Transcript Learning and Memory

Learning and Memory
Learning
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Set of processes by which experience changes
the nervous system, changing behavior
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Resulting changes are memories
 Nondeclarative memories
 Declarative memories
Enduring changes to the neural circuits
Mechanisms of learning –
Synaptic plasticity
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Synaptic plasticity
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Changes in synaptic structure and biochemistry
Long-term potentiation (LTP)
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Change in the strength of synaptic connections
Results from repeated activation
Hippocampal formation anatomy
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Part of the limbic system, located
in the temporal lobes
Composed of:
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Dentate gyrus, CA1-3 & subiculum
Perforant pathway
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Entorhinal cortex to dentate gyrus
Primary source of input
Experimental induction of LTP
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Stimulating electrode inserted
into the perforant pathway,
recording electrode inserted into
the dentate gyrus
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Single burst of stimulation delivered
to the perforant pathway
Resulting EPSP recorded in the
neuron population in the dentate
gyrus
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Provides a baseline measure of
normal synaptic firing strength
Experimental induction of LTP
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To induce LTP – rapid burst of electrical pulses
is delivered to the perforant pathway (~100
pulses/2 seconds)
To detect the presence of LTP - a single, short
stimulating burst delivered to the perforant
pathway, the population EPSP is measured in
the dentate gyrus
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Increased response in the dentate gyrus = LTP has
occurred
Synapses have been strengthened
LTP characteristics
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Synaptic transmission more likely to cause an
action potential in the post-synaptic neuron
Lasts from several minutes to years
Can be induced throughout the brain
Associative long-term potentiation
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Hebbian rule (Donald Hebb):
“Neurons that fire together, wire together”
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Synapses that are reliably active just before
generation of an action potential are strengthened
Simultaneous firing at a weak and a strong
synapse on the same post-synaptic neuron 
strengthens the weak synapse by association
THIS is how associations are learned!
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Ex. Learning to type
Receptor involvement in LTP
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Synaptic strengthening depends on:
1. Neurotransmitter binding at the synapse
2. Simultaneous depolarization of the postsynaptic cell
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Depolarization of a neuron does NOT strengthen
ALL synapses… only those that are active at the
time of depolarization
NMDA receptors and LTP
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LTP relies on calcium influx at
NMDA glutamate receptors
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Calcium channels controlled by the
NMDA receptor are blocked by a
magnesium ion
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Magnesium ion is ejected by:
1. simultaneous glutamate binding
AND
2. depolarization of the post-synaptic
cell (by activity at AMPA receptors on
the membrane)
Strengthening synapses
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Dendritic spike – an action potential results in a backwash of
depolarization up the cell body and dendrites
Dendritic spike + glutamate binding at NMDA receptor =
calcium channels open to allow calcium influx
Role of calcium in LTP
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Calcium is critical to establishing LTP
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Second messenger  activates protein kinases,
which influence chemical reactions in the cell
necessary for LTP
Strengthening synapses
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Three synaptic modifications will support LTP
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Addition of receptors
Addition of synapses
Increased glutamate release from the presynaptic
membrane
Synaptic modifications supporting
LTP – Increased receptors
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Individual synapses are strengthened by an
increase in AMPA receptors on the post-synaptic
membrane
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Increases the cell’s response to glutamate release
Hypothesized mechanism:
1. Calcium activates the CaMK enzyme
2. Activated CaMK binds to an intracellular
portion of the NMDA receptor
3. Linking proteins bind to the CaMK
4. AMPA receptors bind to the linking proteins
and are embedded into the cell membrane
Synaptic modifications supporting
LTP – Synaptogenesis
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LTP results in the multiplication of synapses
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Most synapses are located on dendritic spines
LTP results in division and multiplication of these spines
Mechanism:
1. Postsynaptic density expands until it
perforates – splits into multiple densities
2. Following perforation, the presynaptic active
zone splits into corresponding regions
3. Perforated synapse further divides, until the
