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ScienceWeek
SCIENCEWEEK
ScienceWeek
February 28, 2003
Vol. 7 Number 9
An Online Digest of Research in the Sciences
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For the real amazement, if you wish to be amazed, is this
process: You start out as a single cell derived from the coupling
of a sperm and an egg; this divides in two, then four, then
eight, and so on, and at a certain stage there emerges a single
cell which has as all its progeny the human brain. The mere
existence of such a cell should be one of the great astonishments
of the Earth. People ought to be walking around all day, all
through their waking hours calling to each other in endless
wonderment, talking of nothing except that cell.
-- Lewis Thomas (1913-1993)
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Section 1
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Thematic Issue: Neurobiology of Learning and Memory
1. Introduction
2. Synaptic Plasticity
3. Learning and Memory: Evolutionary Aspects
4. Learning, Memory, and the Hippocampus
5. Learning, Memory, and the Cerebellum
6. Sex Differences, Hormones, and Memory
7. Learning and Memory: Developmental Aspects
Notices and Subscription Information
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Section 2
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1. INTRODUCTION
ON MEMORY AND BRAIN FUNCTION
Essentially, the functions of the brain are to process and
coordinate information currently available to it from the
external environment; to analyze the best course of action to
take on the basis of this information; and to instruct the
remainder of the organism to act on the basis of this analysis.
Of course, the brain has other functions as well. For example, it
is involved in the processing, analyzing and commanding of events
which occur within the organism's domestic economy -- such as
regional blood supply, rate of heartbeat and discharge of
hormones. But these controls generally occur at a lower level of
the brain than those concerned with the external environment.
For an organism to respond successfully to changes in external
environment, it is desirable for it to have some way of comparing
the content of the information reaching it now about the external
world with the content of messages which, in the past, have
described similar or slightly differ ent situations. It must have
a record of the responses it made to past situations and their
relative success or failure so that it can draw from its
behavioural repertoire an appropriate response to this new,
current situation. Evolutionary success among animal species has
to a considerable extent gone to those organisms which have been
able to expand their ability to store records of past experience
so as to make increasingly sophisticated comparisons of now and
then and act accordingly. So much is this the case that for
humans a very large proportion of the brain has become involved
in this mechanism of recording, storing, sifting and comparing
information; relatively smaller portions of the brain are
involved solely in the immediate processing of new information or
the issuing of commands for present action. It is this sifting
process, continually occurring within the brain, which we refer
to as consciousness and memory. [Adapted from Steven P. Rose, in:
N. Chalmers et al (eds.): The Biological Basis of Behavior.
Harper & Row 1971, p.232.]
ON SHORT-TERM VS. LONG-TERM MEMORY
It may come as a surprise that all humans have virtually perfect
photographic memories. When a visual scene or an array of letters
or numbers is flashed to your eye for just an instant, much of
the information in the scene is held accurately in memory.
Unfortunately this photographic memory lasts only for about one-
tenth of a second. Most of it is then forgotten. This short-term
photographic memory is called "iconic", from the Greek word icon,
meaning image. When you look up a new telephone number, you can
remember it just long enough to dial. If you do not repeat it to
yourself, it will usually be forgotten in a few seconds. This is
short-term, or immediate, memory. Roughly speaking, it is what
you hold in immediate awareness at any given moment. A person has
limited short-term storage capacity for new information: only
about seven items can be held in short-term memory. If you have
to remember an unfamiliar zip code as well as a new telephone
number, your short-term memory may be taxed beyond its limit.
Immediate awareness, of course, includes more than just a new
item of information; sensory experience of the world about you,
ideas and thoughts and well-established memories all come into
play. It is the ability to hold new information in immediate
awareness that is so limited. If you practice a new telephone
number by repeating it over and over, you can manage to remember
it more or less permanently. You place it in long-term, or
permanent, memory. The memory capacity of the average person
seems almost without limit. Consider the size of your vocabulary.
Each word contains several bits of information. Or consider all
the faces you have seen in your life. If you see some of them
again, you will recognize many of them. [Adapted from: Richard F.
Thompson: The Brain: An Introduction to Neuroscience. W.H.
Freeman 1985, p.302.]
ON MEMORY AND AMNESIA
Revealing though they have been, clinical studies of amnesic
patients have provided relatively little insight into the long-
term storage of information in the brain (other than to indicate
quite clearly that such information is not stored in the midline
diencephalic structures that are affected in anterograde
amnesia). Nonetheless, a good deal of circumstantial evidence
implies that the cerebral cortex is the major long-term
repository for many aspects of memory. One line of evidence comes
from observations of patients undergoing electroconvulsive
therapy (ECT). Individuals with severe depression are often
treated by the passage of enough electrical current through the
brain to cause the equivalent of a full-blown seizure (this
procedure being done under anesthesia in well-controlled
circumstances). This remarkably useful treatment was discovered
because depression in epileptics was perceived to be alleviated
after a spontaneous seizure. However, ECT often causes both
anterograde and retrograde amnesia. The patients typically do not
remember the treatment itself or the events of the preceding
days, and their recall of events of the previous 1-3 years can
also be affected. Animal studies (rats tested for maze learning,
for example) have confirmed the amnesic consequences of ECT. The
memory loss usually clears over a period of weeks to months.
However, to mitigate this side effect (which may be the result of
excitotoxicity), ECT is often delivered to only one hemisphere at
a time. The nature of amnesia following ECT supports the
conclusion that long-term memories are widely stored in the
cerebral cortex, since this is the part of the brain
predominantly affected by this therapy. [Adapted from: D. Purves
et al (eds.): Neuroscience. Sinauer Associates 2001, p.676.]
ON THE NEUROBIOLOGY OF LEARNING AND MEMORY
H. Okano et al (3 authors at 3 installations, JP US) present a
concise summary of current ideas in the neurobiology of learning
and memory, the authors making the following points:
1) The authors state they define memory as a behavioral change
caused by an experience, and they define learning as a process
for acquiring memory. According to these definitions, there are
different kinds of memory. Some memories, such as those
concerning events and facts, are available to our consciousness;
this type of memory is called "declarative memory". However,
another type of memory, called "procedural memory", is not
available to consciousness. This is the memory that is needed,
for example, to use a previously learned skill. We can improve
our skills through practice: with training, the ability to play
tennis, for example, will improve. Declarative memory and
procedural memory are independent: there are patients with
impaired declarative memory whose procedural memory is completely
normal. Because of this fact, current researchers believe there
must be separate mechanisms for each type of memory, and that
these separate mechanisms probably also require separate brain
areas as well.
2) The *cerebrum and *hippocampus are considered important for
declarative memory, and the *cerebellum is considered important
for procedural memory. The current belief is that memory requires
alterations in the brain. The most popular candidate site for
memory storage is the *synapse, where nerve cells communicate
with each other. A change in the transmission efficacy at the
synapse (called "synaptic plasticity") has been considered to be
the cause of memory, and a particular pattern of synaptic usage
or stimulation (conditioning stimulation) is believed to induce
synaptic plasticity. Many questions remain to be answered, such
as how synaptic plasticity is induced and how synaptic plasticity
is implicated in learning and memory.
3) One current frontier in the study of synaptic plasticity is
the attempt to clarify the role of plasticity in learning and
memory. The strategy has been to examine the correlation between
synaptic plasticity and learning by inhibiting the plasticity in
a living animal. To do this, investigators have used inhibitors
for certain molecules that are apparently required for synaptic
plasticity. Another set of useful tools involves genetically
engineered mutant mice, such as "knockout" and transgenic mice. A
"knockout" mouse is a mutant mouse that is deficient in a
specific native molecule. By using mutant mice, the relationship
between synaptic plasticity and learning ability has been
examined in detail.
Proc. Nat. Acad. Sci. 2000 97:12403
Notes:
... ... *cerebrum: What is called the "cerebrum" is the bulk of
brain as seen by the naked eye, the "great ravelled knot" that
sits on top of the phylogenetically older parts (brainstem and
midbrain) of the whole brain. The surface of the cerebrum, an
enormously extended surface because of the many deep folds of the
cerebrum, is a thin sheet called the "cerebral cortex" (cortex =
rind or bark).
... ... *hippocampus: A region of the cerebral cortex in the
*medial part of the temporal lobe. In humans, among other
functions, the hippocampus is apparently involved in short-term
memory, and analysis of the neurological correlates of learning
behavior in animals indicates that the hippocampus is also
involved in memory in other species.
... ... *cerebellum: The human cerebellum is about the size of a
large apple, is placed at the lower back of the head under the
optic lobes of the cerebrum, and is apparently involved in the
input-output control of automatic sensorimotor functions. If you
are sitting at your breakfast table, holding a newspaper in one
hand, and using the other hand to routinely and repetitively dip
a spoon into cold cereal and bring the cold cereal to your mouth
while you read the newspaper, it is the cerebellum which is
governing the automatic feeding movements while your cerebral
cortex processes the information that you read.
... ... *synapse: In general, nerve cells have a single long
extension (the "axon") that propagates the electrical output (the
action potential) of the cell. The term "synapse" refers to the
junction between the terminal of a neuron's axon and another
neuron. When studying the synapse, the first neuron is called the
"presynaptic" neuron, and the second neuron is called the
"postsynaptic" neuron.
Related Background:
NEUROBIOLOGY: ON THE BIOLOGICAL BASIS OF MEMORY
Exactly 100 years ago, two psychologists, G.E. Mueller and A.
Pilzecker, proposed what came to be called the perseveration-
consolidation hypothesis of memory. In studies with human
subjects, Mueller and Pilzecker found that memory of newly
learned information was disrupted by the learning of other
information shortly after the original learning, and they
suggested that processes underlying new memories initially
persist in a fragile state and then consolidate over time. This
consolidation hypothesis still guides research, particularly
research in neurobiology on the time-dependent involvement of
neural systems and cellular processes enabling lasting memory.
At the present time, the concept of "synaptic plasticity"
underlies nearly all theories of memories, the term referring to
changes in the behavior of the junction (synapse) between two
nerve cells resulting from past history. Two prominent aspects of
synaptic plasticity considered to be related to memory are
"facilitation" and "potentiation". The term "facilitation" refers
to a progressive increase in the amount of *neurotransmitter
substance released at a synapse by successive nerve impulses
(action potentials), the increase occurring during an input
barrage consisting of repetitive stimulation (stimulus train).
