Learning rules in the hippocampus and cerebellumLearning rules in the hippocampus and cerebellum

Sam WangPrinceton University

synapse.princeton.edu

Optical physiology and synaptic plasticityOptical physiology and synaptic plasticity

Eugene Civillico, Tycho Hoogland, Bernd Kuhn, Megan Eugene Civillico, Tycho Hoogland, Bernd Kuhn, Megan Lee, Daniel O’Connor, Dmitry Sarkisov, Shy Shoham, Lee, Daniel O’Connor, Dmitry Sarkisov, Shy Shoham, Megan Sullivan, Gayle WittenbergMegan Sullivan, Gayle Wittenberg

Lausanne: Fritjof Helmchen, Werner Goebel, Axel Lausanne: Fritjof Helmchen, Werner Goebel, Axel NimmerjahnNimmerjahn

Princeton: S. Jane Flint, Lynn Enquist, David Tank, Princeton: S. Jane Flint, Lynn Enquist, David Tank, Dan DombeckDan Dombeck

RIKEN: Junichi NakaiRIKEN: Junichi Nakai

Brain scaling and evolutionBrain scaling and evolution

Mark Burish, Damon Clark, Kim Harrison, Aline Mark Burish, Damon Clark, Kim Harrison, Aline Johnson, Jennifer Shultz, Matt Wagers, Krysta WyattJohnson, Jennifer Shultz, Matt Wagers, Krysta Wyatt

NYU: Patrick HofNYU: Patrick Hof

Kirksville College of Osteopathic Medicine: Lex TownsKirksville College of Osteopathic Medicine: Lex Towns

Sam Wang’s laboratory and collaboratorsSam Wang’s laboratory and collaborators

http://synapse.princeton.eduhttp://synapse.princeton.edu

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 tobe mediated by replayed

sequences of activity

A B

CD E

Synaptic learning rulesSynaptic 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 IP3 receptor

• Beyond spike-based rules

The human brain

• Size: 1.2 kg (total body weight 70 kg)

• Processing units:1011 neurons, 1015 synapses

• Power usage:12 W (total energy budget 70 W)

Brain architecture

10cm

Brain ~1011 neurons

Cortical column ~105 neurons

1mm

m

Neuron ~104 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 recordingThe cell biology and plasticity literature is vastOne synapse per connectionHas 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 transitionsin 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 >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 recordingThe cell biology and plasticity literature is vastHas 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 WittenbergJ. Neurophysiol. 2005 94:1565

PNAS 2005 102:9679J. Neurosci. 2006 26:6610

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 burstsRequires high frequency pairings

Broad timing-dependenceRequires prolonged pairing

Components of bidirectional plasticity

Complications

• Spreading plasticity• Priming• Homeostatic plasticity• Subcellular instruction

Häusser, Spruston, StuartScience 2000(from Vetter, Roth, HausserJ 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

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

The end