular up into the cortex to the motor and premotor cortices
brain region can grow to accommodate a need for this (along with the prefrontal association cortex).
capacity in people with a high dependence on navi- This basic and simplified wiring diagram (see
gational skills. Overall, these data are also consistent Figure 13) illustrates that the basal ganglia are part
with a role for the hippocampus in spatial navigation of a signal-processing recurrent loop that downloads
and spatial memory formation. information from the cortex, processes it, and returns
it to the cortex. The upshot of all this wiring is that the
basal ganglia do not directly control movement—they
coordinate motor programs. Thus, it is very important
III. Motor learning to note that the striatal system does not perform learn-
ing operations independently. As is suggested by the
One cannot help but be awed when watching an anatomical wiring described above, the motor cortex
accomplished gymnast, professional athlete, or virtu- and premotor cortex also are integrally involved in
oso guitarist in action (Figure 10). The human capacity striatum-dependent learning.
for learning and executing finely-tuned motor pat- In addition, it is important to note that the basal
terns is the product of millions of years of evolution- ganglia are also involved in goal-oriented behavior.
ary refinement through natural selection. Indeed, it’s Reward systems involving the nucleus accumbens
fairly easy to imagine how the three examples I gave and the substantia nigra dopaminergic system are
in the first sentence may translate into an improved important for positively motivated learning (12–14).
 III. MOTOR LEARNING 39

Figure 10 Examples of excellence in human motor learning and memory: University of Alabama gymnast (photo courtesy of Dusty
Compton), a University of Alabama at Birmingham basketball player (image courtesy of the UAB Athletic Department), and a University
music student playing guitar.

This system can also be “hijacked” in order to pro- automatically. Habits are generally not consciously
mote drug addiction (see Box 3). Finally, recent find- perceived unless the parameters change—for exam-
ings suggest that the striatal system is also likely ple when someone changes laboratory locations and
involved in learning certain non-motor cognitive tasks needs to turn right instead of left when they get off
that involve repetition—a good example is becoming the elevator. For a while after the laboratory moves
facile with reading mirror-images of words (15). The locations they may keep “accidentally” turning left
basal ganglia system may indeed be involved in lan- when they get off the elevator, until they reform a new
guage learning and cognition in general, although this appropriate habit.
is fairly speculative at this point in time (16).
C. Stereotyped Movements
B. Habits
Another category of striatum-dependent learn-
This striatum-associated system is involved in ing is the learning of stereotyped movements. A clas-
learning several different subtypes of memorized sic example of this from animal behavioral studies is
responses that involve motor responses as an out- memory involving stereotyped motor movements,
put. One category is habits—for example you might such as bar-pressing for food rewards. Normal human
always turn left after you get off the elevator, in order stereotyped movements can be fairly complex and
to get to your laboratory. With time this will become based on contingencies—for example “step on the gas
a simple ingrained motor response that you execute when the stoplight turns green.” One may perform
40 2. Studies of Human Learning and Memory

Cerebral cortex - motor areas Skilled

movements

Initiation
Relay
Selection of Thalamus
station
motor programs
CS
Basal ganglia Posture
Brain stem Eye movements
Cerebellum
Motor RS VS RbS
coordination
and correction 1 2
Spinal reflexes
Spinal cord
Locomotion
Muscle movement
and contraction
Sensory
receptors

Basic functions of descending tracts

Cortico- and rubrospinal
1. Transmission of commands for skilled movements.
2. Corrections of motor patterns generated by the spinal cord.

Reticulospinal
1. Activation of spinal motor programs for stepping and other stereotypic movements.
2. Control of upright body posture.

Vestibulospinal
Generation of tonic activity in antigravity muscles

Copyright © 2002, Elsevier Science (USA). All rights reserved.

Figure 11 Summarizing scheme of the interaction between different motor centers. The different major compartments of the motor sys-
tem and their main pathways for interaction are indicated. The basic functions of the different compartments and descending tracks are sum-
marized on and below the scheme. CS, corticospinal; RbS, rubrospinal; VS, vestibulospinal; RS, reticulospinal. Adapted from Fundamental
Neuroscience, Fundamentals of Motor Systems, Sten Grillner. Copyright Elsevier 2003.