The term "potentiation" refers to an increase in neurotransmitter
substance released by an action potential following repetitive
stimulation of a synapse. Both facilitation and potentiation can
be long-lasting, and "long-term potentiation" has been a focus of
much research on the cellular basis of memory, particularly in
the hippocampus, a brain cortex structure in the medial part of
the temporal lobe. In humans, among other functions, the
hippocampus is apparently involved in short-term memory, and
analysis of the neurological correlates of learning behavior in
the rat indicates that the hippocampus of the rat is also
involved in memory.
James L. McGaugh (University of California Irvine, US) presents a
review of current research on memory, the author suggesting the
following caveats concerning the present state of the field:
1) The author points out that the idea that synaptic mechanisms
of long-term potentiation and long-term facilitation underlie
memory remains a hypothesis.
2) The author points out that although studies of long-term
potentiation and memory have focused on the involvement of the
hippocampus, much evidence indicates that the hippocampus has
only a time-limited role in the consolidation and/or
stabilization of lasting memory.
3) The author points out that there are forms of memory that
apparently do not involve the hippocampus and that may not use
any known mechanisms of synaptic plasticity.
4) The author points out that despite theoretical conjectures,
little is known about system and cellular processes mediating
consolidation that continues for several hours or longer after
learning, consolidation that creates lifelong
memories.
Concerning the above caveats, the author concludes: "These issues
remain to be addressed in this new century of research on memory
consolidation."
Science 14 Jan 00 287:248
Notes:
... ... *neurotransmitter substance: Neurotransmitters are
chemical substances released at the terminals of nerve axons in
response to the propagation of an impulse to the end of that
axon. The neurotransmitter substance diffuses into the synapse,
the junction between the presynaptic nerve ending and the
postsynaptic neuron, and at the membrane of the postsynaptic
neuron the transmitter substance interacts with a receptor.
Depending on the type of receptor, the result may be an
excitatory or an inhibitory effect on the postsynaptic nerve
cell.
Related Background:
ON THE BIOLOGICAL SUBSTRATES OF MEMORY FORMATION
The capacity of the nervous system to change (often referred to
as neural or brain "plasticity") is particularly prominent during
development, but the ability to learn new skills and establish
new memories clearly continues throughout life. The central
question is simply stated: How does the adult nervous system
mediate such changes? An understanding of the mechanisms
responsible for learning and other plastic changes in the adult
brain continues to be one of the most important challenges of
neuroscience, with a great deal of devoted research effort in
many laboratories in a number of associated disciplines. At the
present time, after nearly a century of research, there is a
consensus among investigators that the mechanisms of memory
formation involve carefully regulated changes in the strength of
existing connections between nerve cells (*synapses). Experiments
carried out in a variety of animals have demonstrated that
synaptic strength can be altered over periods ranging from
milliseconds to months, and that the cellular mechanisms
underlying these changes are transient modifications of the
transmission of activity from one nerve cell to another
(*neurotransmission) and, in the case of longer-lasting
alterations, changes in *gene expression.
Jerry Chi-Ping Yin (Cold Spring Harbor Laboratories, US) presents
a review of current research on the localization of memory
functions, the author making the following points:
1) Concerning investigations of memory localization at the
anatomical systems level, Karl Lashley (1890-1958) used
anatomical lesions in the rat brain to search for the memory
"engram", the physical locus of long-term memory. Over a 30-year
period, Lashley performed surgical removal ("ablations") of
various regions in the rat *cerebral cortex, and came to the
disappointing view that no single well-defined lesion could
totally disrupt learning and memory formation [*Note #1]. This
resulted in the general hypothesis that memories are distributed
throughout the brain. Beginning in the late 1930s, however,
Wilder Penfield (1891-1976), in the course of neurosurgical
procedures for the treatment of human epilepsy, electrically
stimulated the temporal cortex of patients and caused them to
experience extremely vivid "memories" [*Note #2]. These
observations led Penfield to conclude that memories are
localized. Recent studies using non-invasive brain imaging,
coupled with refined animal ablation studies, have led to the
contemporary view that interacting widely distributed networks of
neurons participate in memory formation. A complication is the
apparent existence of functional redundancy ("backup" circuits)
and the possibility that different anatomical regions may be used
at different times after memory formation.
2) Concerning investigations of memory localization at the
cellular level, neurophysiologists during the second half of this
century have developed a conceptual framework involving activity
dependent strengthening of neuronal connections. The search for
the loci of memory formation has become reduced to a search for
mechanisms that strengthen synaptic connectivity. The current
favorite cellular model for learning and memory formation is
"long-term potentiation", a physiological description of
increased synaptic efficacy following high-frequency stimulation.
A continuing controversy is whether the primary locus of changes
is on the pre- or post-synaptic side of the synapse. Proponents
of presynaptic change suggest that potentiation results from
changes in the amount of *transmitter release through one of many
possible mechanisms. Advocates of postsynaptic change propose
alterations in the efficiency of *receptor activation, perhaps
modulated through the "unmasking" of silent synapses.
3) Concerning investigations of memory localization at the
molecular level, recent insights have been made into key
molecules whose activity apparently affects the process of memory
formation. These studies highlight two different uses of the term
"location": a) the various subcellular compartments where
important molecular entities are located; b) the changes in
specific protein amino-acid-residues produced by *post-
translational modification. In both cases, the activity and
interactions of important proteins are involved. At the present
time, there are at least 4 major *kinase systems believed to be
involved in memory formation: a) the *cyclic-AMP (cAMP)-dependent
protein kinase (protein kinase A); b) the *calcium-calmodulin
kinases; c) the *protein kinase C family; and d) the *mitogen-
activated protein (MAP) kinase pathway. The subcellular
localization of these kinases are apparently all regulated
through interactions with other proteins.
Proc. Nat. Acad. Sci. 1999 96:9985
Notes:
... ... *synapses: In general, nerve cells have a single long
extension (the "axon") that propagates the electrical output (the
action potential) of the cell. The term "synapse" refers to the
junction between the terminal of a neuron's axon and another
neuron. When studying the synapse, the first neuron is called the
"presynaptic" neuron, and the second neuron is called the
"postsynaptic" neuron.
... ... *neurotransmission: The term "neurotransmission" refers
to all the events at a synapse, particularly the release of
"neurotransmitters" and their action on the postsynaptic neuron.
Neurotransmitters are chemical substances released at the
terminals of nerve axons in response to the propagation of an
impulse to the end of that axon. The neurotransmitter substance
diffuses into the synapse, the junction between the presynaptic
nerve ending and the postsynaptic neuron, and at the membrane of
the postsynaptic neuron the transmitter substance interacts with
a receptor. Depending on the type of receptor, the result may be
an excitatory or an inhibitory effect on the postsynaptic nerve
cell.
... ... *gene expression: In general, the term "gene expression"
includes any gene activity, but particularly an activity that
produces the synthesis or activation of a specific protein.
... ... *cerebral cortex: (cortex) The cerebral cortex is a thin
surface layering of nerve cells of the brain, the region only
several millimeters thick but covering all of the brain surface.
This is the part of the central nervous system most intimately
involved with the so-called "higher faculties", although the
cortex operates in concert with other parts of the brain. The
structure is primitive in lower mammals, and is found
progressively more pronounced and with greater surface area in
primates and man.
... ... *Note #1: Lashley's failure to localize memory in a
specific region of the mammalian cerebral cortex was one of the
great puzzles of the middle part of the 20th century. In 1950,
Lashley wrote: "This series of experiments... has discovered
nothing directly of the real nature of the engram. I sometimes
feel, in reviewing the evidence on the localization of the memory
trace, that the necessary conclusion is that learning just is not
possible."
... ... *Note #2: The observations that came out of Penfield's
surgery and laboratory at McGill University had dramatic
theoretical consequences in psychology and neurobiology.
Penfield, a neurosurgeon with training in physiology who
specialized in therapeutic surgery in the treatment of certain
forms of epilepsy, used electrical currents to stimulate the
surface of the brain. The therapeutic objective was to make a
brain map for that particular patient prior to deciding exactly
which damaged parts of the brain could be safely removed without
producing problems more severe than the epileptic condition. The
technique had been developed in 1909 by the neurosurgeon Harvey
Cushing. Penfield's research on the neurological basis of
language and long-term memory, much of it in collaboration with
Herbert Jasper and Lamar Roberts, revolutionized the concepts of
brain maps that existed in the 1950s.
... ... *transmitter release: (neurotransmitter release) See
above: "neurotransmission".
... ... *receptor activation: In this context, the term
"receptor" refers to postsynaptic membrane receptors.
... ... *post-translational modification: In this context,
translation is protein synthesis, the process during which
polypeptides are synthesized on ribosomes in accordance with RNA
code. The term "post-translational modification" refers to a
modification of protein that occurs after synthesis of that
protein, i.e., the modification is not a result of changes in the
DNA or RNA coding for that protein.
... ... *kinase: In general, a "kinase" is any enzyme involved in
the transfer of a phosphate group.
... ... *cyclic-AMP (cAMP): Cyclic adenosine monophosphate (cAMP)
is an important postsynaptic intracellular substance activated by
incoming synaptic activity, a "messenger" involved in various
aspects of cell regulation and protein synthesis.
... ... *calcium-calmodulin kinases: Calmodulin is a calcium-ion-
binding protein that mediates many of the regulatory effects of
calcium ions in eukaryotic cells (cells with organelles such as
nuclei). A "calcium-calmodulin kinase" is a kinase enzyme whose
activity is dependent on the presence of calcium-calmodulin.
... ... *protein kinase C family: (PKC family) Any of a family of
protein kinase enzymes that require anionic phospholipid for
activity and are regulated by diacylglycerol and calcium ion.
These enzymes phosphorylate hydroxyl groups in substrate serine
and threonine residues.
... ... *mitogen-activated protein (MAP) kinase: A family of
protein kinases that perform a crucial step in relaying signals
from the plasma membrane to the cell nucleus. They are activated
by a wide range of proliferation- or differentiation-inducing
signals. (A "mitogen" is any compound that stimulates mitotic
cell division.)
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2. SYNAPTIC PLASTICITY
The term "synaptic plasticity" refers to a changeability of
synaptic connections and/or the efficacy of particular
connections. The term "Hebbian modification", named after the
neuropsychologist Donald O. Hebb, refers to the "Hebbian rule"
(first postulated by Hebb in 1949) that essentially states that
when one nerve cell repeatedly activates another nerve cell,
changes involving growth or metabolism occur in one or both nerve
cells that increase the efficiency of the activation.