spine branches
4. Branched spine ultimately becomes two
spines, each containing a synaptic region
Synaptic modifications supporting
LTP – Synaptogenesis
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Results in the terminal button of one
presynaptic neuron synapsing with multiple
spines on the postsynaptic neuron
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Increases communication potential between the
two cells
Threefold increase in synapses has been
found experimentally
Synaptic modifications supporting
LTP – Presynaptic changes
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LTP is associated with an increase in glutamate
release by the presynaptic neuron
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Influenced by retrograde messengers
Nitric oxide – major retrograde
signal from NMDA receptors to the
presynaptic membrane
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NO is synthesized in the postsynaptic
membrane in response to calcium
influx
Unstable and short-lived, can only
diffuse across the synapse before
breaking down
Acts as a limited, direct messenger
Long-term depression
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Opposite of LTP, long-term depression is a long-lasting
weakening of synapses that are not associated with
strong inputs/production of action potentials
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Seen when two inputs are stimulated at significantly different
times, or when a synapse is activated while a cell is weakly
depolarized or hyperpolarized
Results in the removal of AMPA receptors from the synapse
Weakening of synaptic strength may be necessary
when new learning eliminates the need for previously
established synaptic modifications
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Ex. Remembering a new locker combination
Classifications of memory
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Declarative memory - explicit and readily available
to conscious recollection
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Episodic – memories of events
Semantic memories – memories of facts
Nondeclarative memory - implicit, unconscious
knowledge
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Perceptual – memory of previously experienced stimuli
Motor (procedural) – learned behavioral sequences
Stimulus-response – learned responses to specific stimuli
Perceptual learning
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Neural changes that result in recognizing a
stimulus that has been perceived before
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Ex. Learning to recognize the face of a new
acquaintance
Allows us to identify people, objects & sensations
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New stimuli; changes in previously experienced stimuli
Perceptual learning
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Based on synaptic changes in the sensory
association cortices
Sensory input activates these brain regions;
later input from the same stimulus results in
the same pattern of activation
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Recognition of the stimulus
Classical conditioning
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Learning a specific behavioral response in
the presence of a given stimulus
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Response to an association between two stimuli
Simple, automatic responses
Stimulus-response learning
+
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Steps in classical conditioning
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Neutral stimulus (NS) has no effect
on the subject
Unconditioned stimulus (US) elicits
an unconditioned response (UR)
NS is paired repeatedly with
the US; UR occurs
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NS is presented alone, UR occurs
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NS is now the conditioned stimulus (CS)
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Neural mechanisms of
classical conditioning
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Conditioned emotional response – common
model of classical conditioning
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Demonstrated in footshock paradigm (fear
conditioning)
Tone + Footshock = Freezing behavior
Emotional conditioning relies on the amygdala
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LTP is exhibited in the amygdala following fear
conditioning
Neural mechanisms of
classical conditioning
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Lateral amygdala receives input on both the CS
(tone) and US (footshock)
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Neurons in lateral amygdala receive these signals,
project to the central amygdala (CNA)
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Prior to learning, CS signal forms weak synapses, US
signal forms strong synapses
CNA – generates emotional response (UR: freezing)
Strong synapses from US reliably produce an action
potential in projections to CNA
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Synaptic activation at weak CS synapses + depolarization
by US signal  strengthens CS synapses
CS/US association is formed
Hebb’s rule
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Neurons that fire together, wire together
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Demonstrated by the strengthening of the
connection between neurons signaling the CS
and neurons producing the behavioral response
Repeated firing of the weak tone synapse
+ footshock-produced depolarization
 strengthens the tone synapse
Firing at the tone synapse will now independently
produce an action potential resulting in freezing
behavior.
