Learning and Memory

Learning

Set of processes by which experience changes the nervous system, changing behavior Resulting changes are memories

Nondeclarative memories Declarative memories

Enduring changes to the neural circuits

Mechanisms of learning – Synaptic plasticity

Synaptic plasticity Changes in synaptic structure and biochemistry

Long-term potentiation (LTP) Change in the strength of synaptic connections Results from repeated activation

Hippocampal formation - anatomy

Part of the limbic system, located in the temporal lobes

Composed of: Dentate gyrus, CA1-3 & subiculum

Perforant pathway Entorhinal cortex to dentate gyrus Primary source of input

Experimental induction of LTP

Stimulating electrode inserted into the perforant pathway, recording electrode inserted into the dentate gyrus Single burst of stimulation

delivered to the perforant pathway Resulting EPSP recorded in the

neuron population in the dentate gyrus Provides a baseline measure of

normal synaptic firing strength

Experimental induction of LTP

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 Increased response in the dentate gyrus = LTP has

occurred Synapses have been strengthened

LTP characteristics

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

Hebbian rule (Donald Hebb): “Neurons that fire together, wire together” 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! Ex. Learning to type

Receptor involvement in LTP

Synaptic strengthening depends on:1. Neurotransmitter binding at the synapse

2. Simultaneous depolarization of the post-synaptic cell

Depolarization of a neuron does NOT strengthen ALL synapses… only those that are active at the time of depolarization

NMDA receptors and LTP

LTP relies on calcium influx at NMDA glutamate receptors

Calcium channels controlled by the NMDA receptor are blocked by a magnesium ion 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

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

Calcium is critical to establishing LTP Second messenger activates protein kinases,

which influence chemical reactions in the cell necessary for LTP

Strengthening synapses

Three synaptic modifications will support LTP Addition of receptors Addition of synapses Increased glutamate release from the presynaptic

membrane

Synaptic modifications supporting LTP – Increased receptors

Individual synapses are strengthened by an increase in AMPA receptors on the post-synaptic membrane 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

LTP results in the multiplication of synapses 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

Results in the terminal button of one presynaptic neuron synapsing with multiple spines on the postsynaptic neuron Increases communication potential between the

two cells Threefold increase in synapses has been

found experimentally

Synaptic modifications supporting LTP – Presynaptic changes

LTP is associated with an increase in glutamate release by the presynaptic neuron Influenced by retrograde messengers

Nitric oxide – major retrograde signal from NMDA receptors to the presynaptic membrane 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

Opposite of LTP, long-term depression is a long-lasting weakening of synapses that are not associated with strong inputs/production of action potentials 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 Ex. Remembering a new locker combination

Classifications of memory

Declarative memory - explicit and readily available to conscious recollection Episodic – memories of events Semantic memories – memories of facts

Nondeclarative memory - implicit, unconscious knowledge Perceptual – memory of previously experienced stimuli Motor (procedural) – learned behavioral sequences Stimulus-response – learned responses to specific stimuli

Perceptual learning

Neural changes that result in recognizing a stimulus that has been perceived before

Ex. Learning to recognize the face of a new acquaintance

Allows us to identify people, objects & sensations New stimuli; changes in previously experienced

stimuli

Perceptual learning

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 Recognition of the stimulus

Classical conditioning

Learning a specific behavioral response in the presence of a given stimulus Response to an association between two stimuli Simple, automatic responses Stimulus-response learning

+

Steps in classical conditioning

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

NS is presented alone, UR occurs NS is now the conditioned stimulus (CS)

+

Neural mechanisms of classical conditioning

Conditioned emotional response – common model of classical conditioning Demonstrated in footshock paradigm (fear

conditioning) Tone + Footshock = Freezing behavior

Emotional conditioning relies on the amygdala LTP is exhibited in the amygdala following fear

conditioning

Neural mechanisms of classical conditioning

Lateral amygdala receives input on both the CS (tone) and US (footshock) Prior to learning, CS signal forms weak synapses, US

signal forms strong synapses

Neurons in lateral amygdala receive these signals, project to the central amygdala (CNA) CNA – generates emotional response (UR: freezing)

Strong synapses from US reliably produce an action potential in projections to CNA Synaptic activation at weak CS synapses + depolarization

by US signal strengthens CS synapses CS/US association is formed

Hebb’s rule

Neurons that fire together, wire together 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.

