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 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
Learning
‘An adaptive change in behaviour resulting from
experience’
Memory
The retention of learning. Memory allows the production
of a learned/adaptive behaviour at a later time
Short-term Memory:
temporary
limited 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?
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 in
2) A motorneuron to execute movement
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
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
Associative learning?
UCS
A
C
C
CS
B
CR
Aplysia: Sea snails can learn.
Advantages: large accessible cells amenable to physiology
and the application/injection of drugs or proteins/peptides
The siphon-touch/gill withdrawal paradigm in Aplysia
The siphon withdrawal circuit, physiology in a behaving
preparation
A physiological correlate of an elicited behaviour
Can we find other cellular correlates of learning and memory
in 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
Changes that might mediate PPF or PPD?
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
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
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?
But most important?
Resting [Ca2+]
But can Ca2+ be dispensed with?
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
CAMKII is post-synaptic
On activation CAMKII
translocates to the PSD
Can regulate K+ channels
Receptor activity
Ca2+ channels
Cytoskeletal changes
Transcriptional 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
Changes that might mediate PTP or PTD?
All of the above, AND……..
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Generating a record of synapse use/activity?
cAMP
2s
4s
Neale et al., (2001) European J. of Neuroscience, 14:1313
mGlu1 receptors mediate a post-tetanic depression at
Parallel fibres-Purkinje cell synapses in rat cerebellum
Activation of mGluR can stimulate production of cAMP which
may modulate short-to-medium term changes in plasticity
Glutamate
mGluR
Regulation of local
changes?
Could cAMP regulate longer term changes?
Levels of cAMP
can be modulated
by synthesis and
degradation
cAMP can induce
a transcriptional
response
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 shock
CR: avoidance
Olfactory avoidance
is mediated by the mushroom
bodies, a complex structure
that mediates the
processing of olfactory
information.
(deBelle and Heisenberg (1994)
Science 263:692)
The MBs are the area
of the brain where the protein
products of the dunce,
rutabaga and protein kinase A
are most highly expressed
A pavlovian circuit?
See Waddell and
Quinn (2001)
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)
Flies are smarter than they let on………
LRN=learning
STM=short term memory
MTM= medium term memory
LTM=long term memory
ARM=Anaesthesia resistant memory
CXM=cyclohexamide
In conclusion:
The Engram?
Reading:
Calcium/calmodulin-dependent protein kinase II and synaptic
Plasticity. 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