1. Neuroscience: Exploring the Brain, 3e
Chapter 25: Molecular Mechanisms of Learning and Memory

2. 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. 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. Procedural Learning Associative Learning
Classical Conditioning: Pair an unconditional stimulus (UC) with a conditional stimulus (CS) to get a conditioned response (CR)

5. 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. 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. Simple Systems: Invertebrate Models of Learning
Nonassociative Learning in Aplysia
Gill-withdrawal reflex
Habituation

8. Simple Systems: Invertebrate Models of Learning
Nonassociative Learning in Aplysia (Cont’d)
Habituation results from presynaptic modification at L7

9. 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. Simple Systems: Invertebrate Models of Learning
Nonassociative Learning in Aplysia (Cont’d)
Sensitization of the Gill-Withdrawal Reflex involves L29 axoaxonic synapse

11. 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. 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. 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. 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 Ca2+ into the presynaptic terminal

15. 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. 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. Vertebrate Models of Learning
The structure of the cerebellar cortex

18. Vertebrate Models of Learning
Cancellation of expected reafference in the electrosensory cerebellum of skates- synaptic plasticity at parallel fiber synapses.

19. Vertebrate Models of Learning
Synaptic Plasticity in the Cerebellar Cortex
Long-Term Depression in the Cerebellar Cortex

20. Vertebrate Models of Learning
Synaptic Plasticity in the Cerebellar Cortex (Cont’d)
Mechanisms of cerebellar LTD
Learning
Rise in [Ca2+]i and [Na+]i and the activation of protein kinase C
Memory
Internalized AMPA channels and depressed excitatory postsynaptic currents

21. Vertebrate Models of Learning
Synaptic Plasticity in the Cerebellar Cortex (Cont’d)

22. Vertebrate Models of Learning
Synaptic Plasticity in the Cerebellar Cortex (Cont’d)

23. 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. Vertebrate Models of Learning
Synaptic Plasticity in the Hippocampus (Cont’d)
Anatomy of the Hippocampus

25. Vertebrate Models of Learning
Synaptic Plasticity in the Hippocampus (Cont’d)
Properties of LTP in CA1

26. 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. Vertebrate Models of Learning
Synaptic Plasticity in the Hippocampus (Cont’d)
Long-Term Depression in CA1

28. 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. 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. Vertebrate Models of Learning
LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)

31. Vertebrate Models of Learning
LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)

32. 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. 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. 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

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. Concluding Remarks Learning and memory Occur at synapses
Unique features of Ca2+
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. End of Presentation

39. 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 Ca2+ into the presynaptic terminal

40. 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. Vertebrate Models of Learning
Synaptic Plasticity in Human area IT