1. synaptic plasticity Basic Neuroscience NBL 120

2. classical conditioning • CS (neutral) - no response • US - UR • After pairing: • CS - CR

3. associative learning • ability to learn the relationship between different stimuli / events so that we can make reasonable predictions if we are faced with a certain situation • learning & memory => good • addiction => bad

4. learning & memory in taxi drivers • PET study during recall of London route (Maguire et al, 1997)

5. place cells • some pyramidal cells in the hippocampus have preferred spatial orientations • fire in bursts (O’Keefe & Dostrovsky, 1971)

6. how is a synapse plastic? • synapses “remember” previous activity • short-term, e.g. post-tetanic potentiation at the nmj control motor neuron motor neuron pre nmj muscle muscle time post

7. Hebbian learning • longer term plasticity • Hebbian learning • Hebb (1949) hypothesized that “ if one neuron frequently takes part in exciting another, some growth process or metabolic change takes place in one or both cells and the strength of their connection increases ”

9. hippocampal “integrated circuit” Johnson & Wu (1995)

10. in reality….. • first demonstration of LTP • high-frequency train • rapid induction • lasts weeks in vivo after before amplitude time (hrs) Bliss & Lomo (1973)

11. properties of LTP

12. cellular mechanisms underlying LTP • induction • maintenance

13. excitatory synaptic transmission • NMDA vs non-NMDA • synaptic transmission AP5 control AP5

14. LTP depends specifically on NMDA receptor activation • AP5 prevents high frequency-induced LTP (Collingridge et al, 1983)

15. out +++ Mg+ Mg+ - - - in what is special about NMDA receptors? • voltage-gated channels: voltage • ligand-gated channels: transmitter • NMDA receptors: both + - +

16. NMDA receptor: a molecular switch • co-incidence detector • requires both presynaptic activity (glutamate) and postsynaptic depolarization (relieve Mg block) • satisfies Hebbian co-incidence rules • explains LTP properties: • specificity • associativity / co-operativity • spatial/temporal requirements

17. how does the NMDA receptorcause a change in synaptic strength?

18. synaptic transmission is unreliable • increased transmitter release • altered or new receptors • new synapses

19. NMDA receptors, hippocampus and LTP learning and memory

20. NMDA receptor-dependent learning spatial memory task visual task “Morris” water maze Morris et al (1990)

21. LTP and learning • saturation of LTP prevents learning a new spatial task • new learning can occur after LTP decay LTP decay Castro et al (1989)

22. a natural LTP? • animals raised in a complex environment show enhanced synaptic responses in the hippocampus Sharp et al (1985)

23. hippocampus= temporary memory storage • new patterns stored rapidly and transiently • gradual transfer to neocortex • long-term storage with reduced interference

24. diffuse storage in cortex? • computational theories • Marr (1970’s) • sensory input to neocortex • stored by association • repetition - association • partial pattern recall

26. addiction - definition • compulsive use / abuse of a drug despite adverse consequences

27. recollections of an addict:

28. electrical self-stimulation • Skinner-box • lever-press > reward • rate  reward

34. “pleasure centers” • “a hungry animal often ignored available food in favor of the pleasure of stimulating itself electrically .... 2000 times per hour for 24 consecutive hours” (Olds 1956)

35. where are the pleasure centers? • medial forebrain bundle • VTA - Nucleus Accumbens (after Koob 1992)

36. dopamine

37. DA neurons and reward (Schultz et al, 1993)

38. drug abuse is a form of associative learning • associated cues could trigger “craving” • nicotine is continuously paired with taste and smell of cigarettes • heroin or other drug use may be associated with a specific setting • evidence………….

39. predicting reward • VTA DA response becomes associated with the sound cue i.e. DA response predicts reward • learning

40. what happens to DA in addicts? displacement of [11C]raclopride binding by DA release PET scan “craving” MP = methylphenidate “RITALIN” (Volkow et al, 1997)

41. associations - summary • synaptic plasticity • hippocampus / cortex • NMDA receptor - coincidence detector • Mg2+ & Ca2+ • addiction • midbrain - VTA / Nucleus Accumbens • Dopamine • predictive cues

42. in theory….. (from McNaughton & Morris, 1987)