A this stereotyped response many times every day, in

Putamen Caudate an unconscious fashion. This unconscious stereotyped
nucleus
(body) movement might cause someone to accidentally step
on the gas when the left-hand turn arrow turns green,
Globus palidus
(ext. segment)
while their lane still has a red light.
Thalamus
The term stereotyped, when applied to behaviors,
Internal
capsule can also refer to non-learned behaviors. Psychologists
Globus palidus and ethologists used the term stereotyped to refer
(int. segment) to innate behaviors that are developmentally pro-
Subthalamic Caudate grammed. In the clinical literature, stereotyped also
Cerebral nucleus
nucleus
Substantia nigra Red nucleus peduncle (tail)
refers to unlearned repetitive motor behaviors that
are associated with certain diseases and pathologies.
B For example, girls with Rett’s Syndrome exhibit stere-
Caudate otyped repetitive hand-wringing as part of the disor-
nucleus Body der. Tourette’s Syndrome can involve stereotyped tics
Head
and even extensive involuntary limb movements.
Tail
Putamen D. Sequence Learning
A third category of striatum-dependent learning is
the learning of sequenced movements. A good exam-
Copyright © 2002, Elsevier Science (USA). All rights reserved.
ple of this is dialing telephone numbers. If you think
Figure 12 Location of basal ganglia in the human brain.
(A) Coronal section. (B) Parasagittal section. Figure from Funda-
of a telephone touch-pad as a 3  4 matrix, dialing a
mental Neuroscience: The Basal Ganglia, Jonathan Mink. Copyright phone number is a motor sequence involving serially
Elsevier 2003. touching specific spots on the matrix. How long does
Discovering Diverse Content Through
Random Scribd Documents
Ireland.” After her Majesty had received the presents, and made her
acknowledgments through Major MacMahon, late Political Agent at
Mandalay, the Embassy withdrew, and returned to London.
On the 1st of July the Queen, accompanied by the Duke of Edinburgh,
Princess Louise, Princess Beatrice, and Prince Leopold visited the National
Memorial erected in Hyde Park to the memory of the late Prince Consort.
This was a strictly private visit, the monument being at the time incomplete.
Between the 15th and 20th of August the Queen broke her journey to
Balmoral, and resided at Holyrood Palace, Edinburgh, for a few days.
Though her visit was private, she was so gratified with the reception she
everywhere received that she caused Viscount Halifax to address the
following letter to the Lord Provost of Edinburgh:—
“Dear Lord Provost,—It is not the practice unless the Queen has visited any city or
town in a public manner, to address any official communication to the chief magistrate
or authority of the place. I am commanded, however, by her Majesty to convey to you
in a less formal manner the expression of her Majesty’s gratification at the manner in
which she was received by the people of Edinburgh in whatever part of this city and
neighbourhood her Majesty appeared. Her Majesty has felt this the more because, as
her Majesty’s visit was so strictly private, it was so evidently the expression of their
national feeling of loyalty. Her Majesty was also very much pleased with the striking
effect produced by lighting up the park and the old chapel.”

The death of the amiable and accomplished Princess Feodore of

Hohenlohe-Langenburg on the 23rd of September plunged the Queen into
deep despondency. The Princess was half-sister to her Majesty, and the tie
that bound them together through life had been close and affectionate. “All
sympathise with you,” wrote the Princess Louis to the Queen when she
heard of her mother’s bereavement, “and feel what a loss to you darling aunt
must be, how great the gap in your life, how painful the absence of that
sympathy and love which united her life and yours so closely.”
 CHAPTER XVIII.

GOVERNMENT UNDER DIFFICULTIES.

A Lull Before the Storm—Dissent in the Dumps—Disastrous Bye-Elections—The

Queen’s Speech—The Irish University Bill—Defeat of the Government—Resignation
of the Ministry—Mr. Disraeli’s Failure to Form a Cabinet—The Queen and the Crisis
—Lord Derby as a Possible Premier—Mr. Gladstone Returns to Office—Power Passes
to the House of Lords—Grave Administration Scandals—The Zanzibar Mail Contract
—Misappropriation of the Post Office Savings Banks’ Balances—Mr. Gladstone
Reconstructs his Ministry—The Financial Achievements of his Administration—The
Queen and the Prince of Wales—Debts of the Heir Apparent—The Queen’s Scheme for
Meeting the Prince’s Expenditure on her Behalf—The Queen and Foreign Decorations
—Death of Napoleon III.—The Queen at the East End—The Blue-Coat Boys at
Buckingham Palace—The Coming of the Shah—Astounding Rumours of his Progress
through Europe—The Queen’s Reception of the Persian Monarch—How the Shah was
Entertained—His Departure from England—Marriage of the Duke of Edinburgh—
Public Entry of the Duchess into London.

When the Session of 1873 opened, it is a curious fact that in London the
universal complaint was that politics had become depressingly dull. But the
lull really presaged a storm, in which the Government was wrecked. It was
known that Mr. Gladstone intended to make the question of Irish University
education the chief business of the Session, and it was admitted that next to
this question the one of most consequence to the Government was that which
was raised by the Dissenters, who demanded the extension of School
Boards, and the establishment of compulsory education all over England,
together with the repeal of the 25th clause of Mr. Forster’s Education Act.
The bye-elections, which had been disastrous to the Ministry, showed that
the Dissenters were in revolt, and that they “sulked in their tents,” instead of
supporting Ministerial candidates. The Irish University Bill could not
possibly be carried without Nonconformist support, and that could obviously
not be hoped for if anything like “concurrent endowment” for the Roman
Catholics defaced it. On the other hand, if the revenues of Trinity College
were shared with Catholic scholars, Liberals like Mr. Fawcett and Mr.
Vernon Harcourt would support Mr. Disraeli in opposing the measure. The
Cabinet resolved to neutralise the expected secession of the small Fawcett-
Harcourt group, by rendering their Bill acceptable to their powerful
Nonconformist contingent, and Liberal tacticians were full of joyful
anticipations when it leaked out that this plan was contemplated. As will be
seen, one important contingency was never taken into consideration—the
possible desertion of Mr. Gladstone’s Roman Catholic followers; and yet it
was their desertion which wrecked the Bill and destroyed the Government.