DYNAMICAL MODEL OF LONG-TERM SYNAPTIC PLASTICITY
H.D. Arbarbanel et al (Scripps Institute, US) discuss synaptic
plasticity, the authors making the following points:
1) Investigations of long-term synaptic plasticity have revealed
many striking results over the past two decades. The intense
interest in this feature of nervous systems comes in part from
the fact that these phenomena are widely held to underlie
learning and memory. It is known from recent experiments that the
precise timing of pre- and postsynaptic activity is important for
long-term potentiation (LTP) and long-term depression (LTD) (1-
4). Spikes initiate a sequence of complex biochemical processes
during a short time window after synaptic activation at the
postsynaptic side. Identifying the detailed molecular processes
underlying LTP and LTD remains a complex and challenging problem.
2) It is widely accepted that N-methyl-D-aspartate (NMDA)
receptors are crucial for the development of LTP or LTD. NMDA-
dependent activity determines Ca2+ concentrations in the
postsynaptic cell. The Bienenstock, Cooper, and Munro rule (5)
describes the synaptic plasticity process as a function of
postsynaptic activity presumed to be connected to Ca2+
concentration. Modest activity induces LTD, whereas strong
activation produces LTP. On the basis of this idea, models of
calcium-dependent synaptic plasticity that describe the
experimental data with a fixed set of parameters have been
proposed. Different theoretical hypotheses have also been
suggested, for example, a learning algorithm for regulating
neurotransmitter release probability.
3) In summary: Long-term synaptic plasticity leading to
enhancement in synaptic efficacy (long-term potentiation, LTP) or
decrease in synaptic efficacy (long-term depression, LTD) is
widely regarded as underlying learning and memory in nervous
systems. LTP and LTD at excitatory neuronal synapses are observed
to be induced by precise timing of pre- and postsynaptic events.
Modification of synaptic transmission in long-term plasticity is
a complex process involving many pathways; for example, it is
also known that both forms of synaptic plasticity can be induced
by various time courses of Ca2+ introduction into the
postsynaptic cell. The authors present a phenomenological
description of a two-component process for synaptic plasticity.
Their dynamical model reproduces the spike time-dependent
plasticity of excitatory synapses as a function of relative
timing between pre- and postsynaptic events, as observed in
recent experiments. The model accounts for LTP and LTD when the
postsynaptic cell is voltage clamped and depolarized (LTP) or
hyperpolarized (LTD) and no postsynaptic action potentials are
evoked. The authors are also able to connect their model with the
Bienenstock, Cooper, and Munro rule. The authors provide model
predictions for changes in synaptic strength when periodic spike
trains of varying frequency and Poisson distributed spike trains
with varying average frequency are presented pre- and
postsynaptically. When the frequency of spike presentation
exceeds 30-40 Hz, only LTP is induced.
References (abridged):
1. Markram, H. , Lubke, J. , Frotscher, J. & Sakmann, B. (1997)
Science 275, 213-215.
2. Bi, G. & Poo, M.-m. (1998) J. Neurosci. 18, 10464-10472.
3. Bi, G. & Poo, M.-m. (2001) Annu. Rev. Neurosci. 24, 139-166.
4. Feldman, D. (2000) Neuron 27, 45-46.
5. Bienstock, E. L. , Cooper, L. N. & Munro, P. W. (1982) J.
Neurosci. 2, 32-48.
Proc. Nat. Acad. Sci. 2002 99:10132
Related Background:
REGULATION OF SYNAPTIC EFFICACY BY COINCIDENCE OF POSTSYNAPTIC
APS AND EPSPS
H. Markram et al (Max-Planck-Institut fuer Medizinische, DE)
discuss synaptic plasticity, the authors making the following
points:
1) Repetitive activation of neuronal circuits can induce long-
term changes in subsequent responses generated by synapses in
many regions of the brain, and such plasticity of synaptic
connections is regarded as a cellular basis for developmental and
learning-related changes in the central nervous system (1,2). The
actual triggers for synaptic modifications between two neurons
are, however, unclear (3). Postsynaptic APs are initiated in the
axon and then propagate back into the dendritic arbor of
neocortical pyramidal neurons (4), evoking an activity-dependent
dendritic Ca2+ influx (5) that could be a signal to induce
modifications at the dendritic synapses that were active around
the time of AP initiation. To test this hypothesis, the authors
made dual whole-cell voltage recordings from neighboring, thick,
tufted pyramidal neurons in layer 5 of the neocortex for which
the dendritic locations of synaptic contacts were known, and the
authors investigated whether the postsynaptic AP could induce
changes in unitary EPSP amplitudes.
2) In summary: Activity-driven modifications in synaptic
connections between neurons in the neocortex may occur during
development and learning. In dual whole-cell voltage recordings
from pyramidal neurons, the coincidence of postsynaptic action
potentials (APs) and unitary excitatory postsynaptic potentials
(EPSPs) was found to induce changes in EPSPs. Their average
amplitudes were differentially up- or down-regulated, depending
on the precise timing of postsynaptic APs relative to EPSPs. The
authors suggest these observations indicate that APs propagating
back into dendrites serve to modify single active synaptic
connections, depending on the pattern of electrical activity in
the pre- and postsynaptic neurons.
References (abridged):
1. D. O. Hebb, The Organization of Behavior (Wiley, New York,
1949).
2. T. V. P. Bliss and G. L. Collingridge, Nature 361, 31 (1993).
3. M. J. Friedlander, R. J. Sayer, S. J. Redman, J. Neurosci. 10,
814 (1990); R. Malinow, Science 252, 722 (1991); V. Y. Bolshakov
and S. A. Siegelbaum, ibid. 269, 1730 (1995); C. Stricker, A. C.
Field, S. J. Redman, J. Physiol. 490, 443 (1996).
4. G. Stuart and B. Sakmann, Nature 367, 69 (1994).
5. W. G. Regehr, J. A. Connor, D. W. Tank, ibid. 341, 533 (1989);
H. Markram, P. J. Helm, B. Sakmann, J. Physiol. 485, 1 (1995); J.
Schiller, F. Helmchen, B. Sakmann, ibid. 487, 583 (1995) ; F.
Helmchen, K. Imoto, B. Sakmann, Biophys. J. 70, 1069 (1996).
Science 1997 275:213
Related Background Brief:
SYNAPTIC MODIFICATIONS IN CULTURED HIPPOCAMPAL NEURONS:
DEPENDENCE ON SPIKE TIMING, SYNAPTIC STRENGTH, AND POSTSYNAPTIC
CELL TYPE. In cultures of dissociated rat hippocampal neurons,
persistent potentiation and depression of glutamatergic synapses
were induced by correlated spiking of presynaptic and
postsynaptic neurons. The relative timing between the presynaptic
and postsynaptic spiking determined the direction and the extent
of synaptic changes. Repetitive postsynaptic spiking within a
time window of 20 msec after presynaptic activation resulted in
long-term potentiation (LTP), whereas postsynaptic spiking within
a window of 20 msec before the repetitive presynaptic activation
led to long-term depression (LTD). Significant LTP occurred only
at synapses with relatively low initial strength, whereas the
extent of LTD did not show obvious dependence on the initial
synaptic strength. Both LTP and LTD depended on the activation of
NMDA receptors and were absent in cases in which the postsynaptic
neurons were GABAergic in nature. Blockade of L-type calcium
channels with nimodipine abolished the induction of LTD and
reduced the extent of LTP. The authors suggest these results
underscore the importance of precise spike timing, synaptic
strength, and postsynaptic cell type in the activity-induced
modification of central synapses and indicate that Hebb's rule
may need to incorporate a quantitative consideration of spike
timing that reflects the narrow and asymmetric window for the
induction of synaptic modification. G-Q Bi and M-M Poo: J.
Neurosci. 1998 18:10464.
Related Background:
SYNAPTIC MODIFICATION BY CORRELATED ACTIVITY: HEBB'S POSTULATE
REVISITED
G-Q. Bi and M-M. Poo (University of California Berkeley, US)
discuss synaptic plasticity, the authors making the following
points:
1) In 1949, the psychologist Donald O. Hebb wrote: "When an axon
of cell A is near enough to excite cell B or repeatedly or
consistently takes part in firing it, some growth or metabolic
change takes place in one or both cells such that A's efficiency,
as one of the cells firing B, is increased." [D.O. Hebb: The
Organization of Behavior. Wiley 1949.]
2) Half a century since the publication of his famous treatise,
Hebb's postulate of synaptic modification by correlated activity
has become a cornerstone in our understanding of activity-
dependent neural development and the cellular basis of learning
and memory. This postulate was originally proposed by Hebb as a
mechanism for the growth of "cell assembly", a hypothetical group
of neurons that act briefly as a closed system after stimulation
has ceased and that serve for the first stage of perception. Over
the past several decades, Hebb's idea has been extended into
various forms of correlation-based rules for synaptic
modification and successfully used in many learning networks and
in the analysis of activity-driven refinement of developing
circuits.
3) A central feature of Hebb's postulate is temporal specificity:
The synaptic connection is strengthened only if cell A "takes
part in firing" cell B, i.e. cell A fires before cell B. Such
temporal specificity of activity-induced synaptic modification
may be relevant for physiological functions, such as learning and
memory, which are known to be temporally specific. Early studies
have demonstrated a requirement for temporal contiguity in
associative synaptic modification in rat hippocampus and Aplysia
ganglia. Recent experiments have revealed the importance of the
temporal order of pre- and postsynaptic spiking for synaptic
modification and have further defined the "critical windows" of
spike timing, with precision on the order of milliseconds. The
precise profile of critical windows appears to depend on the
synapse type, and the underlying molecular mechanisms remain to
be fully understood.
4) In summary: Correlated spiking of pre- and postsynaptic
neurons can result in strengthening or weakening of synapses,
depending on the temporal order of spiking. Recent findings
indicate that there are narrow and cell type specific temporal
windows for such synaptic modification and that the generally
accepted input- (or synapse-) specific rule for modification
appears not to be strictly adhered to. Spike timing dependent
modifications, together with selective spread of synaptic
changes, provide a set of cellular mechanisms that are likely to
be important for the development and functioning of neural
networks.
