Instructor’s Manual
by David Holtzman
to accompany
Biological Psychology, Seventh Edition
Breedlove and Watson
Chapter 17: Learning and Memory
OVERVIEW OF THIS CHAPTER
Learning and memory are integral components of everyday life for us all. In fact, it could
be argued that virtually every behavior we perform is shaped by the experiences of a
lifetime. Virtually every living animal is endowed with a capacity for carrying
information forward in time. Memory is of primary importance in predicting events and
outcomes and in allowing animals to act adaptively. Fascinating, poignant case histories
of people with profound amnesia make clear how much of the enjoyment of our lives
depends on an ability to learn. And, of course, the progress of human society in every
sphere of endeavor is possible only as a consequence of memory, both personal and
institutional.
The chapter opens by placing many of the classic distinctions, hypotheses, and
phenomena of learning and memory research in the context of individual cases of
amnesia. Discussion then moves to neural mechanisms of specific facets of memory
function, with particular emphasis on human learning and memory mechanisms as
revealed by behavioral and imaging studies. The latter part of the chapter is concerned
with more detailed discussion of the neurobiology of memory. The advent of advanced
molecular techniques in the last decade has provoked an enormous research effort aimed
at uncovering the basic cellular events associated with the storage of information by the
brain. This area of study is centered on a basic concept—that memory involves changes in
the functioning of synapses and circuits—but the exact mechanisms by which these
changes occur have been elusive. Nevertheless, the dominant models for the study of
memory have yielded insights into the biochemical processes that occur as memory is
formed. Considerable progress has also been made in the study of pathological and agerelated memory impairments, and some of these findings suggest possible treatments for
reducing the effects of aging on memory.
CHAPTER OUTLINE
Introduction: Trapped in the Eternal Now
FUNCTIONAL PERSPECTIVES ON MEMORY
There Are Several Kinds of Memory and Learning
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For patient H.M., the present vanished into oblivion
Damage to the medial diencephalon can also cause amnesia
Patients with Korsakoff’s syndrome show damage to medial diencephalic
structures and to the frontal cortex
Brain damage can destroy autobiographical memories while sparing general
memories
Different forms of nondeclarative memory serve varying functions
Memory Has Temporal Stages: Short, Intermediate, and Long
 Long-term memory is vast
Successive Processes Capture, Store, and Retrieve Information in the Brain
 Multiple brain regions are involved in encoding
 Different mechanisms are used for consolidating and retrieving declarative
information
 Retrieving memories can strengthen them, or distort them
BOX 17.1 Emotions and Memory
Different Brain Regions Process Different Aspects of Memory
 Medial temporal lobe structures are crucial for declarative memory
 Imaging studies have revealed much about declarative memory
 Hippocampal mechanisms are important in spatial memory
 Imaging studies help us understand nondeclarative memory
 A variety of brain regions are involved in different attributes of working memory
 Brain regions involved in learning and memory: An interim summary
NEURAL MECHANISMS OF MEMORY STORAGE
Memory Storage Requires Neuronal Remodeling
 Plastic changes at synapses can be physiological or structural
 Varied experiences and learning cause the brain to change and grow
Invertebrate Nervous Systems Show Plasticity
Synaptic Plasticity Can Be Measured in Simple Hippocampal Circuits
 LTP occurs at several sites in the hippocampal formation
 NMDA receptors and AMPA receptors collaborate in LTP
 Is LTP a mechanism of memory formation?
Some Simple Learning in Mammals Relies on Circuits in the Cerebellum
In the Adult Brain, Newly Born Neurons May Aid Learning
Learning and Memory Change as We Age
 Age-related impairments of memory have several causes
 Can the effects of aging on memory be prevented or alleviated?
The Cutting Edge: Artificial Activation of an Engram
© 2013 Sinauer Associates, Inc.
KEY CONCEPTS
1. Memory and learning are essential components of ongoing behavior, and the loss of
the capacity to store information about the events of life is utterly debilitating. In
retrograde amnesia, memory for events preceding injury is lost; in anterograde
amnesia, the ability to form new memories is lost.
2. Patient H.M. provided critical information about the neural mechanisms of memory in
humans. As a consequence of the bilateral removal of medial temporal lobe
structures, H.M. lost the ability to form new declarative memories involving the
conscious recollection of events and information, but retained the ability to form
nondeclarative memories, in which the ability to perform a new behavior is acquired.
3. Patient N.A. suffered anterograde amnesia as a result of a diencephalic injury;
therefore, a larger temporal–diencephalic system appears to be important for
declarative memory. Patients with Korsakoff’s syndrome exhibit a characteristic
amnesia due to diencephalic and frontal lobe deterioration.
