Learning and Memory: Behaviour and simple

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Learning and Memory Behaviour and simple
cellular correlates
Module 632 Sean Sweeney
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Aims To describe basic behaviours that are
simple manifestations of learning and
memory. To outline experimental systems and
paradigms that closely 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
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Learning An adaptive change in behaviour
resulting from experience
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Memory The retention of learning. Memory allows
the production of a learned/adaptive behaviour at
a later time Short-term Memory temporary limit
ed capacity requires rehearsal Medium-term
memory? Long-term Memory permanent greater
capacity than short-term no continual rehearsal
required The Engram a memory representation
Discrete steps? or a gradation?
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Forgetting
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Nonassociative mechanisms of learning Habituatio
n 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
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• Habituation
• Simplest form of learning
• Requires
• 1) A sensory neuron to bring information in
• 2) A motorneuron to execute movement

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• Sensitization
• An incremental increase in response to a
  repetitive
• stimulus (usually noxious)
• Requires
• 1) A sensory neuron to bring information in
• 2) A motorneuron to execute movement
• 3) An interneuron between the two

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• 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)

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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.

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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?
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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)
B
A
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Associative learning?
A
UCS
CR
B
CS
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Aplysia Sea snails can learn.
Advantages large accessible cells amenable to
physiology and the application/injection of drugs
or proteins/peptides
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The siphon-touch/gill withdrawal paradigm in
Aplysia
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The siphon withdrawal circuit, physiology in a
behaving preparation
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A physiological correlate of an elicited behaviour
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Can we find other cellular correlates of learning
and memory in other systems?
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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)
B
A
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Physiological short-term Plasticity
Paired-Pulse Facilitation and Paired-Pulse
Depression
stimulate
record
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Changes that might mediate PPF or PPD?
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Short-term presynaptic changes mediating
plasticity Alterations in K channel
function Gating of Ca2 channels Release of more
vesicles Mobilisation of vesicles from the
reserve pool Filling of vesicles with more
transmitter? Alterations in sensitivity of
release mechanisms Short-term Postsynaptic
changes mediating plasticity Gating of
Ca2 Gating of K channels Sensitivity of
receptors Numbers of receptors
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But what can we actually measure?

• Physiological
• EPSP amplitude
• mEPSP size
• mEPSP frequency
• Molecular/cell biological
• Neurotransmitter release (FM1-43 and pHlourin)
• Release from Readily Releasable Pool and
  Reserve Pool
• Synapse size (?)
• Others?

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But most important?
Resting Ca2
But can Ca2 be dispensed with?
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Ca2 can stimulate Ca2/calmodulin dependent
serine/threonine kinase. Sustained activation
generates a Ca2 independent active kinase.
CamKII
The activated meta-state is a record of recent
synaptic activity
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CAMKII is post-synaptic
On activation CAMKII translocates to the PSD Can
regulate K channels Receptor activity Ca2
channels Cytoskeletal changes Transcriptional
output
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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
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Physiological longer-(medium?)-term Plasticity
Post-tetanic Potentiation
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Post-tetanic Depression
2s
4s
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Changes that might mediate PTP or PTD? All of
the above, AND..
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Generating a record of synapse use/activity?
cAMP
Neale et al., (2001) European J. of Neuroscience,
141313 mGlu1 receptors mediate a post-tetanic
depression at Parallel fibres-Purkinje cell
synapses in rat cerebellum
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Activation of mGluR can stimulate production of
cAMP which may modulate short-to-medium term
changes in plasticity
Regulation of local changes?
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Could cAMP regulate longer term changes?
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Levels of cAMP can be modulated by synthesis and
degradation
cAMP can induce a transcriptional response
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Drosophila A genetic Model for behavioural
plasticity Advantages The Awesome Power of
Genetics!!!! Simple behaviours Disadvantages
Limited electrophysiology
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Drosophila Flies can Learn!!!!
A Pavlovian paradigm in flies, the olfactory
avoidance paradigm
UCS odour CS electric shock CR avoidance
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Olfactory avoidance is mediated by the
mushroom bodies, a complex structure that
mediates the processing of olfactory information.
(deBelle and Heisenberg (1994) Science
263692) The MBs are the area of the brain where
the protein products of the dunce, rutabaga and
protein kinase A are most highly expressed
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A pavlovian circuit? See Waddell and Quinn (2001)
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Mutations that affect olfactory avoidance
behaviour can be used to dissect the time
dependence of memory acquisition and
retrieval. (work of Tim Tully and co-workers,
Cold Spring Harbor Laboratory)
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Flies are smarter than they let on
LRNlearning STMshort term memory MTM medium
term memory LTMlong term memory ARMAnaesthesia
resistant memory CXMcyclohexamide
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In conclusion The Engram?
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Reading Calcium/calmodulin-dependent protein
kinase II and synaptic Plasticity. Colbran and
Brown (2004) Current Opinion in Neurobiology.
14318-327 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. 1011063-1068