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Microcircuits Ed Boyden Synthetic Neurobiology Laboratory Massachusetts Institute of Technology Invited lecture at Stanford in CS379C on April 8, 2013 Todays outline STATISTICAL MICROCIRCUITS PRECISE MICROCIRCUITS Goal: not to

  1. Microcircuits Ed Boyden Synthetic Neurobiology Laboratory Massachusetts Institute of Technology Invited lecture at Stanford in CS379C on April 8, 2013

  2. Today’s outline STATISTICAL MICROCIRCUITS ‘PRECISE’ MICROCIRCUITS Goal: not to saturate with examples of microcircuits, but to pick a few canonical examples that highlight the kind of information that one gets.

  3. Microcircuits • Role of a ‘precise’ anatomical connection in a physiological or behavioral function – Usually, but not always, considered as a circuit that is spatially compact • This is an assumption: precise wiring spans multiple regions, but this is less studied

  4. Statistical Microcircuits • Cell type A connected to Cell type B – As you remember from lecture 1, cell types are defined by • Shape • Molecular composition • Firing rate • These arguments are largely statistical in nature – For a computer: might conclude “transistors are connected to capacitors” • Is this helpful? • Specific connections, when altered, cause specific behavioral defects – Schizophrenia, epilepsy, etc. – It tells us something about the brain that when one kind of connection is altered, you can get a specific behavioral deficit – Evolution has let these (connection ßà disorder) links slide

  5. Drive a region, the region rings like a bell (Alilain et al., 2008)

  6. Function of a specific connection • A model of obsessive compulsive disorder: molecular deletion of Sapap3, scaffolding protein important for glutamate receptor presence, and synaptic strength (Welch et al., 2007) • Leads to excessive grooming • Striatal intervention reduces phenotype

  7. Statistical Microcircuits: Looking Within • Last time: cortical regions classified by cytoarchitectonics. This time, peer within: (Silberberg et al., 2005)

  8. Inhibitory neurons • Basket cells are connected by gap junctions and also GABA synapses – Inhibitory neurons often reciprocally connected within class (Hestrin and Galarreta, 2005) (Galarreta and Hestrin, 1999)

  9. Statistical microcircuits can yield insights into statistical dynamics • Low-order dynamics can emerge from statistical connectivity • Tonic drive to the interneuron circuit would be predicted to lead to oscillations Connexin 36 KO (Hormudzi et al., 2001)

  10. Example: optical stimulation of inhibitory neurons • Cardin et al 2009

  12. Molecules make sense in the context of the specific cell type they’re in: schizophrenia • Less gamma oscillations • Blocking NMDA reduces in schizophrenic patients gamma oscillations in a (Spencer et al., 2004) slice model of such oscillations (Cunningham et al., 2006)

  13. Gamma oscillations involve inhibitory interneurons (Cunningham Et al., 2003)

  14. Molecules in the context of cells: Example: GABA receptor and NMDA receptor • In patients: histological changes in subclasses of interneurons (Lewis and Volk 2005) – See reductions in GAT-1 staining, the GABA transporter – In, amongst other cells, PV+ neurons • “chandelier cell”

  15. A possible pipeline from molecule to macroscopic phenotype • NMDA dysfunction à problems with interneurons à less gamma oscillations • Brain stimulation is done pretty ad hoc right now • By moving beyond the molecule, we can start to think about whether brain stimulation could correct deficits directly

  16. Excitatory cells: how many do you need, to get a response? (Huber et al., 2008) Schematic of the behavioural apparatus and reward contingencies. The mouse initiates a trial by sticking its snout into the central port. Photostimuli are applied during a stimulation period (300 ms) accompanied by a series of bright blue light flashes delivered to the behavioural arena (30 Hz, 300 ms) to mask possible scattered light from the portable light source. The mouse then decides to enter either the left or the right port for a water reward. If a photostimulus was present , the choice of the left port was rewarded with a drop of water (hit, green star) whereas the choice of the right port lead to a short timeout (4 s, miss, red star). If the stimulus was absent , only the choice of the right port was rewarded with reward (correct reject, green circle) whereas the left port lead to a timeout (4 s, false alarm, red circle).

  17. DAT-Cre + AAV-FLEX-ChR2-tdTomato Kim et al. (2012) PLoS One 7(4):e33612

  18. Finding circuits in the brain that can mediate reward • Dopamine neurons : implicated in reward and addiction, but largely through pharmacologic al and electrical means • Is a brief activation of them sufficient no light light to drive stimulation stimulation reward? Kim et al. (2012) PLoS One 7(4):e33612

  19. Kim et al. (2012) PLoS One 7(4):e33612

  20. Transgenic mice expressing original-N. pharaonis halorhodopsin in hypocretin neurons Tsunematsu et al. (2011) Journal of Neuroscience 31(29): 10529-10539.

