Learning and Memory: Behaviour and simple cellular correlates

1. Learning and Memory: Behaviour and simple cellular correlates Module 632 Sean Sweeney

2. Aims: To describe basic behaviours that are simple manifestations of learning and memory. To outline experimental systems and paradigms that closely correlate physiological and molecular events that may manifest as learning and memory To describe molecular events that are essential to the acquisition of learning and memory in experimental paradigms

3. Learning ‘An adaptive change in behaviour resulting from experience’

4. Memory The retention of learning. Memory allows the production of a learned/adaptive behaviour at a later time Short-term Memory: temporary limited capacity requires rehearsal Medium-term memory? Long-term Memory: ‘permanent’ greater capacity than short-term no continual rehearsal required The Engram: ‘a memory representation’ Discrete steps? or a gradation?

5. Forgetting

6. Nonassociative mechanisms of learning: • Habituation: decrease in response to a repeated stimulus not accompanied • by changes in other stimuli • Sensitisation: an increase in response to a moderate stimuli as a result of • a previous exposure to a strong stimulus

7. Habituation: Simplest form of learning Requires: 1) A sensory neuron to bring information in 2) A motorneuron to execute movement

8. Sensitization: An incremental increase in response to a repetitive stimulus (usually noxious) Requires: 1) A sensory neuron to bring information in 2) A motorneuron to execute movement 3) An interneuron between the two

9. Associative Learning: classical conditioning: (aka Pavlovian) pairing of 2 stimuli changes the response to one of them conditioned stimulus (CS) - originally neutral (no response) unconditioned stimulus (UCS) - automatically evokes response – unconditioned response (UCR)after repetitive pairing of CS and UCS presentation of CS evokes learned response conditioned response (CR)

10. Operant (instrumental) conditioning: reinforcement by either reward or punishment. The basic principle of operant conditioning is that a response that is followed by a reinforcer ( R) is strengthened and is therefore more likely to occur again. A reinforcer is a stimulus or event that increases the frequency of a response (observable phenomenon) it follows. There are three conditions important to operant conditioning: 1) reinforcement must follow the responses, 2) reinforcement must follow the response immediately, and 3) reinforcement must be contingent of the expected or desired response.

11. Identifying Cellular and Molecular Correlates of Learning and Memory: Synaptic Plasticity What should we be looking for? Framework from Hebb How should we look? Physiological or molecular approach? Where should we look? Simple organisms vs complex Over What Timecourse?

12. Hebbian learning When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased (Hebb 1949) (Or decreased, depending on the paradigm) B A

13. C C Associative learning? UCS A CR B CS

14. Aplysia: Sea snails can learn. Advantages: large accessible cells amenable to physiology and the application/injection of drugs or proteins/peptides

15. The siphon-touch/gill withdrawal paradigm in Aplysia

16. The siphon withdrawal circuit, physiology in a behaving preparation

17. A physiological correlate of an elicited behaviour

18. Can we find other cellular correlates of learning and memory in other systems?

19. Hebbian learning When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased (Hebb 1949) B A

20. Physiological short-term Plasticity: Paired-Pulse Facilitation and Paired-Pulse Depression stimulate record

21. Changes that might mediate PPF or PPD?

22. Short-term presynaptic changes mediating plasticity: Alterations in K+ channel function Gating of Ca2+ channels Release of more vesicles Mobilisation of vesicles from the reserve pool Filling of vesicles with more transmitter? Alterations in sensitivity of release mechanisms Short-term Postsynaptic changes mediating plasticity : Gating of Ca2+ Gating of K+ channels Sensitivity of receptors Numbers of receptors

23. But what can we actually measure? Physiological: EPSP amplitude mEPSP size mEPSP frequency Molecular/cell biological: Neurotransmitter release (FM1-43 and pHlourin) Release from ‘Readily Releasable Pool’ and ‘Reserve Pool’ Synapse size (?) Others?

24. But most important? Resting [Ca2+] But can Ca2+ be dispensed with?

25. Ca2+ can stimulate Ca2+/calmodulin dependent serine/threonine kinase. Sustained activation generates a Ca2+ independent active kinase. CamKII The activated ‘meta’-state is a record of recent synaptic activity

26. CAMKII is post-synaptic On activation CAMKII translocates to the PSD Can regulate K+ channels Receptor activity Ca2+ channels Cytoskeletal changes Transcriptional output

27. Silva, A.J. et al., (1992) Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science, 257(5067): p. 206-11. Silva, A.J. et al., (1992) Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science, 1992. 257(5067): p. 201-6. More complex electrophyisological models of learning: Long Term Potentiation Long Term Depression

28. Physiological longer-(medium?)-term Plasticity: Post-tetanic Potentiation

29. Post-tetanic Depression 2s 4s

30. Changes that might mediate PTP or PTD? All of the above, AND……..

31. 2s 4s Generating a record of synapse use/activity? cAMP Neale et al., (2001) European J. of Neuroscience, 14:1313 mGlu1 receptors mediate a post-tetanic depression at Parallel fibres-Purkinje cell synapses in rat cerebellum

32. Glutamate mGluR Activation of mGluR can stimulate production of cAMP which may modulate short-to-medium term changes in plasticity Regulation of local changes?

33. Could cAMP regulate longer term changes?

34. Levels of cAMP can be modulated by synthesis and degradation cAMP can induce a transcriptional response

35. Drosophila: A genetic Model for behavioural plasticity Advantages: The ‘Awesome Power of Genetics’!!!! Simple behaviours Disadvantages Limited electrophysiology

36. Drosophila: Flies can Learn!!!! A Pavlovian paradigm in flies, the olfactory avoidance paradigm UCS: odour CS: electric shock CR: avoidance

37. Olfactory avoidance is mediated by the mushroom bodies, a complex structure that mediates the processing of olfactory information. (deBelle and Heisenberg (1994) Science 263:692) The MBs are the area of the brain where the protein products of the dunce, rutabaga and protein kinase A are most highly expressed

38. A pavlovian circuit? See Waddell and Quinn (2001)

39. Mutations that affect olfactory avoidance behaviour can be used to dissect the time dependence of memory acquisition and retrieval. (work of Tim Tully and co-workers, Cold Spring Harbor Laboratory)

40. Flies are smarter than they let on……… LRN=learning STM=short term memory MTM= medium term memory LTM=long term memory ARM=Anaesthesia resistant memory CXM=cyclohexamide

41. In conclusion: The Engram?

42. Reading: Calcium/calmodulin-dependent protein kinase II and synaptic Plasticity. Colbran and Brown (2004) Current Opinion in Neurobiology. 14:318-327 deBelle and Heisenberg (1994) Science 263: 692 Flies, Genes and Learning. Waddell and Quinn (2001) Annual Review of Neuroscience 24: 1283-1309 Purves et al. Neuroscience Edition III Chen et al., (2004) Paired Pulse depression of unitary Quantal amplitude at single hippocampal synapses. P.N.A.S. 101:1063-1068