Motor learning

Changes that result in a new sequence of movements (Procedural memories) 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 Learning to walk vs. learning to run, skip and dance

Neural control of motor learning

Learning a new sequence of motor response involves sensory input and motor output

Two pathways connect sensory and motor association cortices: Direct transcortical projections Connections through thalamus and basal ganglia

Neural control of motor learning

Initial learning of a complex behavior requires intense focus on environmental stimuli and processing of sensory input Accomplished by transcortical pathways between

sensory and motor association cortices As the complex behavior is repeated,

behavior becomes more automatic Processing is transferred to the basal ganglia

Neural control of motor learning

Basal ganglia receives input from sensory association areas, and prefrontal cortex (planning)

Projects to the prefrontal motor association area, which initiates motor output 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

Learning to make a response in order to gain reinforcement or avoid punishment Formation of associations between a discriminative

stimulus, behavioral output, and resulting consequences Discriminative stimulus: contextual cue

In response to the discriminative stimulus, behavior occurs 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

Behaviors increase when the consequences are favorable, decrease when outcomes are aversive Learning from our experiences: figuring out

behaviors to repeat, and other behaviors not to repeat

Stimulus-response learning

Reinforcement

Outcomes that increase the likelihood of a behavior Neural reinforcement mechanisms strengthen

synapses between neurons that detect discriminative stimuli and neurons that produce a behavioral response

Neural circuitry of reinforcement

Neural circuitry involved in reinforcement: Medial forebrain bundle (MFB) – axon bundle that

extends from the VTA to the NAc, passing through the lateral hypothalamus Stimulation of the MFB is highly rewarding Common model of reward motivation

Neural circuitry of reinforcement

Mesolimbic system – dopamine neurons that project to the amygdala, hippocampus, and nucleus accumbens (NAc) – major system involved in reward motivation 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

Detection of reinforcing stimuli involves input from regions that project to the VTA Amygdala – detects emotionally relevant stimuli

Determines the reinforcing value of stimuli Lateral hypothalamus – involved in seeking and

detecting biologically relevant stimuli Signals the presence of reinforcing stimuli

Prefrontal cortex – evaluates sensory stimuli, makes strategies and evaluates outcomes Signals that behavior is succeeding

Neural circuitry of reinforcement

Strengthening of synapses by reinforcement Dopamine axons from the VTA and

glutamate axons from hippocampus, amygdala and prefrontal cortex synapse

on the same NAc cells

NAc projects to basal ganglia, influencing behavioral output

Depolarization of NAc neurons by DA (reinforcement) strengthens the glutamatergic synapses, increasing the likelihood of reinforced behaviors

Relational learning

Complex learning involving associations between multiple stimuli, contexts, behaviors and outcomes Most learning involve relational learning

Requires learning of individual stimuli, and how each stimulus is related to the others 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

Hippocampus is critical to relational learning NMDA receptors in the hippocampus

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

Memory of the location of objects and places in space

Relies on the right hippocampal formation 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 Taxi driver study

Hippocampus and spatial memory

Hippocampus is not necessary for most simple stimulus-response learning; it IS critical for relational learning Studied in the Morris water maze - measure of spatial learning

Animal model of relational learning

Hippocampus and spatial memory

Animals and humans with hippocampal lesions can learn stimulus-response tasks 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 Animals with hippocampal lesions fail at the MWM

if released from a different location every time

Hippocampal place cells

Place cells - individual cells in the hippocampus that fire only when an animal is in a particular location Each place cell responds maximally to

one location, known as its spatial receptive field

Hippocampal place cells

Place cells respond based on environmental cues about location 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

Anterograde amnesia – loss of relational learning ability 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

Appearance of anterograde amnesia typically includes some retrograde amnesia 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

Development of anterograde amnesia

Famously discovered in H.M. Both medial temporal lobes

were removed to treat severe epilepsy

Resulted in pervasive anterograde amnesia, accompanied by some retrograde amnesia

Development of anterograde amnesia

Korsakoff’s syndrome 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

Medial temporal lobe contains the hippocampus – critical to memory formation 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 Damage to the hippocampus, or its inputs or outputs,

results in anterograde amnesia

Anatomy of amnesia

CA1 field of the hippocampus – specific site of action Heavily populated with NMDA

receptors Loss of CA1 field results in

anterograde amnesia Identified in patients with ischemic

damage resulting in memory loss – autopsies reveal severe cell loss in the CA1 field

Control brain

Amnestic brainRempel-Clower, et al., J. Neuroscience, 1996, 16.

Hippocampus and memory

Learning consists of two major stages: Short-term memory – immediate and limited

memory for recently perceived stimuli 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

Based on extensive study of HM and others with bilateral medial temporal damage: 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