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Motor learning
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Changes that result in a new sequence of
movements (Procedural memories)
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Establishes new motor skill sequence
Based on changes in the motor system
New behaviors require extensive modification of
brain circuits; adjustments produce changes to
these circuits
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Learning to walk vs. learning to run, skip and dance
Neural control of motor
learning
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Learning a new sequence of motor response
involves sensory input and motor output
Two pathways connect sensory and motor
association cortices:
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Direct transcortical projections
Connections through thalamus and basal ganglia
Neural control of motor
learning
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Initial learning of a complex behavior requires
intense focus on environmental stimuli and
processing of sensory input
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Accomplished by transcortical pathways between
sensory and motor association cortices
As the complex behavior is repeated,
behavior becomes more automatic
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Processing is transferred to the basal ganglia
Neural control of motor
learning
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Basal ganglia receives input from sensory
association areas, and prefrontal cortex
(planning)
Projects to the prefrontal motor association
area, which initiates motor output
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Repetition strengthens the synapses between
sensory inputs and motor outputs
Cortex becomes less involved
Lesions of the basal ganglia disrupt motor
learning and performance of learned motor
behaviors
Operant conditioning
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Learning to make a response in order to gain
reinforcement or avoid punishment
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Formation of associations between a discriminative
stimulus, behavioral output, and resulting
consequences
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Discriminative stimulus: contextual cue
In response to the discriminative stimulus, behavior
occurs
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Reinforcing or punishing stimulus follows the behavior
Animal learns to make the correct behavior in the context,
in order to gain reinforcement/avoid punishment
Operant conditioning
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Behaviors increase when the consequences
are favorable, decrease when outcomes are
aversive
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Learning from our experiences: figuring out
behaviors to repeat, and other behaviors not to
repeat
Stimulus-response learning
Reinforcement
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Outcomes that increase the likelihood of a
behavior
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Neural reinforcement mechanisms strengthen
synapses between neurons that detect
discriminative stimuli and neurons that produce a
behavioral response
Neural circuitry of
reinforcement
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Neural circuitry involved in reinforcement:
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Medial forebrain bundle (MFB) – axon bundle that
extends from the VTA to the NAc, passing through
the lateral hypothalamus
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Stimulation of the MFB is highly rewarding
Common model of reward motivation
Neural circuitry of
reinforcement
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Mesolimbic system – dopamine neurons that project
to the amygdala, hippocampus, and nucleus
accumbens (NAc) – major system involved in
reward motivation
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Dopamine release in the NAc is highly reinforcing
Human research supports a role for the NAc in
reinforcement:
 fMRI: NAc activation when expecting money or sex
Neural circuitry of
reinforcement
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Detection of reinforcing stimuli involves input
from regions that project to the VTA
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Amygdala – detects emotionally relevant stimuli
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Lateral hypothalamus – involved in seeking and
detecting biologically relevant stimuli
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Determines the reinforcing value of stimuli
Signals the presence of reinforcing stimuli
Prefrontal cortex – evaluates sensory stimuli, makes
strategies and evaluates outcomes
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Signals that behavior is succeeding
Neural circuitry of
reinforcement
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Strengthening of synapses by reinforcement
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Dopamine axons from the VTA and
glutamate axons from hippocampus,
amygdala and prefrontal cortex synapse
on the same NAc cells
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NAc projects to basal ganglia, influencing behavioral output
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Depolarization of NAc neurons by DA (reinforcement)
strengthens the glutamatergic synapses, increasing the
likelihood of reinforced behaviors
Relational learning
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Complex learning involving associations between
multiple stimuli, contexts, behaviors and outcomes
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Most learning involve relational learning
Requires learning of individual stimuli, and how each
stimulus is related to the others
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Examples:
 Episodic learning – establishing memories of experiences
 Spatial learning – forming memories of where objects are
located in space
 Observational learning – social learning in which the behaviors
of others are observed and replicated
Hippocampus and
relational learning
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Hippocampus is critical to relational learning
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NMDA receptors in the hippocampus
