Memory2

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Memory2

  1. 1. Molecular Mechanisms of Learning and Memory
  2. 2. Procedural Learning <ul><li>Learning a motor response (procedure) in relation to a sensory input </li></ul><ul><li>Two types: </li></ul><ul><ul><li>Nonassociative learning </li></ul></ul><ul><ul><li>Associative learning </li></ul></ul>
  3. 3. Contrast to Declarative Memory <ul><li>Declarative Memory: </li></ul><ul><ul><li>Easily formed and easily forgotten </li></ul></ul><ul><ul><li>Created by small modifications of synapses </li></ul></ul><ul><ul><li>Widely distributed in the brain </li></ul></ul><ul><ul><li>Difficult to study </li></ul></ul><ul><li>Procedural Memory: </li></ul><ul><ul><li>Is robust (not easily lost) </li></ul></ul><ul><ul><li>Can be formed along simple reflex pathways </li></ul></ul><ul><ul><li>Easier to study </li></ul></ul>
  4. 4. Nonassociative Learning <ul><li>A change in behavior over time in response to a single type of stimulus </li></ul><ul><li>Two types: </li></ul><ul><li>Habituation </li></ul><ul><ul><li>Learning to ignore a stimulus that lacks meaning </li></ul></ul><ul><ul><li>The response to a repeated stimulus decreases </li></ul></ul><ul><li>Sensitization </li></ul><ul><ul><li>A strong sensory stimulus can intensify your response to all stimuli </li></ul></ul><ul><ul><li>The response to a given stimulus increases </li></ul></ul>
  5. 5. Associative Learning <ul><li>Formation of associations between two events </li></ul><ul><li>Two Types: </li></ul><ul><li>Classical conditioning </li></ul><ul><ul><li>associating an effective, response-evoking stimulus with a second, normally ineffective stimulus </li></ul></ul><ul><ul><li>Pavlov’s dogs </li></ul></ul><ul><li>Instrumental conditioning </li></ul><ul><ul><li>associating a motor action with a stimulus </li></ul></ul><ul><ul><li>pressing a lever produces a food pellet </li></ul></ul>
  6. 6. Invertebrate Systems <ul><li>Provide models to study learning & behavior: </li></ul><ul><li>Small nervous systems </li></ul><ul><ul><li>perhaps 1000 neurons, 10 7 fewer than humans </li></ul></ul><ul><li>Large neurons </li></ul><ul><ul><li>easy to study electro-physiologically </li></ul></ul><ul><li>Identifiable neurons </li></ul><ul><ul><li>can be identified from animal to animal </li></ul></ul><ul><li>Identifiable circuits </li></ul><ul><ul><li>identifiable neurons make the same connections with one another from animal to animal </li></ul></ul><ul><li>Simple genetics </li></ul><ul><ul><li>small genomes and short life cycles </li></ul></ul>
  7. 7. Aplysia as a Model for Learning <ul><li>The sea slug Aplysis californica , is used for studies in neurobiology </li></ul><ul><li>Exhibits simple forms of learning, including habituation, sensitization, and classical conditioning </li></ul>
  8. 8. Aplysia & Nonassociative Learning <ul><li>Gill withdrawal reflex </li></ul><ul><ul><li>A jet of water squirted on a portion of the slug (the siphon) causes withdrawal of the siphon & the gill </li></ul></ul><ul><li>Habituation </li></ul><ul><ul><li>After repeated trials, effect is diminished </li></ul></ul>
  9. 9. What Causes Habituation? <ul><li>Motor neuron, L7, receives direct sensory input from the siphon & innervates muscles used for gill withdrawal </li></ul><ul><li>Showed that habituation occurs at the synapse between sensory & motor neuron </li></ul><ul><li>Progressive decrease in the size of excitatory postsynaptic potentials (EPSP's) </li></ul><ul><li>Mechanism: </li></ul><ul><ul><li>less calcium enters presynaptic terminal </li></ul></ul><ul><ul><li>so fewer transmitter molecules are released </li></ul></ul><ul><li>Therfore presynaptic modification </li></ul>
  10. 10. Neurons in Habituation
  11. 11. Gill Withdrawal Reflex Sensitization <ul><li>Shock to head associated with stimulation of siphon increases gill withdrawal reflex = sensitization </li></ul><ul><li>How does this work? </li></ul><ul><ul><li>Neuron from head (L29) synapses on the axon terminal of the sensory neuron </li></ul></ul><ul><ul><li>Releases serotonin </li></ul></ul><ul><ul><li>Causes molecular cascade that sensitizes sensory axon terminal </li></ul></ul>
  12. 12. Neurons in Sensitization
  13. 13. Sensitization Cascade <ul><li>Serotonin receptor on the sensory axon terminal is a G-protein coupled receptor </li></ul><ul><li>Binding activates adenylyl cyclase enzyme </li></ul><ul><li>Which produces cyclic AMP (2 nd messenger) </li></ul><ul><li>Which activates protein kinase A (PKA) </li></ul><ul><li>Which phosphorylates a protein forming the potassium channel </li></ul><ul><li>Which causes it to close </li></ul><ul><li>Prolonging the presynaptic action potential </li></ul><ul><li>So more calcium enters </li></ul><ul><li>Thus more neurotransmitters are released </li></ul>
