Neural Mechanisms of Memory Molecular Basis of Neural Plasticity

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Neural Mechanisms of MemoryMolecular Basis of
Neural Plasticity
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A Strategic Approach(Eric Kandel, Nobel Laureate)

• What Type of Memory to Study?
• What Type of Nervous System to Study?
• Where in the Nervous System are Memories Stored?
• How are they Stored?

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A Strategic Approach(Eric Kandel, Nobel Laureate)

• What Type of Memory to Study?
• There are different types of memory
• Explicit (conscious, verbal e.g. names, faces)
  requiring
• judgement and comparison you look familiar
• Implicit (unconscious, e.g. motor skills like
  typing,
• simple associative classical conditioning)

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Explicit and Implicit Memories Use Different
Parts of CNS

• The Famous Case of HM
• Seizure surgery for temporal lobe epilepsy
  removed the hippocampus in both hemispheres

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Explicit and Implicit Memories Use Different
Parts of CNS

• The Famous Case of HM
• Seizure surgery for temporal lobe epilepsy
  removed the hippocampus in both hemispheres

Effects on HMs Memory Lost the ability to
create new long term explicit memories, but kept
existing memories Retained ability to create
new implicit memories and hold them
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Explicit and Implicit Memories Use Different
Parts of CNS

• The Famous Case of HM
• Seizure surgery for temporal lobe epilepsy
  removed the hippocampus in both hemispheres

Effects on HMs Memory Because HM could retain
new explicit memories only for a short time,but
he kept his existing explicit memories - It
appears that long and short term memories are
stored differently
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Explicit and Implicit Memories Use Different
Parts of CNS

• The Famous Case of HM
• Seizure surgery for temporal lobe epilepsy
  removed the hippocampus in both hemispheres

Effects on HMs Memory It appears that long and
short term memories are stored differently Memorie
s are held for a short time in the hippocampus
(hours, days), then they are transferred to other
cortical areas for long term storage.
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A Strategic Approach(Eric Kandel, Nobel Laureate)

• What Type of Memory to Study?
• Implicit Memories have been most
• intensively studied because
• Simplicity
• Rules of acquisition and retention are common
• from invertebrates to humans

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A Strategic Approach(Eric Kandel, Nobel Laureate)

• Types of Implicit Memories Studied
• Habituation
• Sensitization
• Classical Conditioning

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A Strategic Approach(Eric Kandel, Nobel Laureate)

• What Type of Memory to Study?
• What Type of Nervous System to Study?
• Where in the Nervous System are Memories Stored?
• How are they Stored?

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A Strategic Approach(Eric Kandel, Nobel Laureate)

• What Type of Nervous System to Study?
• Simpler Systems Approach

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A Strategic Approach(Eric Kandel, Nobel Laureate)

• What Type of Memory to Study?
• What Type of Nervous System to Study?
• Where in the Nervous System are Memories Stored?
• How are they Stored?

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Where in the Nervous System are Memories
Stored?How are they Stored?

• A Brief History of the Synaptic Theory of Memory
• S-R theories of learning and memory
• Studies of reflexes in the spinal cord
• Four models of synaptic change arose

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A Brief History of the Synaptic Theory of Memory
Where in the Nervous System are Memories
Stored?How are they Stored?

• Four models of synaptic change
• The Hebb Synapse (1949) Pre-post synaptic
  activity is required
• The Schimbel Synapse (1950) Post synaptic
  activity only
• The Eccles Synapse (1953) Pre synaptic activity
  only
• The Burke Synapse (1966) Pre-Pre synaptic
  activity only
• The Evidence to date favours Burke, Eccles and
  Hebb
• types

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A Strategic Approach to the Functional
Neuroanatomy of Memory

• If memories are stored at synapses, it still
  requires identification of those synapses, both
  their location and their nature.
• Simpler system approach facilitated this process
  of discovery (though it still has taken gt20 years)