QUEEN’S COLLEGE, CORK.

(From a Photograph by W. Lawrence, Dublin.)

The Queen’s speech was read to Parliament by Commission on the 6th of

February, and it promised an Irish Education Bill, a Judicature Bill, a Land
Transfer Bill, an Education Amendment Act, a Local Taxation Bill, and a
Railway Regulation Bill. In the debate on the Address the Opposition leaders
dwelt mainly on foreign questions, pressing the Government to say whether
they were prepared to recommend the rules under which the Alabama case
had been decided to the European Powers; and if so, whether they would
recommend them as interpreted by the legal advisers of the Crown, or as
interpreted by the majority of the arbitrators. Mr. Gladstone first said that the
rules had been recommended for adoption by the Powers, but without any
special construction being put on them. Then he had to correct himself
before the debate closed, by explaining that he had made a mistake, for the
rules had not yet been brought under the notice of Foreign Governments.
This confession naturally forced the public to conclude that the Tories could
not be far wrong when they declared that foreign affairs were neglected
because Lord Granville was indolent and Mr. Gladstone neither knew nor
cared anything about them.

PROFESSOR FAWCETT.
(From a Photograph by the London Stereoscopic Company.)

On the 13th of February Mr. Gladstone introduced the Irish University

Education Bill. It affiliated several other educational institutions besides
Trinity College to the University of Dublin. Two of the Queen’s Colleges,
established by Sir Robert Peel, were to be associated with the University,
and the Queen’s University itself was to be abolished. Queen’s College at
Galway was to be suppressed, because it had failed to attract students to its
classrooms. The so-called Catholic University and several other Roman
Catholic seminaries were also, in the same manner, to be attached to the
Dublin University. The new University was to have an income of £50,000 a
year, a fourth of which was taken from Trinity College, a fourth from the
endowment for Queen’s University, three-eighths from the Irish Church
surplus, whilst fees, it was expected, would make up the balance. It was to
have professors for teaching in Dublin all academical subjects excepting
history and mental philosophy, which were tabooed as too controversial for
Ireland. Bursaries, Scholarships, and Fellowships were liberally endowed.
Tests were to be abolished, the Theological Faculty of Trinity College was to
be transferred—with an endowment—to the Disestablished Church, and the
prohibited subjects, History and Philosophy, were not to be compulsory in
examinations for degrees. The constituency of the University was to consist
of all graduates of the affiliated colleges. The governing council of twenty-
five was to be nominated in the Bill, after which, vacancies were to be filled
up alternately by co-optation and Crown nomination. After ten years,
however, equal numbers of the council were to be chosen, by the Crown, by
co-optation, by the professors, and by the graduates. The Bill, according to
the Bishop of Peterborough—by far the ablest Protestant ecclesiastic Ireland
has produced in the Victorian period—“was as good as could be under the
circumstances,” and “ought to have pleased all parties.”[49] Unfortunately it
pleased nobody, and its weak point was obvious. It attempted to provide for
separate denominational education in the affiliated colleges, and for mixed
secular education in Trinity College and the University of Dublin, to which
they were affiliated—the one system being as incompatible with the other as
an acid with an alkali. As Mr. Gathorne-Hardy said, the exclusion of History
and Philosophy rendered the new University a monster cui lumen ademptum.
The proposal to make the Irish Viceroy its Chancellor recalled, he declared,
the lines of Milton,

“Its shape,
If shape it can be called, which shape had none
Distinguishable in feature, joint, or limb—”

all the more that

 “What seemed its head,
The likeness of a kingly crown had on.”

