1. Learning rules in the hippocampus and cerebellum Sam Wang Princeton University synapse.princeton.edu

2. Optical physiology and synaptic plasticity Eugene Civillico, Tycho Hoogland, Bernd Kuhn, Megan Lee, Daniel O’Connor, Dmitry Sarkisov, Shy Shoham, Megan Sullivan, Gayle Wittenberg Lausanne: Fritjof Helmchen, Werner Goebel, Axel Nimmerjahn Princeton: S. Jane Flint, Lynn Enquist, David Tank, Dan Dombeck RIKEN: Junichi Nakai Brain scaling and evolution Mark Burish, Damon Clark, Kim Harrison, Aline Johnson, Jennifer Shultz, Matt Wagers, Krysta Wyatt NYU: Patrick Hof Kirksville College of Osteopathic Medicine: Lex Towns Sam Wang’s laboratory and collaborators http://synapse.princeton.edu

5. Memento (2001)

6. “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.” Donald Hebb: The Cell-Assembly (1949)

7. “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.” Donald Hebb: The Cell-Assembly (1949) Memory is proposed to be mediated by replayed sequences of activity A B C D E

8. Synaptic learning rules Learning rules: mapping activity to plasticity Hippocampal learning rules –Plasticity at the CA3-CA1 synapse –Saturation and all-or-none storage –Timing-dependent and higher-order learning rules Cerebellar learning rules –Plasticity at the parallel fiber-Purkinje cell synapse –A reverse timing rule –Coincidence detection at the IP 3 receptor Beyond spike-based rules

9. The human brain Size: 1.2 kg (total body weight 70 kg) Processing units: 10 11 neurons, 10 15 synapses Power usage: 12 W (total energy budget 70 W)

10. Brain architecture 10cm Brain ~10 11 neurons Cortical column ~10 5 neurons 1mm mm Neuron ~10 4 synapses

11. Plasticity is usually measured across many synapses… 30,000 synapses …what are its properties at single synapses?

12. CA3-CA1 synapse of hippocampus Rich history of extracellular and single-cell recording The cell biology and plasticity literature is vast One synapse per connection Has AMPA, NMDA, mGluR,…

13. Plasticity at CA3-CA1: a separable process?

14. Is timing between single spikes sufficient to describe the actual learning rule? How different are the requirements for potentiation and depression? How might the learning rule map to behavior? What unitary events underlie plasticity in the synaptic ensemble? Questions at the CA3-CA1 synapse

16. Calmodulin-dependent protein kinase II: a molecular switch J. Lisman, H. Schulman, and H. Cline (2002) Nature Rev. Neurosci. 3:175

17. Delivery of glutamate receptors

18. 10 pA 5 ms Plasticity occurs in sudden steps O’Connor, Wittenberg and Wang (2005) PNAS 102:9679

19. Potentiation and depression events are symmetrically sized

20. Unitary properties of plasticity at CA3-CA1 synapses All-or-none Single steps up and down Steps are of similar size

21. Unitary events can account for the time course of plasticity

23. Binary transitions in single synapses

25. LTD is fully reversible

26. LTP is not fully reversible!

27. After being induced, LTP becomes locked in

29. The starting distribution of CA3-CA1 synapses >1 Hz >10 Hz

30. Ensemble learning rules L.F. Abbott and S.B. Nelson (2000) Nat. Neurosci. Gayle Wittenberg

31. The CA3-CA1 synapse of hippocampus Rich history of extracellular and single-cell recording The cell biology and plasticity literature is vast Has AMPA, NMDA receptors, kinases, phosphatases… One synapse per connection Sorra and Harris (1993)

32. Spike timing-dependent plasticity at CA3-CA1 synapses Daniel O’Connor & Gayle Wittenberg J. Neurophysiol. 2005 94:1565 PNAS 2005 102:9679 J. Neurosci. 2006 26:6610

33. During active exploration, CA1 neurons fire repeated bursts Huxter et al. (2003) Nature 425:828 Wittenberg & Wang 2006

35. The potentiation rule The depression rule Requires postsynaptic bursts Requires high frequency pairings Broad timing-dependence Requires prolonged pairing Components of bidirectional plasticity

38. Complications Spreading plasticity Priming Homeostatic plasticity Subcellular instruction

39. Häusser, Spruston, Stuart Science 2000 (from Vetter, Roth, Hausser J Neurophysiol 2001) Backpropagation of somatic sodium spike Forward propagation of dendritic calcium spike No! A simple passive dendritic arbor? http://www.wam-bamm.org/WB05/Tutorials/genesis-intro/genesis-intro.html

40. 20,000 locations per second

42. Imaging neural activity in the intact cerebellum Sullivan, Nimmerjahn, Sarkisov, Helmchen and Wang (2005) J. Neurophysiol.

43. Calcium responses in Purkinje cell dendrites

44. Evidence for regional calcium events in vivo Megan Sullivan

45. Optical physiology and synaptic plasticity Eugene Civillico, Tycho Hoogland, Bernd Kuhn, Eve Schneider, Megan Sullivan, X. Richard Sun, H. Megan Lee Lausanne: Fritjof Helmchen, Werner Goebel MIT: Michale Fee, Carlos Lois Princeton: S. Jane Flint, Lynn Enquist, David Tank, Dan Dombeck RIKEN: Junichi Nakai Wang laboratory and collaborators http://synapse.princeton.edu Support NIH, NSF, W.M. Keck Foundation, Human Frontier Science Project, N.J. Governor’s Council on Autism

46. The end