4. Patient K.C. selectively lost autobiographical memory following brain trauma,
supporting the view that the semantic (generalized) and episodic (autobiographical)
forms of declarative memories may involve separable neural substrates.
5. Learning involves both nonassociative forms—such as habituation, dishabituation,
and sensitization—and associative forms, including classical conditioning and
instrumental (operant) conditioning.
6. Memories may be classified on the basis of their durability. Iconic memories are
fleeting and represent the contents of sensory buffers. Short-term memories range
from seconds to hours. Intermediate-term memories last for hours to days. Long-term
memories may last for many years: Some long-term memories are said to be
permanent memories (if they last for the life span).
7. Shorter- and longer-term memories are evident in serial position effects. Recency
effects are thought to represent short-term memory, while primacy effects are thought
to reflect longer-term memory. The selective effects of hippocampal lesions on
primacy but not recency—which resemble the deficits shown by H.M. on similar
tasks—provide evidence that shorter-term and longer-term memories involve
different neural systems.
8. Long-term memory has enormous capacity, but these memories are subject to
distortion over time.
9. Memory has specific attributes, such as space, time, sensory perception, response, and
affect. Different attributes appear to depend on different neural substrates, to some
extent. In particular, the hippocampus seems to be important for spatial memory.
© 2013 Sinauer Associates, Inc.
10. Memory formation and use involve three stages: encoding, consolidation, and
retrieval. Imaging and lesion studies are revealing that different brain systems are
involved in each stage. Information processing aspects of memory appear to depend
on temporal–diencephalic mechanisms, whereas long-term storage appears to occur in
the neocortex.
11. Emotion may have a powerful enhancing influence on memory via the actions of
stress hormones. Treatment with adrenergic antagonists may prevent posttraumatic
stress disorder in people subjected to severe trauma.
12. Imaging studies suggest that the acquisition of skills depends on the basal ganglia,
and sensorimotor learning in particular also involves the cerebellum and motor cortex.
Eye-blink conditioning involves not only the cerebellum but also the hippocampus,
basal ganglia, and cortex.
13. Birds and mammals that cache food or range widely, and thus rely on spatial memory,
tend to have larger hippocampi than noncaching animals. Hippocampal size may also
reflect sex differences within species.
14. Memory formation has, for many years, been hypothesized to involve changes in the
function and organization of synapses and cell circuits. Plasticity associated with
learning may be evident at many levels of the nervous system, ranging from simple
synaptic chains to complex superordinate circuits. Furthermore, learning and memory
are now known to involve the formation of new neurons in some species.
15. Much modern research stems from two theoretical models advanced by D. O. Hebb.
Hebbian synapses are synapses that change their relationship when one persistently
takes part in firing the other. Cell assemblies are distributed circuits of neurons that
become associated with each other when events occur that cause them to fire together.
A more recent refinement notes that a weakening of contacts between neurons can
also mediate learning and memory.
16. Early research found that enriched-condition (EC) rats exhibit increases in
biochemical activity, dendritic branching, synaptic contacts, and overall size of brain
regions. Early enriched experience promotes better performance on memory tests and
offers protection against processes that impair memory.
17. Plasticity is evident in the nervous system of Aplysia, which offer the advantages of
relative simplicity and the presence of identifiable neurons. Simple training of Aplysia
has demonstrated changes in synaptic number and function associated with learning,
both in simple reflex circuits and in superordinate circuits.
18. Long-term potentiation (LTP) is a lasting increase in the magnitude of responses of
neurons subsequent to afferent stimulation by high-frequency bursts of electricity.
© 2013 Sinauer Associates, Inc.
LTP in hippocampal region CA1 appears to depend on the activity of glutamate
receptors, whereas LTP in CA3 appears to rely on opiate mechanisms.
19. The induction of LTP is calcium-dependent. Calcium influx activates protein kinases,
which in turn activate CREB, leading to the transcription of immediate early genes
and changes in the production of cellular proteins. Cellular changes in LTP also
appear to involve signaling by retrograde messengers. Long-term depression (LTD)—
the converse of LTP—is a long-lasting decrease in magnitude of neural
responsiveness, mediated by protein phosphatases.
20. Conclusive evidence that LTP is involved in memory formation does not yet exist.
Nevertheless, the characteristics of LTP resemble those of memory formation in
several ways, and the induction of LTP following conditioning has been observed in
several experiments.
21. Research on eye-blink conditioning has led to the description of a complete neural
circuit for this form of learning. In eye-blink conditioning, a CS (tone) and US
(corneal stimulation) become associated in a cerebellar circuit that is superordinate to
the basic reflex circuit for eye blinking. The hippocampus is not necessary for eyeblink conditioning in which there is little or no delay between the CS and US, but it is
necessary for conditioning in which a delay is inserted between the CS and US.