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Functional Neuroanatomy of Memory Unraveling
the neural circuitry used in implicit memory
formation in Aplysia
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Habituation of Gill Withdrawal in AplysiaWhat,
Where and How
Habituation is a simple form of learning NOT to
respond. Repeated and regular siphon stimulation
results in reduced response (slower and less
strong) gill withdrawal. The same could be
produced by touching the tail. Repeated
stimulation produces long lasting reduction of
response (gt 3 weeks)
Recovery can be spontaneous over time (memory
fading) or reversed temporarily by strong
stimulation (dishabituation).
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Habituation of Gill Withdrawal in Aplysia
Where
Habituation involves a change in strength of
synaptic transmission at the sensory-motor
synapse from siphon sensory to gill motor neurons
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Habituation of Gill Withdrawal in Aplysia
Where and How
Homosynaptic Depression

• Mechanisms
• Not fully understood
• Changes involved -
• functional
• structural

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Habituation of Gill Withdrawal in Aplysia
Where and How

• Mechanisms
• Functional

Homosynaptic Depression
Reduced transmitter release to the same
input May reflect n type Ca channel
conductance changes as in NE autoreceptor function
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Habituation of Gill Withdrawal in Aplysia
Where and How

• Mechanisms
• Functional

Homosynaptic Depression
Reduced transmitter release to the same
input Reduction in vesicles in the
releasable pool Reflects the fact that there is
a reduction in sensory neuron synapses with
active zones, a type of structural change.
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Habituation of Gill Withdrawal in Aplysia
Where and How

• Mechanisms
• Structural
• Loss of synaptic
• knobs
• Loss of active zones
• in synapses with
• synaptic knobs
• Molecular steps are
• not yet understood

Homosynaptic Depression
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A Brief History of the Synaptic Theory of Memory
Where in the Nervous System are Memories
Stored?How are they Stored?

• Four models of synaptic change
• The Hebb Synapse (1949) Pre-post synaptic
  activity is required
• The Schimbel Synapse (1950) Post synaptic
  activity only
• The Eccles Synapse (1953) Pre synaptic activity
  only
• The Burke Synapse (1966) Pre-Pre synaptic
  activity only
• Habituation in Aplysia is an Eccles type of
  synaptic change

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A Strategic Approach(Eric Kandel, Nobel Laureate)

• Types of Implicit Memories Studied
• Habituation
• Sensitization
• Classical Conditioning

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Sensitization of Gill Withdrawal in AplysiaWhat,
Where and How
Sensitization is a simple form of learning to
respond more strongly to one stimulus after
strong stimulation from another source, such as
a shock. Often seen as an indiscriminant form
of defense - when in doubt, protect
yourself. Strong shocks to the tail will
increase later gill withdrawal to siphon (or
mantle shelf) tactile stimulation. Repeated
shocks result in increased response (faster and
stronger) gill withdrawal. Repeated stimulation
produces long lasting enhancement of response
(gt 3 weeks).
Recovery can be spontaneous over time (memory
fading).
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Sensitization of Gill Withdrawal in Aplysia
Where
Sensitization involves a change in strength of
synaptic transmission at the sensory-motor
synapse from siphon sensory to gill motor neurons
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Sensitization of Gill Withdrawal in Aplysia
Where and How
A Form of Presynaptic Facilitation

• Mechanisms
• Short and long term
• sensitization involve
• different but related
• mechanisms
• Changes are -
• functional
• structural

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Sensitization of Gill Withdrawal in Aplysia
Where and How

• Mechanisms
• Functional

Short Term Sensitization
Serotonin S receptor (metabatrobic)
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Sensitization of Gill Withdrawal in Aplysia
Where and How

• Mechanisms
• Functional

Short Term Sensitization
Serotonin S receptor (metabatrobic) Engages
phosphoinositide metabatrobic receptor which
activates PLC, PLC produces DAG, IP3. IP3
raises terminal free calcium, moving vesicles
from storage to releasable pools. DAG activates
PKC
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Sensitization of Gill Withdrawal in Aplysia
Where and How

