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

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

Memento (2001)

“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)

“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

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

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

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

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

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,…

Plasticity at CA3-CA1: a separable process?

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

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

Delivery of glutamate receptors

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

Potentiation and depression events are symmetrically sized

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

Unitary events can account for the time course of plasticity

Binary transitions in single synapses

LTD is fully reversible

LTP is not fully reversible!

After being induced, LTP becomes locked in

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

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

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)

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

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

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

Complications Spreading plasticity Priming Homeostatic plasticity Subcellular instruction

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?

20,000 locations per second

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

Calcium responses in Purkinje cell dendrites

Evidence for regional calcium events in vivo Megan Sullivan

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 Support NIH, NSF, W.M. Keck Foundation, Human Frontier Science Project, N.J. Governor’s Council on Autism

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