1. Slide 1 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Bear: Neuroscience: Exploring the Brain 3e Chapter 25: Molecular Mechanisms of Learning and Memory

2. Slide 2 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Introduction Neurobiology of memory Identifying where and how different types of information are stored Hypothesis by Hebb Memory results from synaptic alterations Study of simple invertebrates Synaptic alterations underlie memories (procedural) Electrical stimulation of brain Experimentally produce measurable synaptic alterations - dissect mechanisms

3. Slide 3 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Procedural Learning Declarative and procedural memories Nonassociative Learning Habituation Learning to ignore stimulus that lacks meaning Sensitization Learning to intensify response to stimuli

4. Slide 4 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Procedural Learning Associative Learning Classical Conditioning

5. Slide 5 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Procedural Learning Associative Learning (Cont’d) Classical Conditioning Associates a stimulus that evokes response- unconditional stimulus with second stimulus that does not evoke response- conditional stimulus Instrumental Conditioning Experiment by Edward Thorndike Complex neural circuits due to motivation

6. Slide 6 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 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. Slide 7 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia

8. Slide 8 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia (Cont’d) Habituation of the Gill-Withdrawal Reflex

9. Slide 9 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia (Cont’d) Sensitization of the Gill-Withdrawal Reflex

10. Slide 10 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning Associative Learning in Aplysia Classical conditioning CS-US pairing Cellular level Molecular level

11. Slide 11 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Simple Systems: Invertebrate Models of Learning The molecular basis for classical conditioning in Aplysia

12. Slide 12 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Vertebrate Models of Learning Neural basis of memory 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

13. Slide 13 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 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

14. Slide 14 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Vertebrate Models of Learning The structure of the cerebellar cortex

15. Slide 15 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Cerebellar Cortex Long-Term Depression in the Cerebellar Cortex

16. Slide 16 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Cerebellar Cortex (Cont’d) Long-Term Depression in the Cerebellar Cortex (Cont’d) Cerebellar LTD and Classical Conditioning in Aplysia Similarity: Input-specific synaptic modification Dissimilarity: Site of convergence and nature of synaptic changes

17. Slide 17 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 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

18. Slide 18 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 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

19. Slide 19 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont’d) Anatomy of the Hippocampus

20. Slide 20 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont’d) Properties of LTP in CA1

21. Slide 21 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 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 NMDARs and AMPARs

22. Slide 22 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont’d) Long-Term Depression in CA1

23. Slide 23 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 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)

24. Slide 24 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 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

25. Slide 25 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Vertebrate Models of Learning LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)

26. Slide 26 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins Vertebrate Models of Learning LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)

27. Slide 27 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 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

28. Slide 28 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins The Molecular Basis of Long-Term Memory Phosphorylation as a long term mechanism: Problematic (transient and turnover rates) Persistently Active Protein Kinases Phosphorylation maintained: Kinases stay “on” CaMKII and LTP Molecular switch hypothesis

29. Slide 29 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins The Molecular Basis of Long-Term Memory Protein Synthesis Requirement of long-term memory Synthesis of new protein Protein Synthesis and Memory Consolidation Protein synthesis inhibitors Deficits in learning and memory CREB and Memory CREB: Cyclic AMP response element binding protein

30. Slide 30 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins The Molecular Basis of Long-Term Memory Protein Synthesis (Cont’d) Structural Plasticity and Memory Long-term memory associated with formation of new synapses Rat in complex environment: Shows increase in number of neuron synapses by about 25%

31. Slide 31 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 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

32. Slide 32 Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins End of Presentation