22. New neurons and glial cells are produced in the brain throughout life and appear to
play a functional role in learning and memory. Living in enriched conditions greatly
increases the rate of neurogenesis.
23. People tend to show systematic age-related memory decrements. These decrements
are particularly evident for memory tasks that require significant effort of recall and
for tasks that involve internal generation of recall rather than the use of external cues.
24. Declines in cholinergic activity of the brain are believed to play an especially
important role in age-related memory impairment, and changes in the cholinergic
projections from the nucleus basalis to the cortex are associated with Alzheimer’s
disease.
25. Using optogenetics, researchers have recently shown that activation of specific
neurons appears to encode memories for behaviors specific to a given experience.
Transgenic mice expressing channelrhodopsin in the dendate gyrus (DG) were
subjected to fear conditioning and give a fear response, freezing, in a specific
environment. When tested in a familiar non-threatening environment, these mice
froze when the DG neurons were activated by blue light.
LECTURE OUTLINE
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(Textbook figures are available on the Instructor’s Resource Library disc.)
There Are Several Kinds of Memory and Learning
Learning is the process of acquiring new information.
Memory is:
 The ability to store and retrieve information.
 The specific information stored in the brain.
Patient H.M., Henry Molaison, suffered from severe epilepsy.
Because his seizures began in the temporal lobes, a decision was made to remove the
anterior temporal lobes on both sides.
H.M.’s surgery removed the amygdala, the hippocampus, and some cortex.
FIGURE 17.1 Brain Tissue Removed from Henry Molaison (Patient H.M.)
Retrograde amnesia is the loss of memories formed before onset of amnesia and is not
uncommon after brain trauma.
Anterograde amnesia is the inability to form memories after onset of amnesia.
H.M. had normal short-term memory but had severe anterograde amnesia.
Damage to the hippocampus can produce memory deficits.
H.M. was able to show improvement with motor skills but could not remember
performing them (i.e. he could not recall the tasks verbally.).
H.M.’s memory deficit was confined to describe the tasks he performed.
FIGURE 17.2 Henry’s Performance on a Mirror-Tracing Task
Two kinds of memory:
 Declarative memory deals with what—facts and information acquired through
learning that can be stated or described. (Things we are aware that are learned.)
 Nondeclarative (procedural) memory deals with how—shown by performance
rather than conscious recollection.
FIGURE 17.3 Two Main Kinds of Memory: Declarative and Nondeclarative
Damage to other areas can also cause memory loss.
Patient N.A. has amnesia due to accidental damage to the left dorsal thalamus, bilateral
damage to the mammillary bodies (limbic structures in the hypothalamus), and
probable damage to the mammillothalamic tract.
Like Henry Molaison, he has short-term memory but cannot form declarative long-term
memories.
FIGURE 17.4 The Brain Damage in Patient N.A.
© 2013 Sinauer Associates, Inc.
Korsakoff’s syndrome is a memory deficiency caused by lack of thiamine—seen in
chronic alcoholism.
Patients often confabulate—fill in a gap in memory with a falsification which they
accept as true.
Brain damage occurs in mammillary bodies and dorsomedial thalamus, similar to N.A.,
and to the basal frontal cortex.
Two subtypes of declarative memory:
 Semantic memory—generalized memory.
 Episodic memory—detailed autobiographical memory.
Patient K.C. cannot retrieve personal (episodic) memory due to accidental damage to the
cortex and severe shrinkage of the hippocampus and parahippocampal cortex; his
semantic memory is good.
Three subtypes of nondeclarative memory:
 Skill learning—learning to perform a task requiring motor coordination.
 Priming—repetition priming—a change in stimulus processing due to prior
exposure to the stimulus.
 Conditioning—the association of two stimuli or of a stimulus and a response.
FIGURE 17.5 Subtypes of Declarative and Nondeclarative Memory
Memory Has Temporal Stages: Short, Intermediate, and Long
Iconic memories are the briefest memories and store sensory impressions that only last a
few seconds.
Short-term memories (STMs) usually last only for up to 30 seconds or throughout
rehearsal.
 Short-term memory is also known as working memory.
FIGURE 17.6 Stages of Memory Formation
Working memory can be subdivided into three components, all supervised by an
executive control module:
 Phonological loop—contains auditory information.
 Visuospatial sketch pad—holds visual impressions.
 Episodic buffer—contains more integrated, sensory information.
An intermediate-term memory (ITM) outlasts a STM, but is not permanent.