Annu. Rev. Neurosci. 2001 24:139
Related Background Brief:
THEORY FOR THE DEVELOPMENT OF NEURON SELECTIVITY: ORIENTATION
SPECIFICITY AND BINOCULAR INTERACTION IN VISUAL CORTEX. The
development of stimulus selectivity in the primary sensory cortex
of higher vertebrates is considered in a general mathematical
framework. A synaptic evolution scheme of a new kind is proposed
in which incoming patterns rather than converging afferents
compete. The change in the efficacy of a given synapse depends
not only on instantaneous pre- and postsynaptic activities but
also on a slowly varying time-averaged value of the postsynaptic
activity. Assuming an appropriate nonlinear form for this
dependence, development of selectivity is obtained under quite
general conditions on the sensory environment. One does not
require nonlinearity of the neuron's integrative power nor does
one need to assume any particular form for intracortical
circuitry. This is first illustrated in simple cases, e.g., when
the environment consists of only two different stimuli presented
alternately in a random manner. The following formal statement
then holds: the state of the system converges with probability 1
to points of maximum selectivity in the state space. The authors
next consider the problem of early development of orientation
selectivity and binocular interaction in primary visual cortex.
Giving the environment an appropriate form, the authors obtain
orientation tuning curves and ocular dominance comparable to what
is observed in normally reared adult cats or monkeys. Simulations
with binocular input and various types of normal or altered
environments show good agreement with the relevant experimental
data. Experiments are suggested that could test this theory
further. E.L. Bienenstock et al: J. Neurosci. 1982 2:32.
Related Background Brief:
A BIOPHYSICAL MODEL OF BIDIRECTIONAL SYNAPTIC PLASTICITY:
DEPENDENCE ON AMPA AND NMDA RECEPTORS. In many regions of the
brain, including the mammalian cortex, the magnitude and
direction of activity-dependent changes in synaptic strength
depend on the frequency of presynaptic stimulation (synaptic
plasticity), as well as the history of activity at those synapses
(metaplasticity). The authors present a model of a molecular
mechanism of bidirectional synaptic plasticity based on the
observation that long-term synaptic potentiation (LTP) and long-
term synaptic depression (LTD) correlate with the
phosphorylation- dephosphorylation of sites on an acid receptor
of subunit protein GluR1. The primary assumption of the model,
for which there is wide experimental support, is that
postsynaptic calcium concentration and consequent activation of
calcium-dependent protein kinases and phosphatases are the
triggers for the induction of LTP/LTD. As calcium influx through
the n-methyl-D-aspartate (NMDA) receptor plays a fundamental role
in the induction of LTP/LTD, changes in the properties of NMDA
receptor-mediated calcium influx will dramatically affect
activity-dependent synaptic plasticity (metaplasticity). The
authors demonstrate that experimentally observed metaplasticity
can be accounted for by activity-dependent regulation of NMDA
receptor subunit composition and function. This model produces a
frequency-dependent LTP/LTD curve with a sliding synaptic
modification threshold similar to what has been proposed
theoretically by Bienenstock, Cooper, and Munro and observed
experimentally. G.C. Castellani et al: Proc. Nat. Acad. Sci.
2001 98:12772.
Related Background:
ON THE PLASTICITY OF SYNAPSES
M. Sur et al (Massachusetts Institute of Technology, US) discuss
synaptic plasticity, the authors making the following points:
1) An important and difficult task in neuroscience is to
integrate knowledge of the rules governing the behavior of single
neurons studied in reduced systems into our understanding of the
behaviors of networks of neurons in an intact brain. From work on
reduced preparations, such as cultured neurons and brain slices,
numerous forms of synaptic plasticity have been described and
their properties characterized. In recent years, rules for
changing synaptic efficacy based on the precise timing of
presynaptic and postsynaptic activity, on the scale of tens of
milliseconds, have been revealed at several synapses in the
central nervous system (CNS). This spike-timing-dependent
plasticity has several properties which are desirable, on
theoretical grounds, for transforming changes in environmental
inputs into changes in neural representations. The implementation
of such a "learning rule" in functional neural circuits has been
largely limited to theoretical work, because of the technical
difficulty of observing and controlling synaptic activity in the
intact brain at an adequate spatial and temporal resolution.
Whether spike-timing-dependent plasticity is instantiated in vivo
has been unclear, but recent studies [1,2] have demonstrated its
role in the intact cortex using similar, but complementary,
approaches.
2) Experiments in a number of systems have shown that the
strength of synaptic transmission can be modified up or down
depending on the precise timing of presynaptic and postsynaptic
activity [3,4]. When presynaptic activity repeatedly precedes
postsynaptic activity by 5 20 milliseconds, a synapse will
undergo a long-lasting (approximately 30 60 minute) increase in
strength; when the temporal order of pairing is reversed, a long-
lasting depression of synaptic strength ensues. The functional
consequence of this "learning rule" is that synapses from a
presynaptic neuron which contribute to the firing of the
postsynaptic neuron will be strengthened, whereas synapses which
are uncorrelated or anti-paired with postsynaptic spike times
will tend to be weakened. Such a rule for the modification of
synaptic weights expands current thinking about "Hebbian rules"
governing the development of sensory cortex and its plasticity in
the mature brain (for an interesting computational analysis of
how spike-timing-dependent rules can explain synaptic plasticity
and cortical maps, see [5]).
3) The primary visual cortex (V1) of the mammalian brain has been
a rich proving ground for work on the experience-dependent
development and plasticity of functional cortical circuits. The
responses of V1 neurons are selective for the orientation of
lines presented in their receptive fields . V1 contains a map of
orientation preference, such that neurons sharing the same
orientation preference are grouped together, with the preferred
orientation changing gradually across expanses of the cortex.
This selectivity presumably arises from the specific arrangement
of thalamic and cortical synaptic inputs a neuron receives. By
selectively manipulating these inputs, either pharmacologically
or by altering the visual inputs to developing or adult brains,
one can change the selectivity of the responses of neurons and
the structure of the orientation map.
4) In summary: Recent studies have tested whether synaptic
learning rules, inferred earlier from work on cell cultures and
brain slices, apply in intact brains. The evidence indicates that
they do, and reveals interesting implications for brain
development and perceptual learning.
References (abridged):
1. Schuett S., Bonhoeffer T. and Hubener M. (2001) Pairing-
induced changes of orientation maps in cat visual cortex. Neuron,
32:325-337
2. Yao H. and Dan Y. (2001) Stimulus timing-dependent plasticity
in cortical processing of orientation. Neuron, 32:315-323
3. Markram H., Lubke J., Frotscher M. and Sakmann B. (1997)
Regulation of synaptic efficacy by coincidence of postsynaptic
APs and EPSPs. Science, 275:213-215
4. Zhang L.I., Tao H.W., Holt C.E., Harris W.A. and Poo M. (1998)
A critical window for cooperation and competition among
developing retinotectal synapses. Nature, 395:37-44
5. Song S., Miller K.D. and Abbott L.F. (2000) Competitive
Hebbian learning through spike-timing-dependent synaptic
plasticity. Nat. Neurosci., 3:919-926
Current Biology 2002 12:R168
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3. LEARNING AND MEMORY: EVOLUTIONARY ASPECTS
ON LEARNING AND MEMORY IN INVERTEBRATES
The capacity to store and recall information, is a necessary
component of learning. Animals as low on the evolutionary scale
as the flatworms (Planaria can show classical conditioning, which
implies that there is a memory mechanism present. Whether this is
distributed throughout the peripheral nerves or body cells of
this animal, as some of the more sensational experiments imply,
is still a controversial question. In higher invertebrates and
vertebrates, it is clear that memory mechanisms related to
behavioral experiences depend on the brain.
The octopus has the largest brain among the invertebrates. It
also has highly developed eyes and a highly developed tactile
system in its tentacles. J.Z. Young (1907-1997) and his
colleagues in London showed that the octopus can readily learn
visual discrimination tasks, such as distinguishing between
vertical and horizontal lines. By making ablations of different
parts of the brain, they showed that visual memory is stored in
the vertical lobe. Octopuses can also learn tactile
discriminations with their tentacles (though they cannot learn
proprioceptive discriminations). It was found that tactile
memories are stored in the octopus inferior frontal and
subfrontal lobes. Thus, the visual and tactile memory systems are
mostly separate, though there is some overlap in the vertical
lobe.
This separation of memory systems is more distinct than is the
case in vertebrates, at least as far as is known at present. The
vertical lobe of the octopus is packed with millions of very
small neurons; many of these lack axons, and thus appear to form
microcircuits by means of dendrodendritic interactions. Young
(1978) hypothesized that these "microneurons" are crucial for
memory, and that during learning they inhibit unwanted pathways,
leaving others open to be used selectively in the learned task.
Adapted from: Gordon M. Shepherd: Neurobiology. 2nd Ed. Oxford
University Press 1988, p.604.
EXPERIMENTAL EVOLUTION OF LEARNING ABILITY IN FRUIT FLIES
F. Mery and T.J. Kawecki (University of Fribourg, CH) discuss the
evolution of learning ability, the authors making the following
points:
1) Learning ability is known to respond readily to direct
artificial selection on a particular conditioned behavior (1-5).
In such experiments the conditionability of the focal behavior is
the sole criterion that determines whether an individual is
allowed to breed. However, in natural populations learning and
memory may entail fitness costs, if only because of the energy
needed to maintain neuronal information and underlying
structures. It remains unclear how readily learning evolves under
natural selection, when its contribution to reproductive success
is indirect and has to be set against its potential costs.
2) To address this issue, the authors kept populations of
Drosophila melanogaster under ecological conditions expected to
favor the evolution of learning ability in the context of
oviposition substrate choice. The choice of a suitable
oviposition substrate is an ecologically important decision with
a direct impact on fitness. It may be modified by experience
because in nature Drosophila females lay eggs over extended time,
potentially on many different substrates, which are also fed on
by the adults. They can thus assess the quality of the
oviposition medium, which, together with relatively well
developed associative memory, opens an opportunity for learning
to contribute to Darwinian fitness.
3) In summary: The presence of genetic variation for learning
ability in animals opens the way for experiments asking how and
under what ecological circumstances improved learning ability
should evolve. The authors report experimental evolution of
learning ability in Drosophila melanogaster. The authors exposed
experimental populations for 51 generations to conditions
expected to favor associative learning with regard to oviposition
substrate choice. Flies that learned to associate a chemical cue
(quinine) with a particular substrate, and still avoided this
substrate several hours after the cue had been removed, were
expected to contribute more alleles to the next generation. From
about generation 15 on, the experimental populations showed
marked ability to avoid oviposition substrates that several hours
earlier had contained the chemical cue. The improved response to
conditioning was also expressed when the flies were faced with a
choice of novel media. The authors demonstrate that these
behavioral changes are caused by the evolution of both a higher
learning rate and a better memory.
