molecular biology of memory storage: the persistence of...
TRANSCRIPT
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Molecular Biology of Memory Storage:
The Persistence of Memory
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The Study of Memory Has Two Parts:
(1) The Systems Problem of Memory:Where in the brain is memory stored?
(2) The Molecular Problem of Memory:How is memory stored at each site?
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Explicit (Declarative) Implicit (Procedural)
There are Two Major Forms of Long-Term Memory
Requires Conscious Attention
Medial Temporal LobeHippocampus
Factsand
Events
People,Objects and
Places
Does Not Require Conscious Attention
Amygdala, Striatum,Cerebellum, Reflex Pathways
Skills andHabits
Nonassociativeand Associative
Learning
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Explicit (Declarative) Implicit (Procedural)
There are Two Major Forms of Long-Term Memory
Requires Conscious Attention
Medial Temporal LobeHippocampus
Place:Spatial Memory
Does Not Require Conscious Attention
Reflex Pathways
Nonassociative Learning:Learned Fear (Sensitization)
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Temporal
Frontal
Occipital
Parietal
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Abdominal Ganglion of Aplysia
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Identified Cells and Clusters of the Abdominal Ganglion
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The Gill Withdrawal Reflex has a Simple Stereotypical Neural Circuit.Repetition of Sensitization Training Leads to Altered Gene Expression
and the Growth of New Synaptic Connections.
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Sensitization Produces Both Pre- and PostsynapticStructural Changes in the Intact Animal (HRP)
Control Sensitized
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Explicit (Declarative) Implicit (Procedural)
There are Two Major Forms of Long-Term Memory
Requires Conscious Attention
Medial Temporal LobeHippocampus
Place:Spatial Memory
Does Not Require Conscious Attention
Reflex Pathways
Nonassociative Learning:Learned Fear
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Hippocampus of Humans Encodes Space (Mental Time Travel)
Route from Hyde Parkto Primrose Hill
Hyde Park
Primrose Hill
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Hippocampus of Mice Also Encodes Space
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Multi-Sensory Information About Spatial Memory is BroughtTogether in the CA1 Region of the Hippocampus
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Relating Molecular Signaling to the Cognitive Map for Space:The Hippocampal Pyramidal Cells in the CA1 Region Encode
Space
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Is Synaptic Plasticity in the Hippocampal Ca1 RegionImportand for Learning a Spatial Representation and for
Storing a Spatial Memory?
LTP
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The Long-Term Stability of Hippocampal SynapticPlasticity( Long Term Potentiation) Requires PKA
x
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Both the Long-Term Memory for Space and the Long-Term Stability of the Place Cell Map Require PKA
1 h 24 h
Sim
ilarit
y Sc
ore
WTR(AB)
Long-Term Stability ofthe Place Cell Map
% F
reez
ing
(5 m
in)
1 h 24 h
Long-Term Memory ofSpatial Context
x
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How Does Attention Affect the Internal Representation of Space?
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Is Attention Important to Form the Spatial Map or to Stabilize and Perpetuate it?Four Degrees of Attention
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0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
1
30 min
longterm
Short vs. Long Term Instability
Short Term Stability of Place CellsDoes Not Require Selective Attention
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Long Term Place Cell Stability RequiresSelective Attention
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Dopamine as a Candidate Mediator of Attention
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Both Explicit and Implicit Memory Storage Use ModulatoryTransmitters as a Salience Signal and a CREB-Mediated
Transcriptional Switch for Converting Short-term toLong-term Memory
Aplysia(bottom up modulation)
Hippocampus(top down modulation)
Where-PosteriorParietalCortexWhat-
PrefrontalCortex
How is synapse specificity achieved? How is it maintained for the long term?
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What is the Molecular Nature of theSynaptic “Mark”?
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There are Two Molecular Components to the “Synaptic” Mark
0
50
+rp-cAMP
–cAMP
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Rapamycin, a Selective Inhibitor of Protein Synthesis alsoBlocks the Growth-Dependent Late Phase of LTF
Synaptic Capture + Rapamycin Synaptic-Specific LTF + Rapamycin
Initiation Capture Initiation
5 x 5-HT 5 x 5-HT1 x 5-HT
+ or – Rapamycin + or – Rapamycin
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Rapamycin Blocks the Maintenance of Growth @ 72 Hrs
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What is the Function of Local Protein Synthesis?How are the mRNAs that are Transported to the Synapse
Activated Locally?