At first the Bill was very well received, and there was a general
disposition to admit that, in view of the limiting conditions of the problem, it
was impossible to find a solution less offensive to the Protestants, and more
generous to the Catholics of Ireland. But in a few days it became apparent
that the measure was doomed. Ministers had been led to believe by their
colleague, Mr. Monsell, who was the spokesman of the Catholic clergy, that
the compromise would be accepted by them. But the Catholic Bishops met
in secret, and decided to oppose the Bill.[50] As the Catholics opposed it for
giving them too little, the Protestants opposed it because it gave the
Catholics too much. The apostles of culture opposed it because it cut History
and Philosophy out of the University curriculum, and in doing so they
furnished all discontented Liberals with a good non-political excuse for
voting against the Government. The Bill was defeated on the 12th of March
by a vote of 287 to 284, the votes of 36 Catholic Members and 9 Liberals[51]
having turned the scale. To the very last moment the issue was uncertain,
because it was known that if Mr. Gladstone had offered to abandon the
teaching clauses of the Bill, he would have won over a sufficient number of
Catholic votes to carry it.[52]
Mr. Gladstone’s defeat was followed by the resignation of his Ministry,
and the crisis was a most embarrassing one for the Queen. Mr. Disraeli,
when sent for by the Sovereign, attempted to form a Cabinet, but did not
succeed, mainly because Mr. Gathorne-Hardy objected to the party holding
office on sufferance. When Mr. Disraeli reported his failure to the Queen,
she again consulted Mr. Gladstone, who, however, suggested that some other
Conservative leader—obviously hinting at Lord Derby—might succeed
where Mr. Disraeli had failed. But Lord Derby was at Nice when the crisis
became acute; and though the Tory Party felt that he was in a special sense
their natural leader at such a juncture,[53] they knew that it was decidedly
inconvenient for the Prime Minister to be a member of the Upper House, and
that he would refuse to enter into anything like rivalry with Mr. Disraeli. Yet
a restful Ministry, competent in administration, under a cool-headed,
sensible Conservative aristocrat, was what the majority of the people,
alarmed by harassed “vested interests,” desired at the time. Be that as it may,
Mr. Disraeli, when appealed to a second time by the Queen, refused to assist
her out of the difficulty, and Mr. Gladstone was again summoned to the
rescue. He returned to power with his Cabinet unchanged and disavowed any
intention to dissolve Parliament. Mr. Disraeli’s refusal to take office had
given the Queen infinite anxiety, and his defence of his conduct was lame
and halting. He was, he said, in a minority; he had not a policy, and could
not get one ready till he had been for some time in office, so that he might
see what was to be done. He did not desire to experience the humiliation of
governing the country under a régime of hostile resolutions. The Queen and
the country were alike conscious of the flimsiness of these excuses. Mr.
Disraeli never met the question—which, to the Queen, seemed unanswerable
—Why did he paralyse the existing Administration, if he was not prepared to
put another in its place?

QUEEN’S COLLEGE, GALWAY.

