Neural Plasticity

1. Neural Plasticity Lecture 7

2. Neural Plasticity • Nervous System is malleable • learning occurs • Structural changes • increased dendritic branching • new synapses • Changes in synaptic efficiency • Long-term potentiation • Long-term depression ~

3. Neural Mechanism of Memory • Donald Hebb • Short-term Memory • Change in neural activity • not structural • temporary • Reverberatory Circuits - • cortical loops of activity ~

4. Reverberating Loops • Maintains neural activity for a period • Activity decays ~

5. Hebb’s Postulate • Long-Term Memory • required structural change in brain • relatively permanent • Hebb Synapse • use strengthens synaptic efficiency • concurrent activity required • pre- & postsynaptic neurons ~

6. Long-term Potentiation • According to Hebb rule • use strengthens synaptic connection • Synaptic facilitation • Structural changes • Simultaneous activity • Experimentally produced • hippocampal slices • associative learning also ~

7. Inducing LTP Stimulating electrode Record Perforant Pathway DG

8. Postsynaptic Potential Single elec. stimulation 100 stim. burst + Single stim. -70mv -

9. Pattern Of Stimulation • Strong, high frequency stimulation • Minimum stimulation • 1 + burst of 4 • 4-7 Hz • Theta • HC: Arousal & REM ~

10. LTP Duration • Experimentally-induced LTP • Intact animals • seconds - months • HC slice • 40 hrs ~

11. LTP: Molecular Mechanisms • Presynaptic & Postsynaptic changes • HC ---> Glutamate • excitatory • 2 postsynaptic receptor subtypes • AMPA ---> Na+ • NMDA ---> Ca++ • Glu ligand for both ~

12. NMDA Receptor • N-methyl-D-aspartate • Glu binding opens channel? • required, but not sufficient • Membrane must be depolarized • before Glu binds ~

13. Single Action Potential • Glu ---> AMPA • depolarization • Glu ---> NMDA • does not open • Mg++ blocks channel • no Ca++ into postsynaptic cell • Followed by more APs ~

14. Mg Ca++ Na+ G G AMPA NMDA

15. Mg Ca++ Na+ G G AMPA NMDA

16. Activation of NMDA-R • Ca++ channel • chemically-gated • voltage-gated • Mg++ blocks channel • Ca++ influx --->post-synaptic changes • strengthens synapse ~

17. LTP: Postsynaptic Changes • Receptor synthesis • More synapses • Shape of dendritic spines • Nitric Oxide synthesis ~

18. Before LTP Presynaptic Axon Terminal Dendritic Spine

19. After LTP less Fodrin Less resistance Presynaptic Axon Terminal Dendritic Spine

20. Nitric Oxide - NO • Retrograde messenger • Hi conc. ---> poisonous gas • Hi lipid solubility • storage? • Synthesis on demand • Ca++ ---> NO synthase ---> NO • Increases NT synthesis in presynaptic neuron • more released during AP ~

21. Glu cGMP NO NOS NO Ca++ G G Ca++

22. Cerebellum The Cerebellum & Long-term Depression • Motor functions • Coordination of movements • Regulation of posture • Indirect control • Adjust outputs of descending tracts • Also nonmotor functions • memory/language ~

23. Cerebellum: Anatomy • Folia & lobules • analogous to sulci & gyri • Vermis - along midline • output ---> ventromedial pathway • Hemispheres • output ---> lateral pathway • Deep cerebellar nuclei • fastigial, interposed, & dentate • Major output structures ~

24. Cerebellum • Programs ballistic movements • feed-forward control • no feedback during execution • direction, force, & timing • long term modification of circuits • Motor learning • shift from conscious ---> unconscious ~

25. Cerebellum • Acts as comparator for movements • compares intended to actual performance • Correction of ongoing movements • internal & external feedback • deviations from intended movement ~

26. Cerebellum: 3 layered cortex • Molecular layer • parallel fibers • axons of granule cells • runs parallel to long axis of folium • Purkinge cell layer • large somas • axons to underlying white matter • perpendicular to main axis of folium ~

27. Cerebellum: 3 layered cortex • Purkinge cell layer • large somas • axons to underlying white matter • perpendicular to main axis of folium ~

28. Cerebellum: 3 layered cortex • Granular layer • innermost layer • small, densely packed granule cells • > # neurons in cerebral cortex ~

29. Cerebellum: 3 layered cortex Molecular Purkinje Granule

30. Cerebellum: & Motor Learning • Purkinje cells only output from cerebellar cortex • inhibit deep cerebellar nuclei • Input to Purkinje cells • Mossy fibers via parallel fibers • from spinal cord & brainstem nuclei • climbing fibers • cerebral cortex & spinal cord • via inferior olivary nucleus ~

31. Cerebellum: & Motor Learning • 1 Purkinje cell synapses.. • 1 each with 200,000 parallel fibers • Many with 1 climbing fiber • strong synaptic connections • Climbing fibers ­effects of mossy fibers • transient ~

32. Cerebellum: 3 layered cortex Molecular Purkinje Granule Mossy fibers Climbing fibers

33. Cerebellum: & Motor Learning • Long-term depression (LTD) • requires concurrent activity • climbing & parallel fibers active together • ¯in activity of specific Purkinje cells • Climbing fibers may carry error signals • corrections ---> ¯ parallel fiberinfluence • input specificity • only affects active synapses of a parallel fiber ~

34. LTD Mechanisms • Similar to LTP • * changes are postsynaptic • Glutamate receptors

35. LTD Mechanisms • *Requires concurrent activity • Climbing fiber 1. Ca++ *influx - voltage-gated • Parallel fibers activate 2. AMPA - Na+ influx 3. mGLUR1 • AMPA desensitized •  Na+ influx ~

36. LTD Mechanisms • mGluR1 • metabotropic • cGMP-mediated • intracellular Ca++ stores • activation of phosphatases • Knockout mice • lack mGluR1 • loss of motor coordination ~