References (abridged):
1. Tryon, R. C. (1940) Yk. Natl. Soc. Stud. Educ. 39, 111-119.
2. McGuire, T. R. & Hirsch, J. (1977) Proc. Natl. Acad. Sci. USA
74, 5193-5197.
3. Brandes, C. , Frisch, B. & Menzel, R. (1988) Anim. Behav. 36,
981-985.
4. Lofdahl, K. L. , Holliday, M. & Hirsch, J. (1992) J. Comp.
Psychol. 106, 172-183.
5. Reif, M. , Linsenmair, K. E. & Heisenberg, M. (2002) Anim.
Behav. 63, 143-155.
Proc. Nat. Acad. Sci. 2002 99:14:274.
Related Background:
DISCOVERY OF REMARKABLE MEMORY IN SHEEP
K.M. Kendrick et al (Babraham Institute, UK) discuss memory in
sheep, the authors making the following points:
1) The human brain has evolved specialized neural mechanisms for
visual recognition of faces, which afford us a remarkable ability
to discriminate between, remember, and think about many hundreds
of different individuals. Sheep also recognize and are attracted
to individual sheep and humans by their faces, as they possess
similar specialized neural systems in the temporal and frontal
lobes for assisting in this important social task, including a
greater involvement of the right brain hemisphere.
2) The authors report a demonstration that individual sheep can
remember 50 other different sheep faces for over 2 years, and
that the specialized neural circuits involved maintain selective
encoding of individual sheep and human faces even after long
periods of separation.
3) The authors report they trained 20 sheep (Ovis aries) to
discriminate in a choice maze between pictures showing frontal
views of 25 pairs of sheep faces by associating one member of
each face pair with a food reward. Animals required 30 or more
trials to reach a learning criterion of over 80 percent correct
choice, and were given a further 400 to 500 trials over a period
of 4 to 6 weeks. These latter trials confirmed that these sheep
could also discriminate between profile views of the same
individuals without having to relearn the task. The authors then
tested the sheep for retention of discrimination performance
after delays of up to 800 days. Sheep could still discriminate
accurately between the 25 face pairs at all retention time
points. Only after 601 to 800 days was retesting performance
significantly poorer than final original levels.
Nature 2001 414:165
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4. LEARNING, MEMORY, AND THE HIPPOCAMPUS
OSCILLATORY BRAIN STATES AND LEARNING: IMPACT OF HIPPOCAMPAL
THETA-CONTINGENT TRAINING.
M.A. Seager et al (Miami University Ohio, US) discuss the
hippocampus, the authors making the following points:
1) Classical conditioning of the rabbit's nictitating
membrane/eyeblink response has become a successful model system
for investigating the neural substrates of associative learning.
Eyeblink conditioning is a highly controlled and well-
characterized paradigm that has been adapted for use in a variety
of species (e.g., mice, rats, ferrets, rabbits, cats, monkeys,
and humans). Striking parallels have emerged among species in
terms of both behavioral learning and the neural mechanisms
involved, making data obtained with animals generalizable to
humans and vice versa. For example, lesion and
electrophysiological experiments have revealed major
contributions from the hippocampus and cerebellum during learning
and performance of this task (1-3). To summarize, the cerebellum
apparently contains the critical neural circuitry required for
learning the basic association between the conditioned stimulus
and unconditioned stimulus (US)(4,5), and the hippocampus plays
an important modulatory role; although the hippocampus becomes
essential as the task demands are increased.
2) The basic paradigm involves presenting a neutral conditioned
stimulus (tone or light) followed 250 ms later by a noxious US
(corneal air puff or peri-orbital shock). Initially, the organism
produces only a reflexive unconditioned response (eyeblink) to
the US. However, after repeated pairings of the conditioned
stimulus and US, the conditioned stimulus begins to elicit
anticipatory, conditioned responses (CRs), similar to the
response originally produced only by the US.
3) In summary: Eyeblink classical conditioning is a relatively
simple form of associative learning that has become an invaluable
tool in our understanding of the neural mechanisms of learning.
The authors report that when studying rabbits in this paradigm,
they observed a dramatic modification of learning rate by
conducting training during episodes of either hippocampal theta
or hippocampal non-theta activity as determined by on-line slow-
wave spectral analysis. Specifically, if animals were given
trials only when a computer analysis verified a predominance of
slow-wave oscillations at theta frequencies (3-8 Hz), they
learned in half as many trials as animals trained during non-
theta hippocampal activity (58 vs. 115). The authors suggest this
finding provides important evidence from awake, behaving animals
that supports recent advances in our knowledge of (i) brain sites
and neurobiological mechanisms of learning and memory,
specifically hippocampus and theta oscillations, (ii) the
biological plausibility of current models of hippocampal function
that posit important roles for oscillatory potentials, and (iii)
the design of interfaces between biological and cybernetic
(electronic) systems that can optimize cognitive processes and
performance.
References (abridged):
1. Berger, T. W. , Berry, S. D. & Thompson, R. F. (1986) in The
Hippocampus, eds. Isaacson, R. L. & Pribram, K. H. (Plenum, New
York), Vol. 4, pp. 203-239.
2. Lavond, D. G. , Kim, J. J. & Thompson, R. F. (1993) Annu. Rev.
Psychol. 44, 317-342.
3. Steinmetz, J. E. (1996) in Acquisition of Motor Behavior in
Vertebrates, eds. Bloedel, J., Ebner, T. & Wise, S. (MIT Press,
Cambridge, MA), pp. 89-114.
4. Gruart, A. & Yeo, C. H. (1995) Exp. Brain Res. 104, 431-448.
5. Krupa, D. J. , Thompson, J. K. & Thompson, R. F. (1993)
Science 260, 989-991.
Proc. Nat. Acad. Sci. 2002 99:1616
Related Background:
INTERACTIVE PROCESSING OF SENSORY INPUT AND MOTOR OUTPUT IN THE
HUMAN HIPPOCAMPUS.
C. D. Teschea and J.Karhua (Helsinki University, FI) discuss the
hippocampus, the authors making the following points:
1) A widely held view of brain organization is that the motor
system is activated only after the immediate sensory scene is
fully elaborated in sensory networks. However, recent studies of
visuomotor integration suggest that the motor system may be
intimately involved in the detection of relevant features of the
sensory scene. The final stages of sensory processing involved in
memory encoding and novelty detection occur in hippocampal
structures. The authors suggest that large-scale cognitive
networks also may recruit additional resources from the
hippocampus during sensorimotor integration in humans.
2) Hippocampus and cortico-hippocampal networks have been
traditionally associated with memory encoding. The foremost
function of reciprocal cortico-hippocampal connections is
believed to be the rapid and accurate exchange of information
between sensory cortical areas and hippocampal structures for the
encoding of memory traces and possibly for the immediate
comparison of novel input with stored traces. Hippocampal
structures thus participate in the selection of pertinent
information that needs to be held "online" during the temporal
interval required for a decision or for the performance of an
operation, that is, to working memory. In everyday life, these
functions are exercised during, and often form an inseparable
part of, goal-directed motor activity.
3) The timing of the attentional enhancement of hippocampal
neuronal population responses has been evaluated in humans by
depth electrode recordings performed on neurological patients
and by magnetoencephalographic (MEG) studies performed on normal
subjects. Event-related potentials (ERPs) and fields (ERFs) have
been observed in the medial temporal lobe to attended infrequent
deviants embedded in trains of standard stimuli. Results include
task-dependent ERPs and ERFs at peak latencies of 300 to 600 msec
following auditory, visual, and somatosensory oddballs. However,
the dynamic interactions between motor networks and hippocampal
structures are poorly known.
4) In summary: Recent studies of visuomotor integration suggest
that the motor system may be intimately involved in the detection
of salient features of the sensory scene. The final stages of
sensory processing occur in hippocampal structures. The authors
report they measured human neuromagnetic responses during motor
reaction to an auditory cue embedded in high-speed multimodal
stimulation. The authors suggest their results demonstrate that
large-scale cognitive networks may recruit additional resources
from the hippocampus during sensorimotor integration. Hippocampal
activity from 300 msec before to 200 msec after cued movements
was enhanced significantly over that observed during self-paced
movements. The dominant hippocampal activity appeared equally
synchronized to both sensory input and motor output, consistent
with timing by an intrinsic mechanism, possibly provided by
ongoing theta oscillations.
J. Cognitive Neurosci. 1999 11:424
Related Background Brief:
SINGLE NEURON ACTIVITY IN HUMAN HIPPOCAMPUS AND AMYGDALA DURING
RECOGNITION OF FACES AND OBJECTS. The hippocampus and its
associated structures play a key role in human memory, yet the
underlying neuronal mechanisms remain unknown. The authors report
that during encoding and recognition, single neurons in the
medial temporal lobe discriminated faces from inanimate objects.
Some units responded selectively to specific emotional
expressions or to conjunctions of facial expression and gender.
Such units were especially prevalent during recognition, and the
responses depended on stimulus novelty or familiarity. Traces of
exposure to faces or objects were found a few seconds after
stimulus removal as well as 10 hr later. Some neurons maintained
a record of previous stimulus presentation that was more accurate
than the person's conscious recollection. The authors propose
that the human medial temporal lobe constructs a "cognitive map"
of stimulus attributes comparable to the map of the spatial
environment described in the rodent hippocampus. I. Fried et al:
Neuron 1997 18:753.
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5. LEARNING, MEMORY, AND THE CEREBELLUM
SYNAPSE FORMATION IS ASSOCIATED WITH MEMORY STORAGE IN THE
CEREBELLUM
J.A. Kleim et al (University of Lethbridge, CA) discuss memory
storage in the cerebellum, the authors making the following
points:
1) "For every act of memory, every exercise of bodily aptitude,
every habit, recollection, train of ideas, there is a specific
neural grouping, or co-ordination, of sensations and movement, by
virtue of specific growths in cell junctions." (1)[Bain, A.
(1873) Mind and Body: The Theories of Their Relation (Henry King,
London).
2) The neural circuits critical for the acquisition and
performance of the conditioned eyeblink response are localized to
the cerebellum (2). Information regarding the unconditioned
stimulus (US) and conditioned stimulus (CS) converge within both
the cerebellar cortex and the interpositus nucleus. CS
information is relayed via ponto-cerebellar projections, whereas
US information is relayed via the olivo-cerebellar pathway (2,3).
