1. Integration of neural plasticity Multiple mechanisms per synapse Multiple synapses per cell Multiple cells per function Examples –Tritonia escape response –Aplysia gill withdrawal reflex –Leech central pattern generator –Autonomic control of hypertrophy

2. Tritonia/Aplysia flight Stereotypical swim response –Phasic, fixed duration Simple pattern generator –Individually identified neurons –Simple connectivity Getting, 1980

3. Metabotropic Neuromodulation DSI stimulation triggers fast and slow depolarization –Slow depolarization is GTP dependent –Blocked by non-hydrolyzable GDP-  -S Stimulation Recording

4. Tritonia Metabotropic Neuromodulation DSI stimulation triggers fast and slow depolarization –Slow depolarization is GTP dependent –Blocked by non-hydrolysable GDP-  -S Stimulation Recording Slow metabotropic depolarization Fast Ionotropic depolarization Blocks metabotropic process

5. Network effect of metabotropic NT Intracellular injection of GDP-bS in C2 CPG behavior disappears Clemmens & Katz, 2003

6. Neuromodulation Multiple receptor types at a single synapse induce divergent actions –Fast/slow –Excitatory/inhibitory Multiple substance release at a single synapse induce multiple actions –Multiple neurotransmitters Serotonin/norepinepherine/dopamine –Neuromodulatory peptides Somatostatin, substance P, vasopressin Accommodation/facilitation over sec - min

7. Aplysia gill withdrawal Gill & siphon normally exposed for metabolite exchange Tactile/ nocioceptive stimulation triggers withdrawal Similar pathways in all species UTMB Magazine Leonard & Edstrom, 2004 Gill Siphon Mantle Tail

8. Neural Circuit SN L16 INin L7 LD G1 LD G2 INin L25 Sensory neurons (SN) Motorneurons (L7, LDg1, LDg2…) Interneurons (ex: L16, L25) Leonard & Edstrom, 2004

9. Habituation EPSP amplitude declines during habituation –Quantal –SN goes from releasing 3 NT vesicles to 0 Castellucci & Kandel, 1974 EPSP Amplitude (uV) Number observed Est # vesicle release Record post-synaptic EPSP amplitude in response to sensory nerve stimulus, construct a histogram, and look for discrete quanta

10. Habituation Presynaptic neurotransmitter vesicles separate from the cell membrane –Depletion –Ca 2+ dose-dependent untethering (calpain), channel inactivation (CaV), recruitment of SV (PKC) (?) Bailey & Chen, 1988 Naïve sensory terminalHabituated sensory terminal Note: greater distance between vesicles and membrane.

11. Sensitization EPSP amplitude is potentiated by prior stimulation of separate pathway SN L16 L7 LD G1 LD G2 L25 Leonard & Edstrom, 2004 SN SiphonTail L29

12. Sensitization Tail interneuronal collaterals synapse with siphon interneurons –Facilitating interneuron L29 –Serotonergic + SCP –Presynaptic Serotonin –G  S  AC  PKA--|K IR K IR --|CaV  NT release SCP Hawkins, 1981 Sensory neuron spike recordings L7 PSP recordings PSP and spike width show habituation Until L29 is briefly tetanized Small cardioactive peptide Wider spike restores PSP

13. Sensitization Amplification within sensitization –Single stimulus  hours of increased gain –Multiple stim  days Rate/dose decoding –PKA: fast acting, slow transport –Local K/Ca channels –Distributed K/Ca channels –Nuclear import, CREB

14. PKC/PKA mediated plasticity AP  Ca2+  PKC/CaMKII--|SNARE 5HT  AC  PKA --|Kir  SNARE  CREB  PKA  growth Kandel 2001

15. Long term sensitization CREB induces new synapse formation by formation of sensory collaterals. Similar processes in hippocampus for “declarative” memory Stimulation of cultured neuron results in rapid development of a new dendritic spine Goldin, et al., 2001