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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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