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Lack of NMDA receptors prevents the establishment of
LTP in the hippocampus and impairs spatial task
learning
Mice with a genetic mutation for more efficient NMDA
receptors exhibit greater EPSPs in the hippocampus
and learn a spatial task much faster than control mice
Spatial memory
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Memory of the location of objects and places
in space
Relies on the right hippocampal formation
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Damage to this area produces profound deficits in
spatial memory
PET shows increased activity in this region while
recalling spatial locations and navigating through
an environment
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Taxi driver study
Hippocampus and spatial
memory
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Hippocampus is not necessary for most simple
stimulus-response learning; it IS critical for relational
learning
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Studied in the Morris water maze - measure of spatial learning
 Animal model of relational learning
Hippocampus and spatial
memory
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Animals and humans with hippocampal
lesions can learn stimulus-response tasks
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Animals with lesions can perform well in the MWM
if released from the same spot every time –
simple stimulus-response learning
Animals with hippocampal lesions fail to learn
spatial relations, and cannot navigate
according to contextual cues
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Animals with hippocampal lesions fail at the MWM
if released from a different location every time
Hippocampal place cells
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Place cells - individual cells in the
hippocampus that fire only when an
animal is in a particular location
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Each place cell responds maximally to
one location, known as its spatial
receptive field
Hippocampal place cells
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Place cells respond based on environmental
cues about location
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Do not intrinsically know where the animal is located
Same arrangement of environmental cues in two different
locations  identical place cell response
Cues that indicate a difference in environments  different
place cell response
Place cells aid in spatial learning by providing a
signal about where the animal is in space
Place cells are concentrated in the dorsal
hippocampus in rats; posterior hippocampus in
humans
Human anterograde amnesia
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Anterograde amnesia – loss of relational
learning ability
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New declarative memories are not formed
Simple stimulus-response, perceptual and motor
learning abilities remain intact
Previously formed memories remain intact
Retrograde amnesia – loss of previously
formed declarative memories
Development of anterograde
amnesia
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Appearance of anterograde amnesia typically
includes some retrograde amnesia
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May be loss of hours, days or years
Results from bilateral damage to, or removal
of the medial temporal lobes
Unilateral damage may produce minor
memory deficits
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Development of anterograde
amnesia
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Famously discovered in H.M.
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Both medial temporal lobes
were removed to treat severe
epilepsy
Resulted in pervasive
anterograde amnesia,
accompanied by some
retrograde amnesia
Development of anterograde
amnesia
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Korsakoff’s syndrome
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Brain damage to the mammillary bodies resulting in
anterograde amnesia
Caused by a lack of vitamin B1 (thiamine) in the
brain
Typically the result of severe alcoholism
Anatomy of amnesia
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Medial temporal lobe contains the
hippocampus – critical to memory formation
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Input to the hippocampus: from the cingulate
cortex and cortical association areas, via
entorhinal cortex
Output: back to cingulate cortex and cortical
association areas, through entorhinal cortex
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Damage to the hippocampus, or its inputs or outputs,
results in anterograde amnesia
Anatomy of amnesia
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CA1 field of the hippocampus –
specific site of action
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Heavily populated with NMDA
receptors
Loss of CA1 field results in
anterograde amnesia
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Control brain
Identified in patients with ischemic
damage resulting in memory loss –
autopsies reveal severe cell loss in
the CA1 field
Amnestic brain
Rempel-Clower, et al., J. Neuroscience, 1996, 16.
Hippocampus and memory
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Learning consists of two major stages:
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Short-term memory – immediate and limited
memory for recently perceived stimuli
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Holds 5-7 items for a few moments
Information can be held in STM indefinitely with
rehearsal – repetition of the information
Long-term memory – stable and unlimited
memory for all learning
Consolidation – shifts information from STM
to LTM
Hippocampus and memory
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Based on extensive study of HM and others with
bilateral medial temporal damage:
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Hippocampus is NOT the location of long-term memory
storage, nor is it responsible for retrieval of long-term
memories
 HM’s long-term memories were intact
Hippocampus is NOT the location of short-term memory
 HM was able to answer questions and hold information in his
mind as long as he rehearsed it
Hippocampus IS involved in consolidation of long-term
memories
 HM was unable to form memories of new information and
experiences