Long-term memories (LTMs) last for days to years.
Mechanisms differ for STM and LTM storage but are similar across species.
 The primacy effect is the higher performance for items at the beginning of a list
(LTM).
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The recency effect shows better performance for the items at the end of a list
(STM).
FIGURE 17.7 Serial Position Curves from Immediate-Recall Experiments
Long-term memory has a large capacity.
Information can also be forgotten or recalled inaccurately.
Successive Processes Capture, Store, and Retrieve Information in the Brain
A functional memory system incorporates three aspects:
 Encoding—sensory information is passed into short-term memory.
 Consolidation—short-term memory information is transferred into long-term
storage.
 Retrieval—stored information is used.
FIGURE 17.8 Hypothesized Memory Processes: Encoding, Consolidation, and Retrieval
Multiple brain regions are involved in encoding, as shown by fMRI.
For recalling pictures, the right prefrontal cortex and parahippocampal cortex in both
hemispheres are activated.
For recalling words, the left prefrontal cortex and the left parahippocampal cortex are
activated.
Thus, the prefrontal cortex and parahippocampal cortex are important for consolidation.
These mechanisms reflect hemispheric specializations (left hemisphere for language and
right hemisphere for spatial ability).
The engram, or memory trace, is the physical record of a learning experience and can be
affected by other events before or after.
Each time a memory trace is activated and recalled, it is subject to changes.
Consolidation of memory involves the hippocampus, but the hippocampal system does
not store long-term memory.
LTM storage occurs in the cortex, near where the memory was first processed and held in
short-term memory.
FIGURE 17.9 Encoding, Consolidation, and Retrieval of Declarative Memories
In posttraumatic stress disorder (PTSD, characterized as reliving and being
preoccupied by traumatic events), memories produce stress hormones that further
reinforce the memory.
GABA, ACh, and opioid transmission can also enhance memory formation in animal
models.
© 2013 Sinauer Associates, Inc.
Treatments that can block chemicals acting on the basolateral amygdala may alter the
effect of emotion on memories.
BOX 17.1 The Amygdala and Memory
The process of retrieving information from LTM can cause memories to become unstable
and susceptible to disruption or alteration.
Reconsolidation is the return of a memory trace to stable long-term storage after it’s
temporarily volatile during recall.
Reconsolidation can distort memories.
Successive activations can deviate from original information.
New information during recall can also influence the memory trace.
Leading questions can lead to “remembering” events that never happened.
“Recovered memories” and “guided imagery” can have false information implanted into
the recollection.
FIGURE 17.10 Are “Recovered” Memories Reliable?
Different Brain Regions Process Different Aspects of Memory
Testing declarative memories in monkeys:
 Delayed non-matching-to-sample task—a test of object recognition memory,
where the subject must choose the object that was not seen previously.
FIGURE 17.11 The Delayed Non-Matching-to-Sample Task
Medial temporal lobe damage causes impairment on the delayed nonmatching-to-sample
task.
The amygdala is not necessary for declarative memory tasks.
The hippocampus (in conjunction with the entorhinal, parahippocampal) and perirhinal
cortices, is important for these tasks.
FIGURE 17.12 Memory Performance after Medial Temporal Lobe Lesions
Imaging studies confirm the importance of medial temporal (hippocampal) and
diencephalic regions in forming long-term memories.
Both are activated during encoding and retrieval, but long-term storage depends on the
cortex.
Episodic and semantic memories are processed in different areas.
Episodic (autobiographical) memories cause greater activation of the right frontal and
temporal lobes.
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FIGURE 17.13 My Story versus Your Story
Early research indicated that animals form a cognitive map—a mental representation of
spatial relationships.
Latent learning is when acquisition has taken place but has not been demonstrated in
performance tasks.
FIGURE 17.14 Biological Psychologists at Work
The hippocampus is also important in spatial learning.
It contains place cells that become active when in, or moving toward, a particular
location.
Place cells remap when a rodent is placed in a new environment.
Grid cells and border cells are neurons that fire when animal is at an intersection and at
the perimeter of an abstract grid map, respectively.
In rats, place cells in the hippocampus are more active as the animal moves toward a
particular location.
In monkeys, spatial view cells in the hippocampus respond to what the animal is looking
at.
Comparisons of behaviors and brain anatomy show that increased demand for spatial
memory results in increased hippocampal size (relative to the rest of the brain) in
mammals and birds.
In food-storing species of birds, the hippocampus is larger but only if used to retrieve
stored food.
FIGURE 6.6 Food Storing in Birds as Related to Hippocampal Size
Spatial memory and hippocampal size can change within the life span.