Although the cerebellar cortex is involved in modulating some
aspects of the conditioned response (CR) (4,5), the interpositus
nucleus is the critical brain structure supporting long-term
retention of the CR (2). Neuronal activity within the
interpositus nucleus is highly correlated with development of the
CR (5), and inactivation of the interpositus prevents both CR
acquisition and performance.
3) Although the locus of the memory trace is clear, the cellular
mechanisms underlying the formation of the CS/US association are
poorly understood. Several mechanisms have been proposed,
including increases in the intrinsic excitability of interpositus
neurons and reduced inhibition via depression of Purkinje cell
activity. The fact that inhibition of specific synaptic enzymes
and neurotransmitter receptors within the interpositus nucleus
impair learning suggests that changes in synaptic function are
involved. Transient changes in enzyme or receptor activity,
however, would seem incapable of supporting the long-term
encoding of the CS/US association. Recent work has shown that
microinjections of a protein synthesis inhibitor into the
interpositus nucleus impairs the acquisition but not the
expression of the CR. This finding suggests that strengthening of
the CS pathway may involve more permanent changes in cell
structure.
4) In summary: The idea that memory is encoded by means of
synaptic growth is not new. However, this idea has been difficult
to demonstrate in the mammalian brain because of both the
complexity of mammalian behavior and the neural circuitry by
which it is supported. The authors examine how eyeblink classical
conditioning affects synapse number within the cerebellum; the
brain region essential for long-term retention of the conditioned
response. Results show eyeblink-conditioned rats to have
significantly more synapses per neuron within the cerebellar
interpositus nucleus than both explicitly unpaired and untrained
controls. Further analysis demonstrates that the increase was
caused by the addition of excitatory rather than inhibitory
synapses. Thus, development of the conditioned eyeblink response
is associated with a strengthening of inputs from precerebellar
nuclei rather than from cerebellar cortex. The authors suggest
these results demonstrate that the modifications of specific
neural pathways by means of synaptogenesis contributes to
formation of a specific memory within the mammalian brain.
References (abridged):
1. Bain, A. (1873) Mind and Body: The Theories of Their Relation
(Henry King, London).
2. Thompson, R. F. (1986) Science 223, 941-947.
3. Steinmetz, J. E. (2000) Behav. Brain Res. 110, 13-24.
4. Lavond, D. G. & Steinmetz, J. E. (1989) Behav. Brain Res. 33,
113-164.
5. Perrett, S. P. , Ruiz, B. P. & Mauk, M. D. (1993) J.
Neurosci. 13, 1708-1718.
Proc. Nat. Acad. Sci. 2002 99:13228
Related Background Brief:
BRAIN SUBSTRATES OF CLASSICAL EYEBLINK CONDITIONING: A HIGHLY
LOCALIZED BUT ALSO DISTRIBUTED SYSTEM. The rabbit classical
nictitating membrane/eyeblink conditioning preparation has proven
highly valuable for delineating neural structures and systems
involved in associative learning. Research conducted over the
last 20 years has revealed that the essential neural circuitry
for acquisition and performance of this simple, learned, motor
response resides in the cerebellum and related brain stem
structures. While this system appears to be highly localized,
many other brain areas are recruited during eyeblink
conditioning. Further, involvement of the cerebellum in
associative learning and memory seems to be limited by certain
parametric conditions present at the time of learning. These data
suggest that classical eyeblink conditioning can also be
characterized as a distributed system. Data in support of the
highly localized, yet distributed nature of the neural systems
involved in classical eyeblink conditioning are presented and
discussed here. J.E. Steinmetz: Behav Brain Res 2000 110:13.
Related Background:
CEREBELLAR CORTEX LESIONS DISRUPT LEARNING-DEPENDENT TIMING OF
CONDITIONED EYELID RESPONSES
S.P. Perrett et al (University of Texas Houston, US) discuss
learning and the cerebellum, the authors making the following
points:
1) Among the many issues surrounding the involvement of the
cerebellum in motor learning, the relative roles of the
cerebellar cortex and cerebellar nuclei in Pavlovian conditioning
have been particularly difficult to assess. While previous
studies have investigated the effects of cerebellar cortex
lesions on the acquisition and retention of conditioned
movements, the authors have examined the effects of these lesions
on the timing of Pavlovian eyelid responses. The rationale for
this approach arises from previous studies indicating that this
timing is a component of Pavlovian eyelid responses that is
learned and that involves temporal discrimination.
2) To permit within-animal comparisons, rabbits were trained to
produce differently timed responses to high- and low-frequency
auditory conditioned stimuli (CSs). Before the lesion the
conditioned responses to both CSs were appropriately timed --
each peaked near the time at which the unconditioned stimulus was
presented for that CS. However, after the lesion both CSs could
elicit similarly timed conditioned responses that peaked
inappropriately at very short latencies. The changes in responses
timing were sensitive to the size of the lesion, particularly its
rostral-caudal extent. Similar results were obtained in animals
trained with one CS, indicating that the disruption of response
timing is not related to impaired auditory discrimination.
3) Because response timing is learned and therefore requires
synaptic plasticity, the authors suggest these data indicate that
there are at least two sites of plasticity involved in the motor
expression of Pavlovian eyelid responses. Plasticity at one site
is necessary for the learned timing of conditioned responses,
while plasticity at another site is revealed by the
inappropriately timed responses observed following removal of the
cerebellar cortex. This lesion-induced dissociation of the
expression of motor responses and their learned timing supports a
synthesis of competing views by suggesting that motor learning
involves both the cerebellar cortex and cerebellar nuclei.
4) The authors hypothesize that motor learning involves a
decrease in strength of the granule cell-Purkinje cell synapses
(e.g., Ito and Kano, 1982) in the cerebellar cortex and an
increase in strength of the mossy fiber-cerebellar nuclei
synapses (e.g., Racine et al., 1986). Finally, the authors
suggest these data indicate that the cerebellar cortex may
mediate the temporal discriminations that are necessary for the
learned timing of conditioned responses.
J. Neurosci. 1993 13:1708
Related Background:
MOTOR LEARNING AND THE CEREBELLUM
R.D. Seidler et al (University of Minnesota, US) discuss the
cerebellum, the authors making the following points:
1) Despite extensive research, the role of the cerebellum in
learning motor skills remains controversial (1,2). The concept of
the cerebellum as a learning machine comes from the theoretical
work of Marr (3) and Albus (4) and has been supported by data
showing that it is essential for adaptive modification of reflex
behavior (5) and is activated during motor learning. However,
learning invariably leads to changes in motor performance, which
in itself can activate the cerebellum. Efforts to deal with the
issue of learning versus performance have required complex
behavioral manipulations, such as subtracting an estimate of the
performance effect.
2) The authors present a learning paradigm in which learning and
performance change are effectively dissociated, using a
modification of the serial reaction time task. Typically,
participants learn the sequence embedded in the serial reaction
time task within a few hundred trials. However, when asked to
perform the task concomitantly with certain distractor tasks,
they show no evidence of sequence learning. When retested upon
removal of this distractor, it is evident that participants did
actually learn the sequence during the initial training.
Therefore, the distractor task served only to suppress
performance change but did not prevent learning, allowing the
determination of the underlying neural substrates for sequence
learning separately from performance.
3) The authors report they performed a functional magnetic
resonance imaging investigation during an implicit, motor
sequence-learning task that was designed to separate the two
processes, the effects of motor learning and changes in
performance. During the sequence-encoding phase, human
participants performed a concurrent distractor task that served
to suppress the performance changes associated with learning.
Upon removal of the distractor, participants showed evidence of
having learned. No cerebellar activation was associated with the
learning phase, despite extensive involvement of other cortical
and subcortical regions. There was, however, significant
cerebellar activation during the expression of learning. The
authors conclude that the cerebellum does not contribute to
learning of the motor skill itself but is engaged primarily in
the modification of performance.
References (abridged):
1. J. R. Bloedel and V. Bracha, Behav. Brain Res. 68, 1 (1995)
2. J. P. Welsh and J. A. Harvey, J. Neurosci. 9, 299 (1989)
3. D. A. Marr, J. Physiol. 202, 437 (1969)
4. J. S. Albus, Math. Biosci. 10, 25 (1971)
5. M. Ito, Annu. Rev. Neurosci. 5, 275 (1982)
Science 2002 296:2043
Related Background Brief:
ON CEREBELLAR LESIONS AND THE NICTITATING MEMBRANE REFLEX.
Unilateral cerebellar lesions abolished the occurrence of
ipsilateral conditioned nictitating membrane responses during the
285 msec interval between onset of the conditioned and
unconditioned stimuli on paired trials. This effect was obtained
in 15 animals sustaining damage to the dorsolateral aspects of
the interpositus nucleus and the adjoining white matter. However,
conditioned responses did occur during the 800 msec observation
interval employed on tone-alone test trials, and these responses
exhibited the classic performance deficits normally associated
with cerebellar damage: a low frequency of occurrence (14%, as
compared with 96% before the lesion); a 3.1 mm decrease in
amplitude; a 236 msec increase in onset latency; a 563 msec
increase in latency of peak amplitude; and a 327 msec increase in
rise time. Four of the 15 animals failed to demonstrate greater
than 5% responding during the test trials. These performance
deficits were not specific to the learned, conditioned response.
Unconditioned responses were also reduced in frequency and
increased in latency of peak amplitude and rise time, especially
when elicited at lower air-puff intensities. These deficits in
the unconditioned response were observed in animals that failed
to exhibit conditioned responses on either paired or test trials,
as well as in animals demonstrating conditioned responses only
during test trials. We conclude that the cerebellum has a general
role in regulating the nictitating membrane reflex so that
deficits in learned responses observed after cerebellar lesions
are secondary to a broader deficit in performance. The
performance deficits appear to consist of a sensory component, as
reflected by an increase in stimulus threshold for elicitation of
the nictitating membrane reflex, and a motor component, as
reflected by the altered topography of the evoked response. The
authors suggest the results of this study reaffirm the role of
the cerebellum in regulating the sensorimotor processes necessary
for the optimal performance of both conditioned and unconditioned
responses and extends this role to the expression of a simple
cranial nerve reflex. JP Welsh and JA Harvey: J. Neurosci 1989
9:299.