Mr. Disraeli in refusing to govern England himself whilst he prevented

Mr. Gladstone from governing it, was pursuing a policy which was as
unconstitutional as it was unpatriotic. When he said he could not take office
because he must dissolve in May in any case, and that he could not dissolve
because he had not a policy to go to the country with, and when he explained
that till he had time to study the archives of the Foreign Office he could not
tell what ought to be done with questions such as the Russian advance on
Khiva, and the Three Rules of the Washington Treaty, men smiled cynically.
They asked each other if Lord Palmerston in 1869 was afraid to take the
place of the Tory Government because he wanted time to form an opinion on
Lord Malmesbury’s policy towards the Italian war of Liberation. Yet Mr.
Disraeli gave a truthful account of his motives. He had no policy. Hence
when he dissolved Parliament, as he was bound to do after winding up the
business of the Session, he must have gone to the country on a purely
personal issue between himself and Mr. Gladstone. Doubtless at a time when
the nation was getting wearied of restless statesmen, a contest of the sort
would have been disastrous to Mr. Gladstone, but not when raised by Mr.
Disraeli, who was notoriously even flightier than his antagonist. To have
won a General Election on such an issue the Tories must have fought under
Lord Derby’s banner. Mr. Disraeli, however, had no intention of giving way
to Lord Derby, and his followers did not dare to put him aside, more
especially as he had in view a clever scheme of strategy. His idea was to
force Mr. Gladstone to dissolve on a positive programme, and then to defeat
him by a running fire of destructive criticism. These tactics might bring the
Tories back to office under his own leadership, absolutely uncommitted to
any definite policy whatever.
When Mr. Gladstone resumed office it was soon seen that he had not only
wrecked his party, but compromised the prestige of the House of Commons.
His was admittedly a weakened and discredited Ministry. It had been one of
Mr. Disraeli’s favourite theories that whenever a feeble Ministry attempted
to govern England, power passed from Parliament to the Crown. At one
time, no doubt, the theory seemed plausible enough, but the Session of 1873
completely upset it. No sooner had Mr. Gladstone returned to office than
power passed from the Crown and the House of Commons to the House of
Lords. The will of the Peers was supreme over all. They said or did what
they pleased, and quashed Bill after Bill without the least regard to the
sentiments of the Queen, the desire of the Commons, or the interests of the
country. The Peers rejected the Bill improving Church organisation
contemptuously, though it had passed the Commons without a division. By
asserting obsolete privileges of appellate jurisdiction over Scotland and
Ireland, they disfigured the Judicature Bill, which consolidated the law
courts and constituted a high court of appeal. They destroyed Mr. Stansfeld’s
useful Rating Bill almost without debate. They opened a way for the
reintroduction of purchase in the army, rejected the Landlord and Tenant Bill
without even seeing it, and quashed a Bill, promoted by Mr. Vernon
Harcourt and supported by the Government, to protect working men against
being imprisoned under the law of conspiracy for non-statutable offences
committed in the course of a strike. And the curious thing was that from the
day Mr. Gladstone returned to office to lead a moribund Ministry and a
disorganised House of Commons, the people submitted without a murmur to
the resolute and decisive despotism of the Peers. Thus it came to pass that
when the Session ended the Ministry seemed to have sunk into a dismal
swamp of humiliation—a humiliation which was intensified by
administrative scandals and internal feuds. It was shown that Mr. Lowe, as
Chancellor of the Exchequer, prepared plans of his own for public works,
without consulting the Public Works Office. Mr. Ayrton, as head of that
Department, in his place in the House of Commons, repudiated all
responsibility for the votes of money for his department which were altered
without his knowledge and consent by Mr. Lowe. There was a painful
“scene” in the House of Commons at the end of July when these disclosures
were made, and when Mr. Ward Hunt formally asked the Government if its
Chancellor of the Exchequer and Chief Commissioner of Works were on
speaking terms. Mr. Baxter created another scandal by suddenly resigning
office as Financial Secretary to the Treasury, because Mr. Lowe had ignored
him in the matter of the Zanzibar mail contract. Mr. Lowe was proved to
have given the contract for carrying letters from the Cape to Zanzibar to the
Union Steam Company for £26,000, whereas the British India Steam
Company had offered to do the work for £16,000. Mr. Lowe declared he had
never heard of the offer; yet Lord Kimberley, the Secretary for the Colonies,
knew of it, and the tender was transmitted by the Indian Postmaster-General
to Mr. Monsell, the British Postmaster-General, who passed it on to the
Treasury. At the Treasury Mr. Lowe concealed the papers relating to the
contract from Mr. Baxter, avowedly because he was known to be hostile to
it. A Committee of the House investigated the scandal, and disallowed the
contract. This affair was also accompanied by the final revelation of the truth
as to what was known as the telegraph scandal.
 In spring the working classes were profoundly disturbed by a rumour that
the Government had seized the Savings Banks balances, and were building
great extensions of telegraph lines with the money without consulting
Parliament on the subject. The foundation for the story was a discovery
made by the Auditor-General of Public Accounts. He reported that the
Telegraph Department of the Post Office had for some time evaded the
control of the House of Commons over its expenditure. Instead of submitting
to the House estimates for proposed works, and asking for a vote on account,
Mr. Scudamore, the Chief of the Department, a brilliant but too zealous
official, took whatever money he wanted from the Post Office receipts, and
spent it as he pleased on works of extension and improvement. He submitted
no estimates in detail, but always asked the House of Commons for a sum
for new works, which enabled him to replace the Post Office receipts which
he had used. A large portion of the money thus spent was taken from the
Savings Banks balances which everybody understood were always paid in
for safety to the Commissioners of National Debt, who invested them in
Consols. Though no money was missing, it shook public confidence in the
Government to find its administrative power so feeble that it could not
prevent its own servants from tampering with the Savings Banks Deposits,
and further investigation aggravated the scandal. It was shown that Lord
Hartington when Postmaster-General had, like Mr. Monsell, allowed Mr.
Scudamore to manage the Telegraph Department without any supervision,
and that the Treasury had so far condoned this gross and culpable negligence
that when it did business with Mr. Scudamore it communicated with him
directly, and not through either Lord Hartington or Mr. Monsell, who had
meekly submitted to be treated as official “dummies.” It was shown that the
Treasury knew of Mr. Scudamore’s irregularities in 1871, and condoned
them; that in 1872 it knew of them again, and acted so feebly that even Mr.
Lowe admitted he regretted his lack of firmness. It was utterly impossible to
defend the conduct of Mr. Lowe, Lord Hartington, Mr. Monsell, and the
Chief Commissioner of National Debt, for countenancing these grave
irregularities, and the scandal was simply disastrous to the administrative
prestige of the Ministry.
The Queen was alarmed at the dismal prospect of ruling England by
means of a Cabinet so hopelessly discredited, and Mr. Gladstone was equally
conscious of the gravity of the situation. Whenever Parliament was
prorogued he tried to parry attacks on the administrative incapacity of his
Cabinet by reconstructing it. To the great relief of the Queen, he himself took
the Chancellorship of the Exchequer into his own hands, so that the public
might have a guarantee that the era of chaos at the Treasury was closed.[54]
Mr. Bruce was elevated to the Peerage as Lord Aberdare, and became
President of the Council, Lord Ripon having retired for private reasons. Mr.
Childers (also for private reasons) vacated the Chancellorship of the Duchy
of Lancaster, and Mr. Bright took his place and re-entered the Cabinet. Mr.
Lowe was removed to the Home Office, and ere the year closed Mr. Adam
became Chief Commissioner of Works, Mr. Ayrton taking the office of
Judge-Advocate-General. Mr. Monsell also retired from the Postmaster-
Generalship, and was succeeded by Dr. Lyon Playfair. The death of Sir
William Bovill, Chief Justice of the Common Pleas, in November, elevated
Sir J. D. Coleridge to the Bench. Mr. Henry James accordingly became
Attorney-General, and, to the amazement of the Bar, he was succeeded as
Solicitor-General by Mr. Vernon Harcourt, whose attacks on the Ministry
had thus met with their reward.
Mr. Gladstone’s hope was to reinvigorate the Government with a little
new blood, and rehabilitate it by means of his influence and reputation as a
financial administrator and Mr. Bright’s personal popularity among the
Nonconformists. Yet the financial work of the Government alone, when
administrative
 VIEWS IN WINDSOR: OLD MARKET STREET, AND THE TOWN HALL, FROM HIGH
STREET.