In some species, there can be sex differences in spatial memory, depending on behavior.
Polygynous male meadow voles travel further (to find females) and have a larger
hippocampus than female meadow voles or males of monogamous pine voles.
FIGURE 17.15 Sex, Memory, and Hippocampal Size
Imaging studies help to understand learning and nondeclarative memory for different
skills:
 Sensorimotor skills, such as mirror-tracing.
 Perceptual skills—learning to read mirror-reversed text.
 Cognitive skills—planning and problem solving.
All three of these depend on functional basal ganglia; the motor cortex and cerebellum
are also important for some skills.
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Imaging studies of repetition priming show reduced bilateral activity in the
occipitotemporal cortex, related to perceptual priming.
Perceptual priming reflects prior processing of the form of the stimulus.
Conceptual priming (priming based on word meaning) is associated with reduced
activation of the left frontal cortex.
Imaging of conditioned responses can show changes in activity.
PET scans made during eye-blink tests show increased activity in several brain regions,
but not all may be essential.
Patients with unilateral cerebellar damage can acquire the conditioned eye-blink response
only on the intact side.
Different brain regions are involved with different attributes of working memories such
as space, time, or sensory perception.
Memory tasks assess the contributions of each brain region.
The eight-arm radial maze is used to test spatial location memory.
Rats must recognize and enter an arm that they have entered recently to receive a reward.
Only lesions of the hippocampus produce a deficit in this predominantly spatial task.
FIGURE 17.16 Tests of Specific Attributes of Memory (Part 1)
In a memory test of motor behavior, the animal must remember whether it made a left or
right turn previously.
If it turns the same way as before, it receives a reward.
Only animals with lesions to the caudate nucleus showed deficits.
FIGURE 17.16 Tests of Specific Attributes of Memory (Part 2)
Sensory perception can be measured by the object recognition task.
Rats must identify which stimulus in a pair is novel.
This task depends on the extrastriate cortex.
FIGURE 17.16 Tests of Specific Attributes of Memory (Part 3)
Interim summary of brain regions involved in learning and memory:
 Many brain regions are involved.
 Different forms of memory are mediated by at least partly different mechanisms
and brain structures.
 The same brain structure may be involved in many forms of learning.
FIGURE 17.17 Brain Regions Involved in Different Kinds of Learning and Memory
Neural Mechanisms of Memory Storage
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Molecular, synaptic, and cellular events store information in the nervous system.
New learning and memory formation can involve new neurons, new synapses, or changes
in synapses in response to biochemical signals.
Neuroplasticity (or neural plasticity) is the ability of neurons and neural circuits to be
remodeled by experience or the environment.
Memory Storage Requires Neuronal Remodeling
Sherrington speculated that alterations in synapses were the basis for learning.
Synaptic changes can be measured physiologically, and may be presynaptic, postsynaptic,
or both.
Changes include increased neurotransmitter release and/or a greater effect due to changes
in neurotransmitter-receptor interactions.
FIGURE 17.18 Synaptic Changes That May Store Memories (Part 1)
Changes in the rate of inactivation of transmitter would also increase effects.
Inputs from other neurons might increase or decrease neurotransmitter release.
Structural changes at the synapse may provide long-term storage.
New synapses could form or some could be eliminated with training.
Training might also lead to synaptic reorganization.
FIGURE 17.18 Synaptic Changes That May Store Memories (Parts 2–4)
Lab animals living in a complex environment demonstrated biochemical and anatomical
brain changes from those living in simpler environments.
Three housing conditions:
 Standard condition (SC)
 Impoverished (or isolated) condition (IC)
 Enriched condition (EC)
FIGURE 17.19 Experimental Environments to Test the Effects of Enrichment on
Learning and Brain Measures
Animals housed in EC, compared to those in IC, developed:
 A heavier, thicker cortex
 Enhanced cholinergic activity
 More dendritic branches (especially on basal dendrites near the cell body), with
more dendritic spines suggesting more synapses
FIGURE 17.20 Measurement of Dendritic Branching
Invertebrate Nervous Systems Show Plasticity
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Aplysia is used to study plastic synaptic changes in neural circuits.
The advantages of Aplysia:
 Has fewer nerve cells
 Can create detailed circuit maps for particular behaviors—little variation between
individuals
Invertebrates demonstrate nonassociative learning, which involves a single stimulus
presented once or repeated.
Three types of nonassociative learning:
 Habituation—a decreased response to repeated presentations of a stimulus.
 Dishabituation—restoration of response amplitude after habituation.
 Sensitization—prior strong stimulation increases response to most stimuli.
Habituation is studied in Aplysia.
Squirts of water on its siphon causes it to retract its gill.
