Learning and Memory: Behaviour and simple cellular correlates

Module 632

Sean Sweeney

Aims:

To describe basic behaviours that are simple manifestations of learning and memory.

To outline experimental systems and paradigms thatclosely correlate physiological and molecular events that may manifest as learning and memory

To describe molecular events that are essential to the acquisition of learning and memory in experimental paradigms

Learning

‘An adaptive change in behaviour resulting from experience’

Memory

The retention of learning. Memory allows the productionof a learned/adaptive behaviour at a later time

Short-term Memory:temporarylimited capacityrequires rehearsal

Medium-term memory?

Long-term Memory:‘permanent’greater capacity than short-termno continual rehearsal required

The Engram: ‘a memory representation’

Discrete steps?or a gradation?

Forgetting

Nonassociative mechanisms of learning:

Habituation:

decrease in response to a repeated stimulus not accompanied

by changes in other stimuli

Sensitisation:

an increase in response to a moderate stimuli as a result of

a previous exposure to a strong stimulus

Habituation:

Simplest form of learning

Requires:1) A sensory neuron to bring information in2) A motorneuron to execute movement

Sensitization:

An incremental increase in response to a repetitivestimulus (usually noxious)

Requires:1) A sensory neuron to bring information in2) A motorneuron to execute movement3) An interneuron between the two

Associative Learning:classical conditioning: (aka Pavlovian) pairing of 2 stimuli changes the response to one of them

conditioned stimulus (CS) - originally neutral (no response)unconditioned stimulus (UCS) - automatically evokes response – unconditioned response (UCR) after repetitive pairing of CS and UCS presentation of CS evokes learned response conditioned response (CR)

Operant (instrumental) conditioning:reinforcement by either reward or punishment. The basic principle of operant conditioning is that a response that is followed by a reinforcer ( R) is strengthened and is therefore more likely to occur again. A reinforcer is a stimulus or event that increases the frequency of a response (observable phenomenon) it follows.

There are three conditions important to operant conditioning: 1) reinforcement must follow the responses, 2) reinforcement must follow the response immediately, and 3) reinforcement must be contingent of the expected or desired response.

Identifying Cellular and Molecular Correlates of Learning and Memory: Synaptic Plasticity

What should we be looking for?

Framework from Hebb

How should we look?

Physiological or molecular approach?

Where should we look?

Simple organisms vs complex

Over What Timecourse?

Hebbian learning

When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased (Hebb 1949)

(Or decreased, depending on the paradigm)

A B

A

B

C

UCS

CS

CRC

Associative learning?

Aplysia: Sea snails can learn.

Advantages: large accessible cells amenable to physiologyand the application/injection of drugs or proteins/peptides

The siphon-touch/gill withdrawal paradigm in Aplysia

The siphon withdrawal circuit, physiology in a behavingpreparation

A physiological correlate of an elicited behaviour

Can we find other cellular correlates of learning and memoryin other systems?

Hebbian learning

When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased (Hebb 1949)

A B

Physiological short-term Plasticity:

Paired-Pulse Facilitation and Paired-Pulse Depression

stimulate

record

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Changes that might mediate PPF or PPD?

Short-term presynaptic changes mediating plasticity:

Alterations in K+ channel functionGating of Ca2+ channelsRelease of more vesiclesMobilisation of vesicles from the reserve poolFilling of vesicles with more transmitter?Alterations in sensitivity of release mechanisms

Short-term Postsynaptic changes mediating plasticity :

Gating of Ca2+

Gating of K+ channelsSensitivity of receptorsNumbers of receptors

But what can we actually measure?

Physiological:EPSP amplitudemEPSP sizemEPSP frequency

Molecular/cell biological:Neurotransmitter release (FM1-43 and pHlourin)Release from ‘Readily Releasable Pool’ and ‘Reserve Pool’Synapse size (?)Others?

Resting [Ca2+]

But most important?

But can Ca2+ be dispensed with?

CamKII

Ca2+ can stimulate Ca2+/calmodulin dependent serine/threonine kinase. Sustained activation generates aCa2+ independent active kinase.

The activated ‘meta’-state is a record of recent synaptic activity

CAMKII is post-synaptic

On activation CAMKIItranslocates to the PSD

Can regulate K+ channelsReceptor activityCa2+ channelsCytoskeletal changesTranscriptional output

Silva, A.J. et al., (1992) Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science, 257(5067): p. 206-11.

Silva, A.J. et al., (1992) Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science, 1992. 257(5067): p. 201-6.

More complex electrophyisological models of learning:

Long Term Potentiation

Long Term Depression

Physiological longer-(medium?)-term Plasticity:

Post-tetanic Potentiation

Post-tetanic Depression

2s 4s

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Changes that might mediate PTP or PTD? All of the above, AND……..

Generating a record of synapse use/activity?

cAMP

2s 4s

Neale et al., (2001) European J. of Neuroscience, 14:1313mGlu1 receptors mediate a post-tetanic depression at Parallel fibres-Purkinje cell synapses in rat cerebellum

Glutamate

mGluR

Activation of mGluR can stimulate production of cAMP which may modulate short-to-medium term changes in plasticity

Regulation of local changes?

Could cAMP regulate longer term changes?

Levels of cAMPcan be modulatedby synthesis and degradation

cAMP can inducea transcriptionalresponse

Drosophila: A genetic Model for behavioural plasticity

Advantages:

The ‘Awesome Power of Genetics’!!!!

Simple behaviours

Disadvantages

Limited electrophysiology

Drosophila: Flies can Learn!!!!A Pavlovian paradigm in flies, the olfactory avoidance paradigm

UCS: odour CS: electric shockCR: avoidance

Olfactory avoidanceis mediated by the mushroombodies, a complex structurethat mediates the processing of olfactoryinformation.(deBelle and Heisenberg (1994)Science 263:692)

The MBs are the areaof the brain where the proteinproducts of the dunce,rutabaga and protein kinase Aare most highly expressed

A pavlovian circuit?

See Waddell andQuinn (2001)

Mutations that affect olfactory avoidance behaviour can beused to dissect the time dependence of memoryacquisition and retrieval.

(work of Tim Tully and co-workers, Cold Spring Harbor Laboratory)

LRN=learning STM=short term memoryMTM= medium term memory LTM=long term memoryARM=Anaesthesia resistant memory CXM=cyclohexamide

Flies are smarter than they let on………

In conclusion:

The Engram?

Reading:

Calcium/calmodulin-dependent protein kinase II and synapticPlasticity. Colbran and Brown (2004) Current Opinion in Neurobiology. 14:318-327

deBelle and Heisenberg (1994) Science 263: 692

Flies, Genes and Learning. Waddell and Quinn (2001) Annual Review of Neuroscience 24: 1283-1309

Purves et al. Neuroscience Edition III

Chen et al., (2004) Paired Pulse depression of unitary Quantal amplitude at single hippocampal synapses.P.N.A.S. 101:1063-1068