blunders were detached from it, and relegated to their true place in political
perspective, ought to have won for them the gratitude of the nation. Mr.
Vernon Harcourt, who perpetually harassed the Ministry because of its
growing expenditure—like many financial critics with an imperfect
knowledge of book-keeping—failed to see that the apparent growth was not
real because much of it was a mere matter of accounting.[55]

SANDRINGHAM HOUSE.

During their five years of power the Government had remitted

£9,000,000 of taxation. They had reduced a chaotic Naval Administration to
something resembling order, and not far removed from efficiency; and yet at
the Admiralty there had been a saving of £1,500,000 on the Estimates of
their predecessors. They had taken the Army out of pawn to its officers by
abolishing Purchase, and had laid the basis for a compact military
organisation; yet they had saved £2,300,000 a year at the War Office. The
Army and Navy, though by no means efficient, were much more efficient
than they had been when Mr. Gladstone’s Ministry came to power; and yet
they were costing the country £4,000,000 less a year.[56] In spite of the great
increase in Civil Service expenditure—much of which, like the Education
Vote, being morally rather than financially reproductive, showed no “results”
in figures on the credit side of the public ledger—there had been since 1857
a decrease in the drain on the taxes of about £1,500,000.[57] Mr. Lowe’s last
Budget in 1873 did not discredit the Ministry. In spite of his reductions of
taxation in the previous year, he had obtained £2,000,000 more than his
estimated income. For the coming year (1873-4) he estimated a surplus of
£4,746,000; but he could promise no great remission of taxation, for he had
to pay the damages (£3,000,000) which had been awarded at Geneva to the
United States Government. Still, he halved the sugar duties and took another
penny off the Income Tax. With all his faults, he was accordingly entitled to
claim credit for reducing the Income Tax to the lowest point it had ever
touched (threepence in the £) since it had been imposed by Peel in 1842.
And yet Mr. Lowe could not, even with such a Budget, refrain from
expressing his thankfulness in an acrid gibe against the populace. Referring
to the marvellous increase in the receipts from Customs and Excise, he said
he had been able to produce a good Budget because the nation had drunk
itself out of debt.
Apart from the political strife and Ministerial embarrassments which so
severely taxed the nerves of the Queen, life at Court was not very eventful.
Indeed, it centred chiefly round the Prince and Princess of Wales, who were
discharging vicariously and with great popular acceptance most of the social
duties of the Crown. This fact was recognised by the Queen herself in a
curious indirect kind of way. The Prince of Wales, though very far from
being a spendthrift, has never shrunk from incurring expenditure which, in
his judgment, was necessary to maintain the dignity and prestige of the
Crown in a manner worthy of the great nation whose Sovereignty is his
heritage. But he has always refrained from appealing to Parliament for
subsidies and subventions, either for himself or his family, other than those
to which he is equitably and legally entitled by his official position in the
State. This was all the more creditable to him, for two reasons. He was
surrounded by companions, some of whom did not scruple to take advantage
of his generosity. A considerable section of the public during the controversy
that raged over the Princess Louise’s dowry had expressed a strong opinion
in favour of limiting future Royal grants to an additional allowance to the
Heir Apparent, for the purpose of meeting the unanticipated expenditure
which he had incurred by taking the Queen’s place as the head of English
Society. Sandringham, moreover, had not turned out a remunerative
property, and the Prince was therefore under strong temptations to give a
favouring ear to unwise counsels on this delicate subject. These, however, he
put aside with manly common sense, and his affairs were arranged on a
business-like basis, which would have met with the approval of his father,
who was always of opinion that matters of the sort were best managed inside
the family circle. The only public indication that was given of arrangements
which must necessarily be spoken of with great reserve was afforded by Mr.
Gladstone when, on the 21st of July, he introduced a Bill enabling the Queen
to bequeath real property to the Prince of Wales, so that he could alienate it
at will. The obvious advantage of such a measure was that it imparted a fresh
elasticity to the financial resources of the Heir Apparent. For he had
discovered a fact hitherto unrevealed in the history of his dynasty in
England, namely, that though the Sovereign could bequeath to the Heir
Apparent alienable personality, such as hard cash, land or real property so
bequeathed, became, when vested in his person on ascending the Throne, the
property of the State, and therefore inalienable. In fact, supposing the Queen
had left Balmoral, an estate which she and her husband bought out of their
private purse, to her eldest son, then, though it had been her own private