• Mechanisms
• Functional

Short Term Sensitization
Serotonin S receptor (metabatrobic) Activates
adenylyl cyclase producing cAMP cAMP activates
cAMP dependent PK which together with DAG-PKC
phosphorylate and Close K Channels Open L type
Ca Channels
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Sensitization of Gill Withdrawal in Aplysia
Where and How

• Mechanisms
• Functional

Short Term Sensitization
Serotonin S receptor (metabatrobic) Closing K
channels reduces rectification of incoming
depolarization's, making them longer. This
prolongs n type Ca currents. More Ca flows into
the terminal and more transmitter is
released Opening L Channels also increases Ca in
the terminal
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Sensitization of Gill Withdrawal in Aplysia
Where and How

• Mechanisms
• Structural

Long Term Sensitization
Serotonin S receptor (metabatrobic) All of the
short term changes occur, but increased
release is prolonged by alterations of gene
transcription. The shift to long term change is
related to short term processes because it
involves the same receptor and cAMP dependent PK
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Sensitization of Gill Withdrawal in Aplysia How
Mechanisms of Long Term Sensitization-Structural-g
enetic
All of the short term changes occur, but
increased release is prolonged by alterations
of gene transcription. The shift to long term
change is related to short term processes
because it involves the same receptor and cAMP
dependent PK. This kinase is translocated to the
nucleus and phosphorylates CREB (Cyclic AMP
Response Element Binding Protein)
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Sensitization of Gill Withdrawal in Aplysia How
Mechanisms of Long Term Sensitization-Structural-g
enetic
Phosphorylated CREB dimerizes, and binds to the
CRE (Cyclic AMP Response Element) in the
enhancer binding site of DNA. This initiates
transcription of new proteins, among them
Ubiquitin Hydrolase (a persistent kinase) and a
variety of other proteins needed for synaptic
structural changes, like synaptic restructuring
and the growth of new synaptic connections.
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Sensitization of Gill Withdrawal in Aplysia How
Mechanisms of Long Term Sensitization-Structural-g
enetic
Ubiquitin Hydrolase acts as a persistent
proteolytic kinase. This enzyme digests
regulatory subunits of PKC, causing a
persistence of phosphorylation of L type Ca
channels and of K channels. This action
prolongs the effects of L type Ca channel
opening and K type channel closing on the
potentiation of transmitter release in response
to action potentials.
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Sensitization of Gill Withdrawal in Aplysia How
Mechanisms of Long Term Sensitization-Structural-g
enetic
Phosphorylated CREB dimerizes, and binds to
the CRE (Cyclic AMP Response Element) in
the enhancer binding site of DNA. This
initiates transcription of new proteins, such
as clathrin and active zone proteins.
These are needed to help complete synaptic
restructuring evident as an increase in
perforated synaptic structures.
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Sensitization of Gill Withdrawal in Aplysia
Mechanisms of Long Term Sensitization -
Structural-genetic
Phosphorylated CREB dimerizes, and binds to
the CRE (Cyclic AMP Response Element) in
the enhancer binding site of DNA. This
initiates transcription of new proteins, such
as clathrin and active zone proteins.
These are needed to help complete synaptic
restructuring evident as an increase in
perforated synaptic structures and a
proliferation of new synapses.
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Sensitization of Gill Withdrawal in Aplysia
Mechanisms of Long Term Sensitization -
Structural-genetic
The orchestration of transcription of so many
new proteins in synaptic restructuring and
proliferation of new synapses likely involves
more than CREB dimers. CREB can dimerize with
other regulating proteins, such as CREB-ATF1
(Activating Transcription Factor 1) or
CREB-CREM (Cyclic AMP Response Element
Modulating Protein). These dimers target
different gene regulating sites to increase
transcription of new proteins, among them other
gene regulating proteins
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Sensitization of Gill Withdrawal in Aplysia
Mechanisms of Long Term Sensitization -
Structural-genetic
Phosphorylated CREB dimerizes, and binds to the
CRE (Cyclic AMP Response Element) in the
enhancer binding site of DNA. This initiates
transcription of new proteins, such as
NCAMs (neural cell adhesion molecules). In
Aplysia these are called APCAMs. NCAMs are
needed to help complete proliferation of new
synapses. CAMs may be recruited in two ways,
one by gene transcription, the other by
endocytosis for delivery to an area of new
synaptic growth or degraded as in the loss of a
synapse in habituation.
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Sensitization of Gill Withdrawal in Aplysia
Mechanisms of Long Term Sensitization -
Structural-genetic
NCAMs (neural cell adhesion molecules)
(APCAMs in Aplysia) are glycoproteins with
sialic acid in their oligosaccaride trees.
One role is to organize actin filament assembly
of cell skeleton as new synapses are formed.
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Sensitization of Gill Withdrawal in Aplysia
Mechanisms of Long Term Sensitization -
Structural-genetic
NCAMs are glycoproteins with sialic acid in
their oligosaccaride trees. They provide a
means of gluing pre and post synaptic
membranes together.
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Sensitization in Aplysia is a Burke Typeof
Synaptic Change