  14. 14. Associative Learning in Aplysia <ul><li>Classical conditioning: </li></ul><ul><li>Unconditioned stimulus = shock to tail </li></ul><ul><li>Conditioned stimulus = siphon stimulation </li></ul><ul><li>If the 2 stimuli were paired, subsequent gill withdrawal response to siphon stimulation alone was greater </li></ul><ul><li>Uses same neuron as sensitization, through an interneuron </li></ul>
  15. 15. Molecular Mechanism <ul><li>CS response (gill withdrawal) results from influx of calcium ions </li></ul><ul><li>US (tail shock) causes G-protein coupled activation of adenylyl cyclase </li></ul><ul><li>Elevated Ca ++ causes adenylyl cyclase to make more cAMP </li></ul><ul><ul><li>This increases total cascade, resulting in more neurotransmitter release </li></ul></ul><ul><li>Learning occurs when presynaptic Ca ++ release coincides with G-protein activation of adenylyl cyclase producing abundant cAMP </li></ul><ul><li>Memory occurs when K + channels are phosporylated increasing transmittere release </li></ul>
  16. 16. Molecular Changes & Memory <ul><li>One synapse affects another synapse. </li></ul><ul><li>Short term memory can be produced when a weak stimulus causes phosphorylation of ion channels, leading to release of an increased amount of transmitter. </li></ul><ul><li>Long term memory requires a stronger and more long-lasting stimulus causing increased cAMP, which causes further activation of protein kinases. </li></ul>
  17. 17. Visualizing Memory Changes <ul><li>Short-term memory </li></ul><ul><ul><li>thin arrows in the left lower part of the figure </li></ul></ul><ul><li>Long-term memory </li></ul><ul><ul><li>bold arrows </li></ul></ul>
  18. 18. Lessons Learned <ul><li>Learning and memory can result from modification of synaptic transmission </li></ul><ul><li>Synaptic modifications can be triggered by conversion of neural activity to 2 nd messengers </li></ul><ul><li>Memories can result from alterations in existing synaptic proteins </li></ul>
  19. 19. Vertebrate Models of Learning <ul><li>The cerebellum, because of its role in motor control, is a model system to study synaptic basis of learning in higher organisms </li></ul><ul><ul><li>Site of motor learning </li></ul></ul><ul><ul><li>Place where corrections of movement are made </li></ul></ul>
  20. 20. Anatomy of the Cerebellar Cortex <ul><li>2 layers of neuronal cell bodies: </li></ul><ul><ul><li>Purkinje cell layer </li></ul></ul><ul><ul><li>Granule cell layer </li></ul></ul><ul><li>Purkinje cells </li></ul><ul><ul><li>modify the output of the cerebellum </li></ul></ul><ul><ul><li>Use GABA – so influence is inhibitory </li></ul></ul><ul><li>Fibers: </li></ul><ul><li>Climbing fibers </li></ul><ul><ul><li>innervate Purkinje cell from inferior olive </li></ul></ul><ul><li>Mossy fibers </li></ul><ul><ul><li>innervate granule cells from pons 1:1 </li></ul></ul><ul><li>Parallel fibers from granule cells </li></ul><ul><ul><li>innervate Purkinje cell 100,000:1 </li></ul></ul>
  21. 21. Layers of Cerebellar Cortex
  22. 22. Long Term Depression (LTD) <ul><li>Occurs when climbing fibers and parallel fibers are active together </li></ul><ul><li>Molecular mechanism: </li></ul><ul><ul><li>Climbing fiber activation causes surge of Ca ++ into Purkinje cell </li></ul></ul><ul><ul><li>Glutamate from parallel fiber activates AMPA receptor (glutamate receptor that mediates excitatory transmission) </li></ul></ul><ul><ul><li>Na+ increases </li></ul></ul><ul><li>But this process employs a second receptor . . . </li></ul>
  23. 23. Mechanism of LTD (cont.) <ul><li>There is a second glutamate receptor postsynaptic to the parallel fibers: metabotropic glutamate receptor </li></ul><ul><ul><li>G-protein-coupled to enzyme phospholipase C. (PLC) </li></ul></ul><ul><ul><li>Which catalyzes formation of a second messenger, diacylglycerol (DAG) </li></ul></ul><ul><ul><li>Which activates protein kinase C (PKC) </li></ul></ul><ul><li>Analogous to what happens in classical conditioning in Aplysia </li></ul>
  24. 24. Molecular Changes in Learning & Memory <ul><li>Learning occurs when the three things happen together: </li></ul><ul><ul><li>Elevated Ca ++ due to climbing fiber activation </li></ul></ul><ul><ul><li>Elevated Na + due to AMPA receptor activation </li></ul></ul><ul><ul><li>Activated PKC due to metabotropic receptor activation </li></ul></ul><ul><li>Memory results from changes in AMPA receptor due to PKC - decrease AMPA openings </li></ul>
