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Cellular Mechanisms of Learning and the Biological Basis of Individuality

Cellular Mechanisms of Learning and the Biological Basis of Individuality. 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?. Karl Lashley (1890-1950).

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Cellular Mechanisms of Learning and the Biological Basis of Individuality

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  1. Cellular Mechanisms of Learning and the Biological Basis of Individuality

  2. 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?

  3. Karl Lashley (1890-1950)

  4. Wilder Penfield (1891-1976)

  5. Brenda Milner 1918–

  6. Explicit (Declarative) Implicit (Procedural) Facts and Events People, Objects and Places Skills and Habits Nonassociative And Associative Learning Medial Temporal Lobe Hippocampus Amygdala, Cerebellum, Reflex Pathways Requires Conscious Attention Does Not Require Conscious Attention But Often Requires Salience Signals There are Two Major Forms of Long Term Memory

  7. (5HT) (5HT) The Gill Withdrawal Reflex has a Simple Stereotypical Internal Representation. Long Term Sensitization Leads to Altered Gene Expression and the Growth of New Synaptic Connections.

  8. Long-Term Memory Requires a CREB1-Mediated Transcriptional Cascade

  9. Sensitization Produces Both Pre- and Postsynaptic Structural Changes in the Intact Animal (HRP)  Sensitized

  10. Explicit (Declarative) Implicit (Procedural) Facts and Events People, Objects and Places Skills and Habits Nonassociative and Associative Learning Medial Temporal Lobe Hippocampus Amygdala, Cerebellum, Reflex Pathways Requires Conscious Attention Does Not Require Conscious Attention There are Two Major Forms of Long Term Memory

  11. Hippocampus of Humans Encodes Space Primrose Hill Route from Hyde Park to Primrose Hill Hyde Park

  12. Hippocampus of Mice Also Encodes Space

  13. Multi Sensory Information About Spatial Memory is Only Brought Together in the CA1 Region of the Hippocampus

  14. The Hippocampal Pyramidal Cells Encode a Cognitive Map of Space :Is Attention Importand for Formation of the Map or for its Perpetuation

  15. Is Attention Important to Form the Spatial Map or to Stabilize and Perpetuate it? Four Degrees of Attention

  16. Selective Attention is not Required for the Formation of the Map but is Essential for its Maintenance No Task (Basal Attention) 10 min 3 Hours Day 1 Spatial Task (Maximum Attention)

  17. Long Term Place Cell Stability Requires Selective Attention;Short Term Stability Does Not.

  18. LTP is a Candidate Synaptic Mechanism for Spatial Memory LTP has both an Early and a Late Phase EPSP Slope (% of control)

  19. Dopamine as a Candidate Mediator of Attention

  20. Both the Long-Term Memory for Spatial Context and the Long-Term Stability of the Place Cell Map Require PKA WT R(AB) 1 h 24 h Long Term Stability ofthe Place Cell Map Similarity Score Long Term Memory ofSpatial Context % Freezing (5 min) 1 h 24 h

  21. Both Explicit and Implicit Memory Storage Use Modulatory Transmitters as a Salience Signal and a CREB-Mediated Transcriptional Switch for Converting Short-Term to Long- Term Memory Aplysia (bottom up modulation) Hippocampus (top down modulation) Where- Posterior Parietal Cortex What- Prefrontal Cortex How is synapse specificity achieved? How is it maintained for the long term?

  22. In Addition to Transcription the Growth of New Synapses Requires 2 Local Marking Signals Two Marking Signals 1. PKA for Growth 2. Local Protein Synthesis for Stabilization Local Protein Synthesis is Required to Stabilize the Long Term Facilitation and the Growth of New Synapses

  23. The Cytoplasmic Polyadenylation Element Binding Protein Is a Regulator of Local Protein Synthesis that Can Activate Dormant Transcripts

  24. Properties of a “Prion” Protein (CPEB) 1) At least two distinct conformational states 2) Conformational states are interconvertible 3) One of the conformational states is dominant and can self-perpetuate epigenetically A B

  25. CRE 1 x 5HT 5 x 5HT Conformation B AA Conformation A AA Growth and proteins CPEB as a Candidate for the Self-Perpetuating Switch of Local Protein Synthesis

  26. The “Prion-Like” Properties of Aplysia CPEB Are 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 new class of proteins with prion like properties, which has normal physiological function.

  27. Dopaminergic Stimulation Induces CPEB-3 Expression in the Hippocampus CPEB-3 Naive animal CPEB-3 D1/D5 receptor agonist 2 hr post injection

  28. Modulatory Transmitters Serve as Salience Signals to Stabilize Synaptic Plasticity and Behavior for Both Implicit and Explicit Memory Is the mechanism for maintenance also general? Implicit Memory: Sensitization in Aplysia Explicit Memory: Spatial Memory in the Mouse

  29. Three Methods of Regulating Synaptic Strength Period 1. Development 2. Critical Period 3. Adult Learning Effect on Synapse Initial Synapse Formation Synaptic Fine Tuning Synaptic Modulation Mechanism Molecular Cues Activity Learning

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