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AAAAAAAAAAAAAAAORF CPE3UTR
Protein
The Cytoplasmic Polyadenylation Element Binding Protein Can Activate Dormant mRNA
CPEB
Richter And Colleagues
MaskinGEFSymplektinCPSF
PAP
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Local inhibition of CPEB blocksmaintenance of LTF
Branch-specific transduction oftat-ss-CPEBAS1 in L15
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CPEBmRNA
CPEB: A Switch for Activating Local Protein Synthesis
AA
AA
CRE
5 x 5HT
TranslationalMachinery
AA
AA
1x 5HTmRNA:(e.g. N-Actin,
Tubulin)
Proteins: N-ActinTubulin
PI3KinasePKA
CPEB(Synaptic
Mark)
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How does CPEB remain active for the long term in the absence of any further synaptic stimulation?
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20 RandomAplysia Proteins
A Prion-Like Domain at the N-terminal End of Aplysia CPEB
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Properties of a “Prion”1) Two distinct conformational states:one of which forms aggregate.
2) The conformational states are metastable and functionally distinct
Inactive Active
3) The aggregated state is self-perpetuating
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The Full-Length CPEB Protein Can Exist inTwo Functional Conformational States
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X
Blue White
W303a Kar1-15pO Kar1-15pO
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CPEB as a Candidate for the Self-PerpetuatingSwitch of Local Protein Synthesis
AA
Growthand
proteins
AA
CRE
5 x 5HT 1 x 5HT
ConformationA
Conformation B
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3) Is the Aggregated Form The Active Form of CPEB?Only Aggregated Aplysia Neuronal CPEB Protein Binds
Selectively to CPE-Containing RNA
FreeRNA
RNAProtein
- 1 2 3 4
ControlProteins
Purified proteins1 2 3 4
1) Aplysia CPEB2) mCPEB13) GEF4) meIF6
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The “Prion-Like” Properties of Aplysia CPEBAre Different from Known Prions
• The conversion from one state to the other is regulated by a physiological signal.
• The dominant self-perpetuating state is the active state.
Aplysia CPEB might be representative of a newclass of proteins with prion-like properties,which has normal physiological function.
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A Prion-Like Domain at the N-terminal End of Mouse CPEB-3:Comparison with Aplysia CPEB
mCPEB-3
mCPEB-4
mCPEB-1 mCPEB-2
Average Q/N content in mammalian proteins
MQDDLLMDKSKTQPQSQQQQRQQQQQQQQLQPEPGAAEAPSTPLSSEIPKPEDSSAVPALSPASAPPAPNGPDKMQMESPLLPGLSFHQPPQQPPPPQEPTAPGASLSPSFGSTWSTGTTNAVEDSFFQGITPVNGTMLFQNFPHHVNPVFGGTFSPQIGLAQTQHHQQPPPPAPQPPQPAQPPQAQPSQQRRSPASPSQAPYAQRSAAAYGHQPIMTSKPSSSSAVAAAAA
MQAMAVASQSPQTVDQAISVKTDYEDNQQEHIPSNFEIFRRINALLDNSLEANNVSCSQSQSQQQQQQTQQQQQQQQQQQQQQHLQQVQQQRLLKQQQQQAQRQQIQQQLLQQQQQKQQLQQQQQQEQLQQQQLQLQQQLQQQLQHIQKEPSSHTYTPGP
Aplysia CPEB(1-160)
mCPEB-3(1-232)
~48% Q/N
~18% Q/N
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Implicit Memory:Sensitization in Aplysia
Explicit Memory:Spatial Memory in the Mouse
Modulatory Transmitters Serve as Salience Signals to StabilizeSynaptic Plasticity and Behavior for Both Implicit and Explicit Memory
Is the mechanism for maintenance also general?
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Kausik Si
Robert Muller
Craig Bailey
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