Related Background Brief:
ON THE CEREBELLUM AND CLASSICAL EYELID CONDITIONING: Over the
past 10 years, a number of laboratories have reported that
classically conditioned skeletal muscle responses, such as
conditioned nictitating membrane/eyelid responses, are critically
dependent on activity in the cerebellum. For example, unilateral
lesions of the cerebellar interpositus nucleus have been shown to
prevent acquisition and abolish retention of the conditioned
eyelid response on the side ipsilateral to the lesions without
affecting conditioned responding (CR) on the contralateral side.
Also, recording studies involving the interpositus nucleus have
consistently revealed patterns of neuronal discharge that predict
execution of the CR. The lesion and recording studies have
generally been cited as evidence that plasticity in the
cerebellum is critically involved in the learning and memory of
classically conditioned responses. This interpretation was
recently challenged by Welsh and Harvey (1989a), who claimed that
cerebellar lesions simply produced a performance deficit and
speculated that the role of the cerebellum was not in learning
and memory processes associated with the CR but only in
performance of the eye blink response. The authors (Steinmetz et
al) present three experiments that provide additional strong
evidence for a critical role of the cerebellum in the learning
and memory of the Pavlovian CR. These experiments include (1)
demonstrations of complete and permanent CR abolition after
appropriate interpositus lesions, (2) a failure to find
systematic or persisting decrements in the unconditioned response
amplitude (i.e., the eye blink reflex) after appropriate
interpositus lesion, and (3) observations of differential effects
on the CR and unconditioned response after lesions were placed in
populations of motoneurons responsible for executing the eye
blink response. The authors discuss these data in the context of
performance versus learning issues. The authors suggest their
evidence rules out the possibility that interpositus lesion
abolition of the eye blink CR is simply due to lesion effects on
performance. J.E. Steinmetz et al: J. Neurosci 1992 12:4403.
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6. SEX DIFFERENCES, HORMONES, AND MEMORY
SEX DIFFERENCES IN THE NEURAL BASIS OF EMOTIONAL MEMORIES.
T. Canli et al (Stanford University, US) discuss sex differences
and memory, the authors making the following points:
1) Emotionally arousing experiences are more memorable than
neutral experiences. There is superior memory for traumatic
relative to mundane events (1) and for emotionally provocative
relative to neutral words (2) and pictures (3). Memory for
emotional stimuli and experiences differs between the sexes
(4,5). Women recall more emotional autobiographical events than
men in timed tests, produce memories more quickly or with greater
emotional intensity in response to cues, and report more vivid
memories than their spouses for events related to their first
date, last vacation, and a recent argument (4).
2) Two explanations for the difference in memory performance have
been proposed. The "affect-intensity" hypothesis posits that
women have better memory because they experience life events more
intensely than men and thus may better encode such events into
memory (4). Controlling for affect intensity at encoding should
therefore eliminate women's superior memory performance. The
"cognitive-style" hypothesis posits that women may differ from
men in how they encode, rehearse, or think about their affective
experiences or in how they generate responses in a memory test
(5). According to this view, controlling for affect intensity at
encoding should not remove sex-based differences in memory
performance.
3) In summary: Psychological studies have found better memory in
women than men for emotional events, but the neural basis for
this difference is unknown. The authors report they used event-
related functional MRI to assess whether sex differences in
memory for emotional stimuli is associated with activation of
different neural systems in men and women. Brain activation in 12
men and 12 women was recorded while they rated their experience
of emotional arousal in response to neutral and emotionally
negative pictures. In a recognition memory test 3 weeks after
scanning, highly emotional pictures were remembered best, and
remembered better by women than by men. Men and women activated
different neural circuits to encode stimuli effectively into
memory even when the analysis was restricted to pictures rated
equally arousing by both groups. Men activated significantly more
structures than women in a network that included the right
amygdala, whereas women activated significantly fewer structures
in a network that included the left amygdala. Women had
significantly more brain regions where activation correlated with
both ongoing evaluation of emotional experience and with
subsequent memory for the most emotionally arousing pictures.
Greater overlap in brain regions sensitive to current emotion and
contributing to subsequent memory may be a neural mechanism for
emotions to enhance memory more powerfully in women than in men.
References (abridged):
1. Christianson, S.-A. & Loftus, E. F. (1987) Appl. Cogn.
Psychol. 1, 225-239.
2. LaBar, K. S. & Phelps, E. A. (1998) Psychol. Sci. 9, 490-493.
3. Bradley, M. M. , Greenwald, M. K. , Petry, M. C. & Lang, P. J.
(1992) J. Exp. Psychol. Learn. Mem. Cognit. 18, 379-390.
4. Fujita, F. , Diener, E. & Sandvik, E. (1991) J. Pers. Soc.
Pychol. 61, 427-434.
5. Seidlitz, L. & Diener, E. (1998) J. Pers. Soc. Pychol. 74,
262-271.
Proc. Nat. Acad. Sci. 2002 99:11802
Related Background Brief:
SEX DIFFERENCES IN THE RECALL OF AFFECTIVE EXPERIENCES. Three
studies tested hypotheses for sex differences in the recall of
life events: differences in (a) affect intensity at encoding, (b)
affect intensity at retrieval, (c) rehearsal, (d) detail of
encoding, and (e) artifacts such as motivation or verbal ability.
In Study 1 (N = 419), women recalled more positive (p < .01) and
more negative (p < .05) life events than men. Differences in
retrieval mood were not found. Study 2 (N = 55) replicated the
recall differences and showed that neither rehearsal nor
artifacts were responsible. Sex differences in recalling neutral
everyday events also were obtained (p < .05), suggesting that
affect intensity was not responsible. In Study 3 (N = 132),
affective reactions to events were unrelated to recall, but sex
differences in the detail of encoding (p < .001) were related to
recall (p < .05). Sex differences in autobiographical memory are
reliable and may be due to differences in the detail of encoding.
L. Seidlitz and E. Diener: J. Personality & Social Psychol. 1998
74:262.
Related Background:
ON PERINATAL TESTOSTERONE, STRESS, AND ADULT LEARNING.
T.J. Shors and G. Miesegaes (Rutgers University, US) discuss
perinatal testosterone, the authors making the following points:
1) Exposure to sex hormones prenatally and early in development
organizes the brain for many behavior patterns that manifest
throughout adulthood (1-5). Reported changes in behavior tend to
be sexual in nature; i.e., in the presence of ovarian hormones,
adult males castrated at birth will exhibit a posture known as
lordosis that normally occurs in sexually receptive females. In
contrast, females that are briefly exposed to testosterone at
birth do not ovulate or exhibit lordosis but will exhibit male
sexual behaviors such as mounting in response to testosterone
exposure. From these studies, it is generally considered that the
background or default condition for reproductive behavior is
feminine and the presence of testosterone in the female converts
the behavior to a masculine one.
2) The authors have reported that the exposure to a stressful and
traumatic event greatly enhances new learning in adult male rats,
whereas exposure to the same stressful experience impairs
performance in adult female rats. The stressful event is acute,
consisting of <30 min of inescapable swimming or exposure to
brief intermittent tail stimulations. The learning paradigm is an
associative task in which a conditioned stimulus (CS) of white
noise predicts the occurrence of a periorbital eyelid stimulus,
which elicits an eyeblink as an unconditioned stimulus (US). As
the animal learns that the CS predicts the occurrence of the US,
it elicits a conditioned eyeblink response (CR) in response to
the CS. The opposite effects of stress on performance are evident
during several paradigms, including trace conditioning, a
hippocampal-dependent task in which the stimuli are discontiguous
in time. Moreover, these opposite effects of stress are dependent
on differing hormonal substrates. In males, the enhancement of
learning in response to stress is dependent on the presence of
the adrenal hormone, corticosterone, whereas in females, the
impaired performance is dependent on the presence of the sex
hormone estrogen. Thus, exposure to a stressful traumatic event
can have opposite effects on an animal's ability to learn simply
by virtue of its sex and these effects are mediated by different
hormonal systems, at least as manipulated in adulthood.
3) In summary: Exposure to an acute stressful event can enhance
learning in male rats, whereas exposure to the same event
dramatically impairs performance in females. The authors report
they tested whether the presence of sex hormones during early
development organizes these opposite effects of stress on
learning in males vs. females. In the first experiment, males
were castrated at birth whereas females were injected with
testosterone. Rats were trained as adults on the hippocampal-
dependent learning task of trace eyeblink conditioning.
Performance in adult males that had been castrated at birth was
still enhanced by exposure to an acute stressful experience.
However, adult females injected with testosterone at birth
responded in the opposite direction, i.e., exposure to the
stressor that typically reduces performance instead enhanced
their levels of conditioning. In the second experiment, exposure
to testosterone was manipulated in utero by injecting pregnant
females with a testosterone antagonist. After foster rearing,
adult offspring were exposed to the stressor and trained on the
hippocampal-dependent learning task of trace conditioning.
Although performance in adult females was unaffected by
antagonizing testosterone in utero, i.e., stress still reduced
performance, the enhancement of conditioning after stress in
adult males was prevented. Thus, the presence of sex hormones
during gestation and development organizes whether and how acute
stressful experience will affect the ability to acquire new
information in adulthood. The authors suggest that as with many
sexual behaviors, these cognitive responses to stress appear to
be masculinized by exposure to testosterone and feminized by its
absence during very early development.
References (abridged):
1. Arnold, A. P. & Breedlove, S. M. (1985) Horm. Behav. 19, 469-
498.
2. Balthazart, J. , Tlemcani, O. & Ball, G. F. (1996) Horm.
Behav. 30, 627-661.
3. Arnold, A. (1996) Horm. Behav. 30, 495-505.
4. Kendrick, A. M. & Schlinger, B. A. (2000) Horm. Behav. 30,
600-610.
5. Williams, C. L. , Barnett, A. M. & Meck, W. H. (1990) Behav.
Neurosci. 104, 84-97.
Proc. Nat. Acad. Sci. 2002 99:13955
Related Background Brief:
ORGANIZATIONAL AND ACTIVATIONAL EFFECTS OF SEX STEROIDS ON BRAIN
AND BEHAVIOR: A REANALYSIS. The actions of sex steroids on brain
and behavior traditionally have been divided into organizational
and activational effects. Organizational effects are permanent
and occur early in development; activational effects are
transient and occur throughout life. Over the past decade,
experimental results have accumulated which do not fit such a
simple two-process theory. Specifically, the characteristics said
to distinguish organizational and activational effects on
behavior are sometimes mixed, as when permanent effects occur in
adulthood. The authors suggest that attempts to determine whether
specific cellular processes are uniquely associated with either
organizational or activational effects are unsuccessful. These
considerations blur the organizational-activational distinction
sufficiently to suggest that a rigid dichotomy is no longer
tenable. A.P. Arnold and S.M. Breedlove: Horm Behav 1985 19:469.
