-Quiz 6 handed out this week -Recitation: Fear memory extinction (Quirk 2010)

1. -Quiz 6 handed out this week -Recitation: Fear memory extinction (Quirk 2010) -Classical conditioning & memory today

2. PKA also acts directly on neurotransmitter release machinery

3. PKA acts directly on the complexin clamp release mechanism post-tetanus Cpx: neg. regulator of vesicle release Neuron 2015; 88(4):749-761

4. Classical conditioning in Aplysia: pairing tail shock with water jet on the siphon; output= gill withdrawal reflex US CS US/CS: unconditional/conditional stimulus Mechanism: activation of interneurons via CS increases Ca2+ to enhance response to stimulus (activation of Ca2+-dep AdCyc)

5. Training and neuronal circuits in learning in Aplysia 5HT neuron (tail) siphon

6. Conditioning vs. sensitization: preceding activity activates calmodulin, AdCyc [timing CS to US is critical! <0.5 sec] Sensory neuron

7. In classical conditioning, presynaptic depolarization increases Glu release to amplify EPSP response

8. Classical conditioning employs coincidence detectors AdCyc (SN) & NMDAR (MN) Figure 21-53. Intracellular signaling pathways during sensitization and classical conditioning in the Aplysia gill-withdrawal reflex arc. Sensitization occurs when the facilitator neuron is triggered by the unconditioned stimulus (US) in the absence of the conditioned stimulus (CS) to the siphon sensory neuron (see Figure 21-52). Classical conditioning occurs when the CS is applied 1 – 2 seconds before the US, and involves coincidence detectors in both the presynaptic siphon sensory neuron and the motor neuron. In the sensory neuron, the detector is an adenylate cyclase that is activated by both Ca2+-calmodulin and by Gsα· GTP (see Figure 21-42). In the motor neuron, the detectors are NMDA glutamate receptors (see Figure 21-40). Partial depolarization of the motor neuron induced by an unconditioned stimulus (via an unknown transmitter) from interneurons activated by the tail sensory neuron enhances the response to glutamate released by the siphon sensory neuron.

9. Conditioning in Drosophila to evaluate short-term memory

10. Genetic mutants in Drosophila identified cAMP-dependent memory pathways amnesiac: enhances AdCyc; dPACAP= pituitary AdCyc activating peptide Ddc: Dopamine decarboxylase rutabaga: defective Ca2+-calmod dep. AdCyc dunce: PDE mutation

11. Declarative (explicit) memory: recall of facts or events Nondeclarative (implicit) memory: unconscious memory for procedural or motor skills (includes associative learned tasks) *Removal of either the ventromed prefrontal cortex (medial temporal lobe) or the perirhinal cortex impairs DNMS performance **HM: epileptic patient who had bilateral medial temporal lobotomy; developed profound anterograde amnesia

12. Declarative memory requires the med temporal lobe & HI

13. The delayed nonmatch-to-sample (DNMS) test: -Measures declarative (explicit) learning and memory -Requires subject to compare a presented object with a previously-presented comparison object -Selection of a novel object is encouraged by an edible reward -After novel object rule is learned, the delay period in object presentation is increased from 10 to 120 sec -Number of displayed objects requiring recollection increases -Model for human anterograde amnesia

15. Medial temporal lesions mimic human amnesia (declarative only)

16. Spatial learning & memory requires NMDARs in the hippocampus (the Morris water maze test)

17. Explicit memory storage in vertebrate medial temporal system: the hippocampus DG to CA3: mossy fiber pathway (nonassociative LTP) CA3 to CA1: Schaffer collateral pathway (associative LTP) EC to DG: perforant pathway (associative LTP)

19. Long-term potentiation: functional model for explicit memory HFS: 100 Hz (brief) LFS: <0.1 Hz *increased EPSP amplitude maintained for >60 min

20. Long-term potentiation in CA1 is highly afferent-specific

21. LTP in the Schaffer collateral pathway requires: Cooperativity: activation of multiple afferents (NMDAR-dep) Synapse selectivity: only the active afferents will be potentiated Associativity: requires simultaneous pre/post activity to depolarize postsynaptic cell

22. Spaced stimuli give larger sustained EPSP amplitude (LTP) vs. one tetanic stimulation

23. Hippocampal neuron LTP requires simultaneous afferent activity and postsynaptic depolarization

24. CamKII Postsynaptic depolarization activates CamKII & leads to greater numbers of AMPARs in postsynaptic membrane

25. CaMKII activity is regulated by Ca2+-calmodulin binding to release regulatory “hinge”

26. LTP may not rely solely upon new AMPAR insertion, but also enhanced NT release probability

27. The number of NT release events increases after LTP induction

28. Multiple spaced trains, or stimuli, leads to late-phase LTP; one train evokes smaller increase in EPSP for less time

29. Genetic blockade of PKA eliminates late-phase LTP

30. Early-phase LTP does not require CREB activation, synapse growth

31. Synaptic structural changes in L-LTP include new AZs, PSDs