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model system: sea hare ( Aplysia californica ) behavior: the gill & siphon withdrawal reflex even more cell biolog

PART 4: BEHAVIORAL PLASTICITY #21: LEARNING & MEMORY of a SIMPLE REFLEX in APLYSIA II. model system: sea hare ( Aplysia californica ) behavior: the gill & siphon withdrawal reflex even more cell biology: learning & memory summary. PART 4: BEHAVIORAL PLASTICITY

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model system: sea hare ( Aplysia californica ) behavior: the gill & siphon withdrawal reflex even more cell biolog

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  1. PART 4: BEHAVIORAL PLASTICITY #21: LEARNING & MEMORY of a SIMPLE REFLEX in APLYSIA II • model system: sea hare (Aplysia californica) • behavior: the gill & siphon withdrawal reflex • even more cell biology: learning & memory • summary

  2. PART 4: BEHAVIORAL PLASTICITY #21: LEARNING & MEMORY of a SIMPLE REFLEX in APLYSIA II • model system: sea hare (Aplysia californica) • behavior: the gill & siphon withdrawal reflex • even more cell biology: learning & memory • summary

  3. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • convergence of CS & US in sensory neuron • adenylyl cyclase (AC) = coincidence detector? • sensitization: • Ca++ channels closed • Ca++not bound to calmodulin • calmodulin not bound to AC • some cAMP ...

  4. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • convergence of CS & US in sensory neuron • adenylyl cyclase (AC) = coincidence detector? • associative learning: • Ca++ channels open • Ca++ bound to calmodulin • calmodulin bound to AC • lots of cAMP ...

  5. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • postsynaptic factors • glutamate, excitatory transmitter • activates N-methyl-D-aspartate (NMDA) receptor

  6. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • postsynaptic factors • glutamate, excitatory transmitter • activates N-methyl-D-aspartate (NMDA) receptor • no signal... • NMDA channel closed • no Ca++ enters cell

  7. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • postsynaptic factors • glutamate, excitatory transmitter • activates N-methyl-D-aspartate (NMDA) receptor • signal... • glutamate binds to receptor • postsynaptic membrane depolarizes • postsynaptic neuron fires • test this model?

  8. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • postsynaptic factors • differential conditioning

  9. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • postsynaptic factors • differential conditioning • aminophosphonovalerate (APV) block of NMDA receptor…

  10. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • postsynaptic factors • differential conditioning • block NMDA receptor with APV during training

  11. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • postsynaptic factors • differential conditioning • block NMDA receptor with APV during training • associative synaptic facilitation 

  12. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • postsynaptic factors • differential conditioning • block NMDA receptor with APV during training • associative synaptic facilitation  • NMDA receptor necessary

  13. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • postsynaptic factors • differential conditioning • same result during training if • postsynaptic neuron: • hyperpolarized • Ca++ blocked • presynaptic neuron: • PKA blocked • Ca++ 

  14. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • postsynaptic factors • implication that the postsynaptic neuron communicates with the presynaptic neuron • retrograde (backward) signaling • evidence (not shown) – associative facilitation mechanism in postsynaptic neuron changes signaling properties in the presynaptic neuron • neurons communicate in both directions • but... what is the signal?

  15. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • revised model • 2 sites of CS-US coincidence • presynaptic AC

  16. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • revised model • 2 sites of CS-US coincidence • presynaptic AC • postsynaptic NMDA receptor gated channels

  17. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of classical conditioning • revised model • 2 sites of CS-US coincidence • presynaptic AC • postsynaptic NMDA receptor gated channels • retrograde signal (hypothetical)

  18. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • terminology: • long-term memory (LTM) behavioral measure • long-term facilitation (LTF) physiological measure

  19. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • distributed sensitization training

  20. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • distributed sensitization training: • siphon withdrawal 

  21. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • distributed sensitization training • siphon withdrawal  • sensory EPSPs 

  22. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • distributed sensitization training • siphon withdrawal  • sensory EPSPs  • S-current  (data not given)

  23. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • distributed sensitization training • siphon withdrawal  • sensory EPSPs  • S-current  • serotonin-induced presynaptic transmitter release  (data not given)

  24. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • distributed sensitization training • siphon withdrawal  • sensory EPSPs  • S-current  • serotonin-induced presynaptic transmitter release  (data not given) • presynaptic neuronal plasticity

  25. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • distributed sensitization training • serotonin substitutes for tail shock @ sensory • cell body  LTF • terminal  STF