• The Burke Synapse (1966) Pre-Pre synaptic
  activity only

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A Strategic Approach(Eric Kandel, Nobel Laureate)

• Types of Implicit Memories Studied
• Habituation (non associative memory)
• Sensitization (non associative memory
• Classical Conditioning
• (a form of associative memory)

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Classical Conditioning

• First described by Pavlov (his famous dog)
• Involves association of a CS (Conditioned
  Stimulus)
• with a UCS (Unconditioned Stimulus)
• Detected by the fact that the CS comes to elicit
• the same response elicited by the UCS, the
  UCR
• (Unconditioned Response).
• The response elicited by the CS is called a CR
• the (Conditioned Response)

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Classical Conditioning

• Rules of association in Classical Conditioning
• imply this may form in part our sense of
  causality
• CS must precede the UCS
• CS and UCS must terminate together
• This form of associative memory is superior
• to non associative memory (habituation,
  sensitization),
• because more discriminating information is
  acquired.
• However, maladaptive superstitious behavior
  can also
• result. Agoraphobia may be a case of
  superstitious
• association.

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Classical Conditioning

• What is it in Aplysia?

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Classical Conditioning of Gill Withdrawal in
Aplysia - Where does it occur?
When CS is Mantle Shelf stimulation, change
is here
When CS is Siphon skin stimulation, change
is here
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Classical Conditioning of Gill Withdrawal in
Aplysia - How does the association occur?
When there is association (CS), CS stimulation
preceding shock to tail opens voltage gated Ca
channels, Ca binds calmodulin and primes
adenylyl cyclase to produce a lot of cAMP when
shock to the tail activates serotonin receptor.
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Classical Conditioning of Gill Withdrawal in
Aplysia - How does the association occur?
When there is association (CS), CS stimulation
preceding shock to tail opens voltage gated Ca
channels, Ca binds calmodulin and primes
adenylyl cyclase to produce a lot of cAMP when
shock to the tail activates serotonin receptor.
Production of cAMP engages cAMP dependent
processes like those in sensitization.
Presumably many of the same changes
are initiated, including structural. The CS must
precede UCS rule arises from the importance of
priming adenylyl cyclase with Ca-calmodulin.
Ca may be said to mediate the association
between CS and UCS.
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Classical Conditioning of Gill Withdrawal in
Aplysia - How does the association occur?
When there is no association (CS-), shock to tail
produces little cAMP in the sensory synapse
because Ca-Calmodulin amplification is not
engaged and no change occurs in the sensory
synapse.
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Classical Conditioning of Gill Withdrawal in
Aplysia - What has study of Aplysia taught us?

• There is accumulating evidence for the importance
  of cAMP
• dependent second messenger based processes and
  phosphorylated
• CREB in formation of associative memories.
• This evidence has been found in many species,
  including
• fruit flies, mice and rats.
• This apparent cross species generality suggests a
  general mechanism
• for establishing associative memories and
  perhaps implicit
• memories per se.
• The precise biochemical pathways engaged by cAMP
  and CREB
• may vary in different species and in different
  learning paradigms,
• however.