  21. Light silences the neurons, resulting in slow-wave sleep Tsunematsu et al. (2011) Journal of Neuroscience 31(29): 10529-10539.

  22. Example: how anesthesia modulates functional connectivity of networks recruited by SI pyramidal cells Opto-fMRI: a translational bridge between animal (causal) and human (behavior/disease) Idea generalizes: Opto-EEG, Opto-ECOG, etc. Desai et al. (2011) Journal of Neurophysiology 105(3):1393-405. Kahn et al. (2011) Journal of Neuroscience 31(42):15086-15091.

  23. Using cell-type specific control to understand the meaning of neurostimulation • Electrical stimulation: has heterogeneous effects on neurons – Example: some neurons can be completely silenced by electrical stimulation – Engaging interneurons? Direct silencing? (Butovas and Schwarz, 2003)

  24. Example: pyramidal cells can drive broad inhibition • Usually you think of a synapse from a cell onto another cell being weak – But, can be strong enough to drive downstream neurons to spike – or to exclusively drive another entire cell class to function (Kapfer et al., 2007)

  25. What mediates this inhibition? • Somatostatin-positive interneurons in layers 2/3 and 5

  26. Prefrontal Cortex • Example: prefrontal cortex for working memory – hypothesize that maintenance of firing over time is important – look for ‘loops’ (Wang et al., 2006) – 1,233 double patch clamp recordings PFC: 89% have two apical dendrites (‘complex’, cPC) 47% of pairs reciprocally connected VC: 87% have one apical dendrite (‘simple’, sPC) 18% of pairs reciprocally connected

  27. Cerebellum • Cerebellar microcircuit – used to try and justify models of motor learning (Marr, Albus, 60’s) (Boyden et al., 2004)

  28. A simpler, take-to-the-bank cerebellar microcircuit conclusion (Vos et al., 1999)

  29. Problem: Canonical Microcircuit really means ‘Statistical’ Microcircuit • These are descriptions of pairwise correlations in connectivity • Often used to generate unfalsifiable models; to disprove them is too much work • Current efforts are mostly spent on moving from pairwise to n- wise descriptions of connectivity – Currently, n is between 3 and 4 – A lot of this is taking new tools to perform

  30. Caveat experimentor • Most of these experiments are done in slice – Across multiple ages, species, brain regions, etc. – More synapses in the hippocampus ~2 hours of slicing, than a perfusion-fixed animal (Kirov et al., 1999)

  31. Extend correlations in connectivity • Patch-clamp four rat visual cortex layer 5 pyramidal cells at a time; analyze the connectivity (Song et al., 2005) Sampling bias: look at nearby cells. Hard to scale beyond 3; very laborious. Only statistical, still.

  32. Extend correlations in space • Find follower cells by stimulating with patch pipette, calcium imaging other cells (Kosloski et al., 2001) Yellow = big interneurons, green = pyramidal, red = fusiform interneurons Small n. Only see super-strong followers. Lose some geometry in the slice.

  33. Photostimulation-assisted mapping • Connected excitatory neurons, receive common excitatory inputs (Yoshimura, et al., 2005)

  34. Excitatory neurons get common inhibition regardless of connectivity to one another

  35. Photostimulation-assisted mapping (Yoshimura et al., 2006)

  36. Channelrhodopsin-2-assisted mapping (Petreanu et al., 2007) Left, laminar positions of recorded cells ipsilateral or contralateral to the electroporated hemisphere. Solid symbols indicate cells showing EPSCs in response to photostimulation of ChR2-positive axons and open symbols indicate cells that did not show EPSCs. Triangles, pyramidal cells; diamonds, stellate cells; blue circles, fast-spiking interneurons. Right, the fraction of stellate and pyramidal cells receiving input from L2/3 cells.

  37. Going beyond ‘statistical connectivity’ • Still an “A projects to B” kind of problem • Moving to higher-order statistics is hard • True understanding requires reconstruction of a circuit all the way from input to output – The worm, C. elegans – Connectomics

  38. Driving a single cell causes flip of the whole- cortex EEG (Li et al, 2009) 350 to 600 ms per step, 30 to 40 steps with 4- to 4.5-s intervals, or 8 ms per pulse, 5 to 15 pulses per burst, 40 to 80 bursts with 2- to 2.5-s intervals

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