After repeated squirts, the animal retracts the gills less; it has learned that the water poses
no danger.
FIGURE 17.21 The Sea Slug Aplysia
The habituation is caused by synaptic changes between the sensory cell in the siphon and
the motoneuron that retracts the gill.
Less transmitter released in the synapse results in less retraction.
FIGURE 17.22 Synaptic Plasticity Underlying Habituation in Aplysia (Part 1)
Over several days, the animal habituates faster, representing long-term habituation.
The number of synapses between the sensory cell and the motoneuron is reduced.
FIGURE 17.22 Synaptic Plasticity Underlying Habituation in Aplysia (Part 2)
Synaptic Plasticity Can Be Measured in Simple Hippocampal Circuits
Hebb proposed that when two neurons are repeatedly activated together, their synaptic
connection will become stronger.
Cell assemblies—ensembles of neurons—linked via Hebbian synapses could store
memory traces.
Hebb’s idea was supported when researchers used tetanus (a brief increase of electrical
stimulation that triggers thousands of axon potentials) on the hippocampus.
Long-term potentiation (LTP)—a stable and enduring increase in the effectiveness of
synapses.
A weakening of synaptic efficacy—termed long-term depression—can also encode
information.
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FIGURE 17.23 Long-Term Potentiation Occurs in the Hippocampus (Part 1)
Synapses in LTP behave like Hebbian synapses:
 Tetanus drives repeated firing.
 Postsynaptic targets fire repeatedly due to the stimulation.
 Synapses are stronger than before.
LTP can be generated in conscious and freely behaving animals, in anesthetized animals,
and in tissue slices and that LTP is evident in a variety of invertebrate and vertebrate
species.
LTP can also last for weeks or more.
Superficially, LTP appears to have the hallmarks of a cellular mechanism of memory.
LTP occurs at several sites in the hippocampal formation—formed by the hippocampus,
the dentate gyrus and the subiculum (also called subicular complex or hippocampal
gyrus).
The hippocampus has regions called CA1, CA2, and CA3 (CA=Cornus Ammon which
means Ammon’s Horn).
FIGURE 17.23 Long-Term Potentiation Occurs in the Hippocampus (Part 2)
The CA1 region has two kinds of glutamate receptors:
 NMDA receptors (after its selective ligand, N-methyl-D-aspartate)
 AMPA receptors (which bind the glutamate agonist AMPA)
Glutamate first activates AMPA receptors.
NMDA receptors do not respond until enough AMPA receptors are stimulated, and the
neuron is partially depolarized.
NMDA receptors at rest have a magnesium ion (Mg2+) block on their calcium (Ca2+)
channels.
After partial depolarization, the block is removed, and the NMDA receptor allows Ca2+ to
enter in response to glutamate.
FIGURE 17.24 Roles of the NMDA and AMPA Receptors in the Induction of LTP in the
CA1 Region (Parts 1 & 2)
The large Ca2+ influx activates certain protein kinases—enzymes that add phosphate
groups to protein molecules.
One protein kinase is CaMKII (calcium-calmodulin kinase II), which affects AMPA
receptors in several ways:
 Causes more AMPA receptors to be produced and inserted in the postsynaptic
membrane.
CaMKII:
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 Moves existing nearby AMPA receptors into the active synapse.
 Increases conductance of Na+ and K+ ions in membrane-bound AMPA receptors.
These effects all increase the synaptic sensitivity to glutamate.
FIGURE 17.24 Roles of the NMDA and AMPA Receptors in the Induction of LTP in the
CA1 Region (Part 3)
The activated protein kinases also trigger protein synthesis.
Kinases activate CREB—cAMP responsive element-binding protein.
CREB binds to cAMP responsive elements in DNA promoter regions.
CREB changes the transcription rate of genes.
The regulated genes then produce proteins that affect synaptic function and contribute to
LTP.
FIGURE 17.25 Steps in the Neurochemical Cascade during the Induction of LTP
Strong stimulation of a postsynaptic cell releases a retrograde messenger, often a
diffusible gas like carbon monoxide (CO) or nitric oxide (NO) or that travels across
the synapse and alters function in the presynaptic neuron.
More glutamate is released and the synapse is strengthened.
LTP can occur without NMDA receptor activation.
There is evidence that LTP may be one part of learning and memory formation:
 Correlational observations—time course of LTP is similar to that of memory
formation.


Somatic intervention experiments—pharmacological treatments that block LTP
impair learning.
Behavioral intervention experiments—training an animal in a memory task can
induce LTP.
Some Simple Learning Relies on Circuits in the Mammalian Cerebellum
Associative learning involves relations between events.