property, it must become public property whenever the Prince of Wales
became King. The state of the law on the subject was inequitable and
inconvenient. For if the Queen wished to aid her eldest son in meeting
expenses which he was every day incurring on her behalf, she had either to
sell her private estates, endeared to her by a thousand tender family
associations, or appeal to Parliament for a grant, a course which was as
objectionable to her as to the Prince. On the other hand, if these private
estates, when inherited by the Prince at her death, could be treated as private
property, the Heir Apparent could easily obtain any additional subsidies he
might need, by mortgaging his expectations. And yet the generous intentions
of the Queen, and the honest purposes of the Prince which formed the
motives for the Bill, were snappishly and churlishly misrepresented by
several Radicals, and by at least one aristocratic Whig. Mr. George Anderson
opposed the Bill because Sovereigns kept their wills secret. Sir Charles
Dilke objected to it because he said it allowed the indefinite accumulation of
private property in the hands of the Sovereign. His argument, in fact, came
to this, that profligacy in the Monarch should be encouraged by the
posthumous confiscation of his private estates. As for Mr. Bouverie, he
asked what business the Sovereign had to possess large private means? The
Bill, however, passed, and an incident which at one time threatened to be
unpleasant for the Queen and her children was discreetly closed.
In March, the Queen’s refusal to permit the persons who represented
England at the French Exhibition of 1867 to accept decorations, was made
the subject of debate by Lord Houghton in the House of Lords. Her
Majesty’s prejudice against introducing Foreign Orders and titles into
England had often given offence to naturalised stockjobbers and pushing
parvenus. She never even took kindly to the use of the title of “Baron” by
the Rothschilds, though she tolerated it for reasons of an entirely exceptional
nature. But if the Orders were admitted the titles must soon follow, and
society might be inundated some day with Russian “Counts,” who, as the
French say, had “a career behind them,” or with Austrian “Barons,” who had
bought their honours out of the profits of financial gambling. The English
Court, for this reason, has such strong opinions on the point that even
English nobles, inheriting foreign titles, conceal them so successfully that
few people ever suspect that the Duke of Wellington is a Portuguese prince,
the head of the House of Hamilton a French duke, or Lord Denbigh a Prince
of an uncrowned branch of the Imperial House of Hapsburg. It need not be
said that Lord Houghton’s complaints were generally admitted to be
frivolous, and that the Queen’s feeling that she must be the sole fountain of
honour in England, was shared by the nation. If the services which an
individual has rendered abroad have benefited England or mankind, or if it is
possible to form a correct estimate of their value in England, the Queen held
she must either reward them herself, or retain the right to permit the
individual to receive a foreign decoration for them. There never has been
any practical difficulty in dealing with such cases, and no self-respecting
person has ever felt aggrieved because he was debarred from accepting
Foreign Orders.[58]
On the 4th of January the Queen was grieved to hear of the death of the
ex-Emperor of the French, at Chislehurst. Her tender sympathy was freely
bestowed on the ex-Empress, who was prostrated by her misfortunes and her
sorrow. Five years before, the death of this strange man, whose Imperial life
seemed ever shadowed by the great crime of the coup d’état, would have
convulsed Europe. Now the world seemed quite indifferent to it, and when
politicians spoke of it, all they said was that by disorganising the Imperialist
party in France, it lessened the labours of M. Thiers in founding the Third
Republic. The English people, whom Napoleon III. had kept in feverish
dread for two decades, and whose support and friendship he had rewarded
with the perfidy of the Benedetti Treaty, did not pretend to mourn over his
grave. They spoke of his character, which was a moral paradox, and his
career, which was a political crime, without prejudice or ill-feeling. But as
they thought of the horrors of the Crimean War, the wasted millions which
Palmerston spent in fortifying the South Coast, and the final act of treachery
which the German Government had revealed in July, 1870, there were some
who considered that the Queen might have been less demonstrative in her
manifestations of sorrow. But Her Majesty has never been free from the
defects of her qualities. Quick to resent betrayal, her anger passes away as
swiftly, when the betrayer broken by an avenging Destiny, and prostrate
amid the wreck of his fortunes and his reputation, appeals to her sympathies.
When Louis Philippe stood before her as a hunted fugitive, the Queen forgot
the Spanish marriages. When Charles Louis Bonaparte fled for refuge to
Chislehurst, she was too generous to remember his scheme for stealing
Belgium.
 THE QUEEN’S VISIT TO VICTORIA PARK.