  25. 25. Declarative Memory & the Hippocampus <ul><li>Declarative memory relies on the neocortex and structures in the medial temporal lobe, including the hippocampus </li></ul><ul><li>Long-term potentiation (LTP) </li></ul><ul><ul><li>Brief high-frequency electrical stimulation of a pathway to the hippocampus produces long lasting increase in strength of stimulated synapses </li></ul></ul><ul><li>LTD also found in the hippocampus </li></ul><ul><li>LTP & LDP may be the basis of how declarative memories form in the brain </li></ul>
  26. 26. Anatomy of the Hippocampus <ul><li>Two thin sheets of neurons folded on each other: </li></ul><ul><li>Dentate gyrus </li></ul><ul><li>Ammon’s horn </li></ul><ul><ul><li>Has 4 divisions </li></ul></ul><ul><ul><li>CA3 & CA1 are important here </li></ul></ul>
  27. 27. Connections in the Hippocampus <ul><li>Entorhinal cortex connects to the hippocampus via axons called the perforant path </li></ul><ul><li>Mossy fibers from the dentate gyrus synapses on CA3 </li></ul><ul><li>CA3 cells synapse via Schaffer collateral on cells in CA1 region </li></ul><ul><li>Both CA3 and CA1 cells have output fibers to the fornix </li></ul>
  28. 28. Hippocampus Structure
  29. 29. Long Term Potentiation (LTP) <ul><li>LTP occurs in CA1 when multiple synapses are active at the same time that the CA1 cell is depolarized </li></ul><ul><li>Recall that glutamate receptors are responsible for excitatory transmission in the hippocampus </li></ul>
  30. 30. Mechanism of LTP <ul><li>Glutamate released from synapse </li></ul><ul><li>Na + ions pass through the AMPA receptor causing EPSPs </li></ul><ul><li>CA1 neurons also have post synaptic N-methyl-D-aspartate (NMDA) receptors </li></ul><ul><li>These conduct Ca++ ions when cell is depolarized </li></ul><ul><li>Thus Ca++ entering the NMDA receptor indicates that presynaptic & postsynaptic elements are active at the same time </li></ul>
  31. 31. Induction of LTP <ul><li>Rise in postsynaptic Ca ++ linked to LTP </li></ul><ul><li>LTP induction is prevented if NMDA receptors are inhibited </li></ul><ul><li>Rise in Ca ++ activates 2 protein kinases: </li></ul><ul><ul><li>Protein kinase C </li></ul></ul><ul><ul><li>Clacium-calmodulin-dependent protein kinase II (CaMKII) </li></ul></ul><ul><li>Inhibition of either of these blocks long term potentiation </li></ul><ul><li>Following LTP a single axon may form multiple new synapses on a single postsynaptic neuron </li></ul>
  32. 32. Long Term Depression (LTD) <ul><li>LTD occurs in CA1 when it is only weakly depolarized by other inputs </li></ul><ul><li>Inward calcium levels are lower, activating a different enzymatic response </li></ul><ul><li>Thus, LTP and LTD are two responses of the same system </li></ul>
  33. 33. LTD, LTP, & Memory <ul><li>LTP & LDP are mechanisms of synaptic plasticity </li></ul><ul><li>They may contribute to the formation of declarative memory </li></ul><ul><li>Recordings from inferotemporal cortex slices from humans shows the same kind of interplay of LTP and LTD </li></ul><ul><li>Rats with damage to the hippocampus show reduced learning in Morris water maze </li></ul><ul><li>Injecting an NMDA-blocker into rats produces the same reduction of learning </li></ul>
  34. 34. Molecular Basis of Long-term Memory <ul><li>Molecular mechanisms all involve the phosphorylation of something </li></ul><ul><li>Phosphorylation is not permanent </li></ul><ul><ul><li>phosphate groups get removed, erasing memory </li></ul></ul><ul><li>Proteins themselves are not permanent, but get replaced </li></ul>
  35. 35. Persistently Active Protein Kinases <ul><li>Maybe memory is a turned on protein kinase </li></ul><ul><li>For LTP in CA1 in the hippocampus, an enzyme activating CaMKII may autophosphorylate and then just stay on </li></ul><ul><li>Molecular switch hypothesis - autophosphorylating kinase could store information at the synapse </li></ul>
  36. 36. Protein Synthesis & Memory Consolidation <ul><li>Inhibitors of protein synthesis block consolidation in experimental animals, both mammals and Aplysia </li></ul><ul><li>Suggests some new protein must arrive to make short-term changes permanent </li></ul>
  37. 37. CREB & Memory <ul><li>(CREB)  = cAMP response element binding protein </li></ul><ul><li>CREB regulates gene expression on DNA </li></ul><ul><li>CREB regulated gene expression is essential for consolidation in the fruit fly </li></ul><ul><li>Similar results have been shown in Aplysia </li></ul><ul><li>CREB may be able to regulate the strength of a memory </li></ul>
  38. 38. Structural Plasticity & Memory <ul><li>In Aplysia long-term learning involves the addition of synapses </li></ul><ul><ul><li>forgetting is the deletion of synapses </li></ul></ul><ul><li>Some indication that such changes occur in mammals, despite being past the critical period for developmental plasticity </li></ul>

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