 In instrumental conditioning—or operant conditioning—an association is
made between:
o Behavior (the instrumental response).
o The consequences of the behavior (the reward).
FIGURE 17.26 Two Types of Conditioning (Part 1)

In classical conditioning—Pavlovian conditioning—a neutral stimulus is paired
with another stimulus that elicits a response.
Eventually, the neutral stimulus by itself will elicit the response.
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FIGURE 17.26 Two Types of Conditioning (Part 2)
Researchers use the eye-blink reflex to study neural circuits in mammals.
An air puff is preceded by an acoustic tone; conditioned animals will blink when just the
tone is heard.
A circuit in the cerebellum is necessary for this reflex.
FIGURE 17.27 Functioning of the Neural Circuit for Conditioning of the Eye-Blink
Reflex
The trigeminal (V) pathway that carries information about the corneal stimulation (the
US) to the cranial motor nuclei also sends axons to the brainstem (specifically a
structure called the inferior olive).
These brainstem neurons, in turn, send axons called climbing fibers to synapse on
cerebellar neurons in a region called the interpositus nucleus.
Blocking GABA in interpositus nucleus stops the behavioral response.
The cerebellum is also important in conditioning of emotions and cognitive learning, as
shown by humans with cerebellar damage.
In the Adult Brain, Newly Born Neurons May Aid Learning
Neurogenesis, or birth of new neurons, occurs mainly in the dentate gyrus in adult
mammals.
Neurogenesis and neuronal survival can be enhanced by exercise, environmental
enrichment, and memory tasks.
Reproductive hormones and experience are also an influence.
FIGURE 17.28 Neurogenesis in the Dentate Gyrus
In some studies, neurogenesis has been implicated in hippocampus-dependent learning.
Conditional knockout mice, with neurogenesis selectively turned off in specific tissues
in adults, showed impaired spatial learning but were otherwise normal.
Genetic manipulations can increase the survival of newly generated neurons in the
dentate, resulting in improved performance.
These animals showed enhanced hippocampal LTP, which was expected since younger
neurons display greater synaptic plasticity.
Adult neurogenesis is also seen in the olfactory bulb.
Activation of newly generated neurons in the olfactory bulb enhances olfactory learning
and memory.
Learning and Memory Change as We Age
© 2013 Sinauer Associates, Inc.
With age, we tend to show some memory impairment in tasks of conscious recollection
that:
1. Require effort.
2. Rely primarily on internal generation of the memory rather than on external cues.
We also experience some decreases in spatial memory and navigational skills.
Some causes of memory problems in old age:
 Impairments of coding and retrieval— less cortical activation in some tasks.
 Loss of neurons and/or neural connections; some parts of the brain lose a larger
proportion of volume.
FIGURE 17.29 Active Brain Regions during Encoding and Retrieval Tasks in Young and
Old People

Deterioration of cholinergic pathways—the septal complex and the nucleus
basalis of Meynert (NBM) provide cholinergic input to the hippocampus and
cortex.
Cholinergic pathways to the cortex are lost in Alzheimer’s disease.
Enhancing cholinergic transmission helps with memory tasks.
Nootropics are a class of drugs that enhance cognitive function.
Cholinesterase inhibitors result can have a positive effect on memory and cognition.
Ampakines, which act via glutamate receptors, work to improve LTP in the hippocampus.
One particular protein kinase—PKMζ (ζ is zeta)—is needed for long-term maintenance of
both hippocampal LTP and cortical memory traces.
Highly selective memory enhancing drugs could be developed in the near future.
Lifestyle factors can help reduce cognitive decline:
 Living in a favorable environment
 Involvement in complex and intellectually stimulating activities
 Having a partner of high cognitive status
The Cutting Edge: Artificial Activation of an Engram
Mice were placed in two contexts:
 Context A—placed in a box with a white plastic floor in a dimly lit room with
black walls and a faint smell of almonds; these mice explored the chamber and
showed no signs of being afraid.
 Context B—classically conditioned to a tone with electrical shock; these mice
learned to freeze to the tone.
These mice had also been genetically modified so that whenever neurons in the dentate
gyrus (DG) of the hippocampus were active, they would start producing
© 2013 Sinauer Associates, Inc.
channelrhodopsin, a protein that would excite those cells, and only those cells, when
exposed to blue light.
FIGURE 17.31 Artificial Activation of an Engram (Part 1)
Activity of the subset of DG neurons with channelrhodopsin was responsible for the mice
finding context B frightening.
Reactivating those neurons caused the mice to freeze in fear, even when they were in a
completely different context.
