1. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Neuroscience: Exploring the Brain, 3e Chapter 25: Molecular Mechanisms of Learning and Memory

2. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Introduction Neurobiology of memory –Identifying where and how different types of information are stored Hebb –Memory results from synaptic modification Study of simple invertebrates –Synaptic alterations underlie memories (procedural) Electrical stimulation of brain –Experimentally produce measurable synaptic alterations - dissect mechanisms

3. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Procedural Learning Procedural memories amenable to investigation Nonassociative Learning –Habituation Learning to ignore stimulus that lacks meaning –Sensitization Learning to intensify response to stimuli

4. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Procedural Learning Associative Learning –Classical Conditioning: Pair an unconditional stimulus (UC) with a conditional stimulus (CS) to get a conditioned response (CR)

5. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Procedural Learning Associative Learning (Cont’d) –Instrumental Conditioning Learn to associate a response with a meaningful stimulus, e.g., reward lever pressing for food Complex neural circuits related to role played by motivation

6. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Experimental advantages in using invertebrate nervous systems –Small nervous systems –Large neurons –Identifiable neurons –Identifiable circuits –Simple genetics

7. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia –Gill-withdrawal reflex –Habituation

8. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia (Cont’d) –Habituation results from presynaptic modification at L7

9. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia (Cont’d) –Repeated electrical stimulation of a sensory neuron leads to a progressively smaller EPSP in the postsynaptic motor neuron

10. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia (Cont’d) –Sensitization of the Gill-Withdrawal Reflex involves L29 axoaxonic synapse

11. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia (Cont’d) –5-HT released by L29 in response to head shock leads to G-protein coupled activation of adenylyl cyclase in sensory axon terminal. –Cyclic AMP production activates protein kinase A. –Phosphate groups attach to a potassium channel, causing it to close

12. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia (Cont’d) –Effect of decreased potassium conductance in sensory axon terminal –More calcium ions admitted into terminal and more transmitter release

13. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Associative Learning in Aplysia –Classical conditioning: CS initially produces no response but after pairing with US, causes withdrawal

14. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning The molecular basis for classical conditioning in Aplysia –Pairing CS and US causes greater activation of adenylyl cyclase because CS admits Ca 2+ into the presynaptic terminal

15. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Neural basis of memory: principles learned from invertebrate studies –Learning and memory can result from modifications of synaptic transmission –Synaptic modifications can be triggered by conversion of neural activity into intracellular second messengers –Memories can result from alterations in existing synaptic proteins

16. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Cerebellar Cortex –Cerebellum: Important site for motor learning –Anatomy of the Cerebellar Cortex Features of Purkinje cells Dendrites extend only into molecular layer Cell axons synapse on deep cerebellar nuclei neurons GABA as a neurotransmitter

17. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning The structure of the cerebellar cortex

18. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Cancellation of expected reafference in the electrosensory cerebellum of skates- synaptic plasticity at parallel fiber synapses.

19. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Cerebellar Cortex –Long-Term Depression in the Cerebellar Cortex

20. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Cerebellar Cortex (Cont’d) –Mechanisms of cerebellar LTD Learning Rise in [Ca 2+ ]i and [Na + ]i and the activation of protein kinase C Memory Internalized AMPA channels and depressed excitatory postsynaptic currents

21. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Cerebellar Cortex (Cont’d)

22. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Cerebellar Cortex (Cont’d)

23. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus –LTP and LTD Key to forming declarative memories in the brain –Bliss and Lomo High frequency electrical stimulation of excitatory pathway –Anatomy of Hippocampus Brain slice preparation: Study of LTD and LTP

24. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont’d) –Anatomy of the Hippocampus

25. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont’d) –Properties of LTP in CA1

26. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont’d) –Mechanisms of LTP in CA1 Glutamate receptors mediate excitatory synaptic transmission NMDA receptors and AMPA receptors

27. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont’d) –Long-Term Depression in CA1

28. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont’d) –BCM theory When the postsynaptic cell is weakly depolarized by other inputs: Active synapses undergo LTD instead of LTP Accounts for bidirectional synaptic changes (up or down)

29. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont’d) –LTP, LTD, and Glutamate Receptor Trafficking Stable synaptic transmission: AMPA receptors are replaced maintaining the same number LTD and LTP disrupt equilibrium Bidirectional regulation of phosphorylation

30. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)

31. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)

32. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont’d) –LTP, LTD, and Memory Tonegawa, Silva, and colleagues Genetic “knockout” mice Consequences of genetic deletions (e.g., CaMK11 subunit) Advances (temporal and spatial control) Limitations of using genetic mutants to study LTP/learning: secondary consequences

33. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Molecular Basis of Long-Term Memory Phosphorylation as a long term mechanism:Persistently Active Protein Kinases –Phosphorylation maintained: Kinases stay “on” CaMKII and LTP Molecular switch hypothesis

34. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Molecular Basis of Long-Term Memory Protein Synthesis –Protein synthesis required for formation of long-term memory Protein synthesis inhibitors Deficits in learning and memory –CREB and Memory CREB: Cyclic AMP response element binding protein

35. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins

36. The Molecular Basis of Long-Term Memory Protein Synthesis (Cont’d) –Structural Plasticity and Memory Long-term memory associated with transcription and formation of new synapses Rat in complex environment: Shows increase in number of neuron synapses by about 25%

37. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Concluding Remarks Learning and memory – Occur at synapses Unique features of Ca 2+ –Critical for neurotransmitter secretion and muscle contraction, every form of synaptic plasticity –Charge-carrying ion plus a potent second messenger Can couple electrical activity with long-term changes in brain

38. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins End of Presentation

39. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning The molecular basis for classical conditioning in Aplysia –Pairing CS and US causes greater activation of adenylyl cyclase because CS admits Ca 2+ into the presynaptic terminal

40. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Associative Learning in Aplysia –Classical conditioning: CS initially produces no response but after pairing with US, causes withdrawal

41. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in Human area IT