When spring came round, “the great joyless city,” as Mr. Walter Besant
calls the East End of London, was gladdened by the Queen, for on the 2nd of
April her Majesty went there to visit Victoria Park. She was accompanied by
the Princess Beatrice, and drove from Buckingham Palace to the park in an
open carriage. Her route was along Pall Mall, Regent Street, Portland Place,
Marylebone Road, and Euston Road to King’s Cross, up Pentonville Hill to
the “Angel” at Islington, beyond which point along Upper Street, Essex
Road, Ball’s Pond Road, through Dalston and Hackney, surging crowds of
people lined both sides of the entire way. Streamers of gaudy bunting floated
overhead from house to house across Islington Green. The Dalston and
Hackney stations of the North London Railway, the Town Hall, and shops of
Hackney were conspicuously decorated, and it was noticed that the Queen
went among the poor of the East End without any military escort, a feat that
few European Sovereigns would have dared to emulate. At the Town Hall
she halted and received a bouquet, while the people sang the National
Anthem. At the temporary entrance to Victoria Park a triple arch, of triumph
had been erected, deep enough to resemble a long marquee in three
compartments, open at both ends. It was handsomely fitted up in scarlet and
gold, and here was stationed a guard of honour of the Fusiliers, while an
escort of Life Guards was in waiting to conduct her Majesty round the park.
Even the slums in this dismal quarter exhibited meagre decorations, eloquent
alike of loyalty and indigence. A poor shoemaker, having nothing better to
show, hung out his leather apron, on which the Queen saw with a thrill of
interest that he had chalked up in flaming red letters, “Welcome as flowers in
May. The Queen, God bless her.” The enthusiasm of the populace on this
occasion was due to a curious idea that prevailed all over the East End. This
visit, they said, was no ordinary one, because the Queen had come of her
own free will to see the East End—a very different thing from the East End
going westwards to see her. Hence a hurricane of cheers greeted the Queen
wherever she went, and was more gladsome to her ears than the ornate
language of the loyal addresses which she received. Her Majesty returned by
Cambridge Heath Road, and when she came to Shoreditch the way was
rendered almost impassable by an eager crowd. From Bishopsgate Street to
the Bank she was hailed with passionate loyalty, which seemed to lose all
restraint when on passing the Mansion House she rose in her carriage and
smilingly bowed to the Lord Mayor, who stood in his State robes under the
portico and saluted her. She then drove along the Embankment to the Palace,
having charmed the sadder quarters of London with a visit which the people
took to mean that they were not forgotten or ignored by their Queen.
On the 3rd of April, at three o’clock in the afternoon, the Duke of
Cambridge, as President of Christ’s Hospital—the famous Blue-coat School
—visited the Queen at Buckingham Palace to present the boys of the
Mathematical School, who had come to exhibit their drawings and charts to
her Majesty. A number of gentlemen connected with the Hospital had the
honour of being presented by the Duke to the Queen when she entered the
Drawing-room. Her Majesty then inspected, apparently with great interest,
the maps and charts which were held before her by each boy separately.
The foreign curiosity of the London season in 1873 was the Shah of
Persia. Soon after the Queen’s visit to the East End ceased to be discussed,
the coming of the Shah was the favourite topic of talk. At the end of April
his departure from Teheran amidst the blessings of an overawed crowd of
80,000 subjects was chronicled. On the 12th of May he was heard of,
painfully navigating the waters of the Caspian in a Russian steamer, and
wonderful tales of his progress were told. He had three wives, and nobody
knew how many other ladies in his train holding brevet-matrimonial rank.
Was he going to bring them to England? If so, could more than one of them
be received, and in that case how were the rest to be disposed of? A cloud of
despondency began to settle over the subordinates in the Lord Chamberlain’s
department. Would it be possible, it was asked, to persuade the Queen to
invite each of the Shah’s wives separately—one to Buckingham Palace, one
to Windsor, and one to Osborne? Later on it was reported that not only was
the Shah bringing his harem, but his Cabinet Ministers also. Was his visit
likely to be free from danger? Might not people begin to cherish strange
fancies, if the Shah thus gave them ocular proof that an ancient country
could get on wonderfully well without a sovereign and without a
government? Gradually astounding rumours of his wealth were sent round.
He had brought only half a million sterling for pocket-money, because there
had just been a famine in Persia; still the sum would meet the modest wants
of his exalted position. Indeed, through a telegraphic blunder, the sum was
first stated as £5,000,000. He was said to be covered with jewels and
precious stones, and he wore a dagger which blazed with diamonds, so that
one could only view it comfortably through ground glass. In June the
officials of the Court were relieved from a supreme anxiety. Ere he got half-
way over Europe the Shah had sent his harem back to Persia. As he
approached England he was described as looking terribly bored, and his
black velvet doublet, covered with diamonds, and ornamented with emerald
epaulettes, was said by one irreverent journalist to give him the appearance
of “a dark shrub under the early morning dew.” To the good English people
he was a mighty Asiatic potentate, representing an ancient dynasty, and the
popular cry was that he must be impressed with the power of England. Had
they understood that his great grandfather was a petty chief, who at a time of
revolution established a dynasty, and promptly began, with the aid of his
relatives, to ruin Persia, and that their visitor himself ruled over a country
with the population of Ireland and twice the area of Germany, they might
have made themselves less ridiculous. Mr. Gladstone was even pestered on
the subject, and had to turn the matter off with a smiling suggestion that it
would be well to let the Shah fix his own programme, and not put him in
chains when he landed on our shores. But in Court circles it was whispered
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