FIGURE 17.31 Artificial Activation of an Engram (Part 2)
Turning the light off again caused the animals to resume activity, indicating that they
remained unafraid of context A.
It wasn’t just that light-induced activation of any random set of DG neurons induced fear,
because when blue light reactivated DG neurons that had been active in a third
(nonfearful) context, C, the animals did not freeze.
FIGURE 17.31 Artificial Activation of an Engram (Parts 3 & 4)
REFERENCES FOR LECTURE DEVELOPMENT
Books and Articles
Baddeley, A. D. (2013). Essentials of human memory. London: Psychology Press.
Cohen, N. J., and Eichenbaum, H. (1993). Memory, amnesia, and the hippocampal
system. Cambridge, MA: MIT Press.
Eichenbaum H. (2002). The cognitive neuroscience of memory. New York: Oxford
University Press.
Fuster, J. M. (1995). Memory in the cerebral cortex. Cambridge, MA: MIT Press.
Gluck, M. A., Mercado, E., and Myers, C. E. (2013). Learning and memory: From brain
to behavior (2nd ed.). New York: Worth.
James, W. (1890). The Principles of Psychology. New York: Henry Holt.
Kahana, M. J. (2012). Foundations of human memory. Oxford, England: Oxford
University Press.
© 2013 Sinauer Associates, Inc.
Kasai, H., Fukuda, M., Watanabe, S., Hayashi-Takagi, A., and Noguchi, J. (2010).
Structural dynamics of dendritic spines in memory and cognition. [Review]. Trends in
Neurosciences, 33 (3): 121–129.
Kesner, R. P., and Martinez, J. L. (Eds.). (2007). The neurobiology of learning and
memory (2nd ed.). San Diego, CA: Elsevier.
Lieberman, D. A. (2012). Human learning and memory. Cambridge, England: Cambridge
University Press.
Prull, M. W., Gabrieli, J. D. E., and Bunge, S. A. (2000). Age-related changes in
memory: A cognitive neuroscience perspective. In F. I. M. Craik and T. A. Salthouse
(Eds.), The handbook of aging and cognition. Mahwah, NJ: Lawrence Erlbaum and
Associates.
Rudy, J. W. (2008). The Neurobiology of Learning and Memory. Sunderland, MA:
Sinauer.
Silva, A. J., Kogan, J. H., Frankland, P. W., and Kida, S. (1998). CREB and memory.
Annual Review of Neuroscience, 21: 127–148.
Squire, L. R., and Kandel, E. R. (2008). Memory: From mind to molecules. Greenwood
Village, CO: Roberts and Company.
Tulving, E., and Craik, F. I. M. (Eds.). (2005). The Oxford handbook of memory. Oxford,
England: Oxford University Press.
Online Resources
Memory (The Exploratorium, San Francisco)
This is a handsome website developed for an exhibition concerned with various topics in
memory. It features a nicely done sheep brain dissection focusing on memory-related
structures.
http://www.exploratorium.edu/memory/
Mapping Memory in 3D interactive (National Geographic)
http://ngm.nationalgeographic.com/2007/11/memory/brain-interactive
The Mind: Teaching Modules (Modules 10–11: The story of Clive Wearing)
This website is a great learning supplement to the course. This module introduces the
viewer to Clive Wearing, who has a form of anterograde memory loss due to viral
encephalitis. The modules raise many questions about the nature of memory.
http://www.learner.org/resources/series150.html
Brain Science Podcast: Memory
© 2013 Sinauer Associates, Inc.
Brain Science Podcasts cover a plethora of subjects related to the brain and mind with
host Ginger Campbell. This episode is a discussion based on the book Memory: From
Mind to Molecules (2000), by Larry Squires and Eric Kandel.
http://brainsciencepodcast.libsyn.com/bsp_12_memory
Brain Science Podcast: In Search of Memory
This episode is a discussion with Eric Kandel on his research with Aplysia.
http://brainsciencepodcast.libsyn.com/bsp_3_in_search_of_memory_by_eric_kandel
The Brain Observatory
The Brain Observatory has streaming video of the landmark dissection of the brain of
patient H.M. into tissue sections. After imaging H.M’s brain using multiple
specialized MRI sequences, it was photographed and prepared to be frozen by
prolonged immersion in sucrose-based antifreeze. This site also has provides a digital
atlas of the human brain.
http://thebrainobservatory.ucsd.edu/
Howard Hughes Medical Institute—Molecular basis of late LTP
The HHMI has prepared a number of interactive animations that are particularly useful as
a supplement to the text. This animation views the molecular cascade of events
underlying LTP.
http://www.hhmi.org/biointeractive/neuroscience/late_LTP.html
© 2013 Sinauer Associates, Inc.