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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are needed to see this picture.
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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are needed to see this picture.
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