  26. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • distributed sensitization training • serotonin substitutes for tail shock @ sensory • cell body  LTF • terminal  STF

  27. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • serotonin induces • LTF • intracellular signal • protein synthesis (?) • neural plasticity (?) • STF • locally @ synapse

  28. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • protein synthesis (?) • transcription • translation • transport  synapses

  29. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • protein synthesis inhibited by blockers • also block LTF • during serotonin application only • not before or after... • narrow temporal window

  30. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • protein synthesis inhibited by blockers • also block LTF • during serotonin application only • not before or after... • narrow temporal window • no block of STF

  31. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term synaptic facilitation in sensory neurons • protein synthesis inhibited by blockers • also block LTF • during serotonin application only • not before or after... • narrow temporal window • no block of STF • ... and does block LTM (behavior) • protein synthesis necessary for LTM

  32. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term sensitization / serotonin treatments  molecular changes in sensory neurons: • persistent phosphorylation of existing proteins • synthesis of new proteins • growth of sensory neurons... neural plasticity

  33. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term sensitization / serotonin treatments  molecular changes in sensory neurons: • growth of sensory neurons... neural plasticity • visual examination •  axonal processes, branching, varicosities

  34. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term sensitization / serotonin treatments  molecular changes in sensory neurons: • growth of sensory neurons... neural plasticity • visual examination •  axonal processes, branching, varicosities

  35. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term sensitization / serotonin treatments  molecular changes in sensory neurons: • growth of sensory neurons... neural plasticity • model for synaptic restructuring / plasticity •  varicosities •  terminal active zones • opposite for habituation

  36. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • long-term sensitization / serotonin treatments  molecular changes in sensory neurons: • growth of sensory neurons... neural plasticity • model for synaptic restructuring / plasticity •  varicosities •  terminal active zones •  long-term increase in synaptic transmission • what are the molecular mechanisms?

  37. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • molecular induction of LTF in sensory neurons • cAMP pathway implicated: • cAMP injection ... S-current  • PKA inhibitors ... block serotonin-induced LTF • serotonin application ... PKA catalytic subunit cytoplasmic  nuclear • activity of genes: • immediate early (IEG), transcription factors • late-responsive, leave nucleus

  38. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • molecular induction of LTF in sensory neurons • cAMP pathway implicated: • cAMP response elements (CREs) on DNA • CRE binding protein (CREB) • phosphorylated by PKA... CREBs  IEGs • IEGs  late-responsive genes

  39. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • molecular induction of LTF in sensory neurons • single training event  some PKA, STF • distributed training  more PKA... nucleus, LTF

  40. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • molecular induction of LTF in sensory neurons • competition studies using injected CRE sequences  block CREB binding & LTF 

  41. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • molecular induction of LTF in sensory neurons • competition studies using injected CRE sequences  block CREB binding & LTF 

  42. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • molecular induction of LTF in sensory neurons • competition studies using injected CRE sequences  block CREB binding & LTF  • enhanced CREB + 1 serotonin application  • LTF • structural enhancement • CREB essential for LTF & LTM • similar findings in Drosophila (next chapter)

  43. CELL BIOLOGY OF LEARNING & MEMORY • mechanistic analysis of long-term memory • LTF molecular model • what proteins? • how do they work? • other 2nd messenger cascades? • homology (flies, mice)

  44. CELL BIOLOGY OF LEARNING & MEMORY • middle-term memory... read the section on your own

  45. SUMMARY • defensive withdrawal reflex after stimulation (CS) of • siphon, mantle, gill • shows non-associative learning properties • habituation, dishabituation, sensitization • sensitization: reflex with preceding tail shock • associative learning • reflex (CS) + paired shock (US) • differential conditioning = CS1+ + US, CS2– • distributed training  long-term memory

  46. SUMMARY • tail shock sensitization • interneuron serotonin release  sensory neuron •  K current flow (out of cell) • spike broadening • synaptic facilitation • cAMP cascade mediated • sensory neuron transmitter release

  47. SUMMARY • classical conditioning • interneuron serotonin release  sensory neuron • tail shock US responses augmented by concurrent CS signal... • activity-dependent presynaptic facilitation • postsynaptic process, NMDA receptor in motor neuron

  48. SUMMARY • long-term memory • dispersed training • protein synthesis-dependent • cAMP & CREB  IEGs • IEGs  late-response genes • proteins  neuron terminals • neuronal plasticity

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