Related Background Brief:
DO SEX DIFFERENCES IN THE BRAIN EXPLAIN SEX DIFFERENCES IN THE
HORMONAL INDUCTION OF REPRODUCTIVE BEHAVIOR? WHAT 25 YEARS OF
RESEARCH ON THE JAPANESE QUAIL TELLS US. Early workers interested
in the mechanisms mediating sex differences in morphology and
behavior assumed that differences in behavior that are commonly
observed between males and females result from the sex
specificity of androgens and estrogens. Androgens were thought to
facilitate male-typical traits, and estrogens were thought to
facilitate female-typical traits. By the mid-20th century,
however, it was apparent that administering androgens to females
or estrogens to males was not always effective in sex-reversing
behavior and that in some cases a "female" hormone such as an
estrogen could produce male-typical behavior and an androgen
could induce female-typical behavior. These conceptual
difficulties were resolved to a large extent by the seminal paper
of C. H. Phoenix, R. W. Goy, A. A. Gerall, and W. C. Young in
(1959, Endocrinology 65, 369-382) that illustrated that several
aspects of sexual behavior are different between males and
females because the sexes have been exposed during their
perinatal life to a different endocrine milieu that has
irreversibly modified their response to steroids in adulthood.
Phoenix et al. (1959) therefore formalized a clear dichotomy
between the organizational and activational effects of sex
steroid hormones. Since this paper, a substantial amount of
research has been carried out in an attempt to identify the
aspects of brain morphology or neurochemistry that differentiate
under the embryonic/neonatal effects of steroids and are
responsible for the different behavioral response of males and
females to the activation by steroids in adulthood. During the
past 25 years, research in behavioral neuroendocrinology has
identified many sex differences in brain morphology or
neurochemistry; however many of these sex differences disappear
when male and female subjects are placed in similar endocrine
conditions (e.g., are gonadectomized and treated with the same
amount of steroids) so that these differences appear to be of an
activational nature and cannot therefore explain sex differences
in behavior that are still present in gonadectomized steroid-
treated adults. This research has also revealed many aspects of
brain morphology and chemistry that are markedly affected by
steroids in adulthood and are thought to mediate the activation
of behavior at the central level. It has been explicitly, or in
some cases, implicitly assumed that the sexual differentiation of
brain and behavior driven by early exposure to steroids concerns
primarily those neuroanatomical/neurochemical characteristics
that are altered by steroids in adulthood and presumably mediate
the activation of behavior. Extensive efforts to identify these
sexually differentiated brain characteristics over the past 20
years has only met with limited success, however. As regards
reproductive behavior, in all model species that have been
studied it is still impossible to identify satisfactorily brain
characteristics that differentiate under early steroid action and
explain the sex differences in behavioral activating effects of
steroids. This problem is illustrated by research conducted on
Japanese quail (Coturnix japonica), an avian model system that
displays prominent sex differences in the sexual behavioral
response to testosterone, and in which the endocrine mechanisms
that control sexual differentiation of behavior have been clearly
identified so that subjects with a fully sex-reversed behavioral
phenotype can be easily produced. In this species, studies of sex
differences in the neural substrate mediating the action of
steroids in the brain, including the activity of the enzymes that
metabolize steroids such as aromatase and the distribution of
steroid hormone receptors as well as related neurotransmitter
systems, did not result in a satisfactory explanation of sex
differences in the behavioral effectiveness of testosterone. J.
Balthazart et al: Horm Behav 1996 30:627.
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7. LEARNING AND MEMORY: DEVELOPMENTAL ASPECTS
BRAIN DEVELOPMENT: MEMORY ENHANCEMENT IN EARLY CHILDHOOD
C. Liston and J. Kagan (Harvard University, US) discuss human
memory development, the authors making the following points:
1) Infants of 6 months old can remember events for up to 24
hours, which extends to up to a month when they are 9 months old.
It has been proposed that early deficiencies in registering and
retaining memories for events in the long term might be related
to the protracted maturation of the neocortex. In humans, the
brain undergoes important changes towards the end of the first
year, including the growth and differentiation of cortical
pyramidal neurons and of dendrites in the hippocampus, which
continue into the second year. These developmental processes
should increase the efficiency of integration and registration of
information in the neocortex, and in the prefrontal cortex in
particular(1, 2).
2) To test this hypothesis, the authors evaluated the ability of
infants to retrieve representations after a delay of 4 months of
motor acts first experienced at 9, 17 or 24 months of age. The
authors used a deferred-imitation procedure in which the
experimenter performed a sequence of actions with the aid of
props while describing these actions verbally (for example,
"Clean-up time!" was used for wiping the table with a paper towel
and then throwing the towel into the waste basket; "Make a
rattle!" was used for inserting a ring into a slot in a bottle
and then shaking the bottle). The authors estimated the
children's recall of these events four months later on the basis
of the number of actions they successfully re-enacted and on the
number of pairs of actions performed in the proper sequence.
3) In summary: Regions of the brain's frontal lobe that are
associated with memory retention and retrieval(1,2) begin to
mature during the last quarter of the first year in humans. This
implies that infants younger than 8 or 9 months should have
difficulty in registering an experience and retrieving it after a
long delay(3,4). The authors demonstrate that 13-month-old
children are unable to recall a sequence of actions performed in
front of them when they were 9 months old, whereas 21- and 28-
month-olds are able to retrieve representations of the same acts
when these were witnessed at 17 and 24 months. The authors
suggest their findings indicate that long-term retention
increases during the second year and support the idea that
maturation of the frontal lobe at the end of the first year
contributes to memory enhancement during this period.
References (abridged):
1. Buckner, R. L. et al. J. Neurosci. 15, 12-29 (1995).
2. Nyberg, L. et al. Proc. Natl Acad. Sci. USA 93, 11280-11285
(1996).
3. Herschkowitz, N., Kagan, J. & Zilles, K. Neuropediatrics 28,
296-306 (1997).
4. Herschkowitz, N., Kagan, J. & Zilles, K. Neuropediatrics 30,
221-230 (1999).
5. Barr, R., Dowden, A., & Hayne, H. Inf. Behav. Dev. 19, 159-170
(1996).
Nature 2002 419:896
Related Background Brief:
NEUROBIOLOGICAL BASES OF BEHAVIORAL DEVELOPMENT IN THE FIRST
YEAR. The authors summarize the temporal relations between
selected psychological milestones in the first year of the human
infant and theoretically relevant developmental neurobiological
changes in the brain, supplemented where appropriate, with
evidence from the non-human primate. The disappearance of the
palmar grasp reflex and the decrease in endogenous smiling and
spontaneous crying, which occur at 2-3 months, are correlated to
emergent cortical inhibition of brainstem circuits. In addition,
the improved ability to recognize an event experienced in the
immediate past (recognition memory) is related to growth of the
hippocampus and adjacent structures at this age. The behavioral
developments at 7-10 months include an enhanced ability to
retrieve stored representations of the past and to compare past
and present (working memory), along with the emergence of the
universal fears of strangers and separation from the caretaker.
These milestones are correlated in time with maturational changes
in the prefrontal and rhinal cortices and hippocampal formation,
the integration of the limbic system and increased responsiveness
of the hypothalamus-pituitary-adrenal axis. The authors suggest
that knowledge of age-dependent correlations of brain and
behavioral maturation is a basis for the investigation of causal
relationships between brain development and behavior. A close
collaboration of pediatricians, psychologists and neuroscientists
is, therefore, necessary. N. Herschkowitz et al: Neuropediatrics
1997 28:296.
Related Background Brief:
NEUROBIOLOGICAL BASES OF BEHAVIORAL DEVELOPMENT IN THE SECOND
YEAR. The authors discuss selected psychological competences that
develop and become noticeable between one and two years of age
and are temporally correlated to structural, biochemical and
physiological changes in the brain. The psychological competences
are: Language development, a sense of "right" and "wrong", self-
awareness, and the ability to make inferences. The accompanying
changes in the brain involve the prefrontal cortex, language-
related cortical areas, hippocampus, cerebellum, basal ganglia
and an increase in the connectivity of the network. Of special
interest are the maturational changes in layers III-IV of the
prefrontal cortex. Layer III is the origin and target of callosal
and commissural axons linking the two hemispheres and the target
of associational axons linking ipsilateral areas within each
hemisphere. Layer IV, the target for axons from the mediodorsal
nucleus of the thalamus, conveys information from other
associational cortices, cerebellum, basal ganglia, and the
reticular and limbic systems. In the second year, intensive
dendritic growth and synaptogenesis in these layers increase the
linking of these two layers and form a neural basis for a more
efficient convergence and integration of information from the two
hemispheres, which are functionally asymmetric. The authors
hypothesize that these changes, together with the maturational
changes in the cortico-subcortical network, are a basis for the
observed emergence of the psychological competences. The authors
state they are aware that temporal correlations cannot prove firm
causal relationships. However, they suggest that knowledge of
these correlations is useful in generating specific hypotheses
that can be tested directly. N. Herschkowitz et al:
Neuropediatrics 1999 30:221.
Related Background Brief:
DEVELOPMENTAL CHANGES IN DEFERRED IMITATION BY 6- TO 24-MONTH-OLD
INFANTS. The authors report that developmental changes in
imitation were examined in three experiments with 6- to 24-month-
old infants. In all experiments, infants in the demonstration
condition observed an experimenter perform three specific actions
with a puppet. Their ability to reproduce those actions was
assessed for the first time during the test in the absence of
prior practice. Infants in the control condition received
equivalent exposure to the puppet and the experimenter but were
not shown the target actions. The results of Experiment 1 showed
that 12-, 18-, and 24-month-old infants exhibited clear evidence
of imitation following a 24-hour delay (deferred imitation). In
addition, the findings of Experiment 1 demonstrated that the 18-
and 24-month-old infants reproduced more of the target actions
during the test than the 12-month-olds. The results of Experiment
2 showed that 6-month-olds performed as well as 12-month-olds
when they were tested in the absence of a delay (immediate
imitation). Finally, the results of Experiment 3 showed that,
with additional exposure to the target actions, even 6-month-old
infants exhibited deferred imitation following a 24-hour delay.
Taken together, these findings have important implications for
current theories of the development of imitation and memory
during the first 2 years of life. R. Barr et al: Infant Behav. &
Dev. 1996 19:159.
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