1. Driving fast-spiking cells induces gamma rhythm and controls sensory responses Driving fast-spiking cells induces gamma rhythm and controls sensory responses Cardin et al., 2009 Rhythms of the Brain Tuesday, November 30, 2010 Timothy Leonard

2. Background/Theory The gamma cycle () The gamma cycle (Fries, Nikolic, & Singer, 2007) 1.rhythmic network inhibition interacts with excitatory input to pyramidal cells 2.amplitude values converted into phase values in the gamma cycle more excited cells fire earlier in the gamma cycle more excited cells fire earlier 3.Functional Consequences enables fast processing and readout enables fast processing and readout – ‘winner take all’ algorithm – coincidence detection, rather than rate integration

3. 1) The process is as follows: Big Picture: After excitatory input, the network of inhibitory interneurons generates rhythmic synchronized activity and imposes rhythmic inhibition onto the entire local network. Big Picture: After excitatory input, the network of inhibitory interneurons generates rhythmic synchronized activity and imposes rhythmic inhibition onto the entire local network. Pyramidal cells will be able to respond to excitatory input only during the time window of fading inhibition. Pyramidal cells will be able to respond to excitatory input only during the time window of fading inhibition. Pyramidal cells provide the major excitatory drive to the interneurons Pyramidal cells provide the major excitatory drive to the interneurons interneurons discharge with some phase delay relative to the pyramidal cells interneurons discharge with some phase delay relative to the pyramidal cells resulting network inhibition terminates the firing of both the pyramidal cells and the interneurons. resulting network inhibition terminates the firing of both the pyramidal cells and the interneurons. The whole network is inhibited and the next gamma cycle starts anew. The whole network is inhibited and the next gamma cycle starts anew. Taken from Taken from Fries, Nikolic, & Singer, 2007 ^ area is important for next slide

4. 2) Conversion of excitatory drive into relative spike timing If all pyramidal cells receive a similar amount of phasic inhibition – pyramidal cells receiving the strongest excitatory drive will fire first during the phase of the cycle Recoding Excitatory Drive into Relative Spike Timing Time Level of Inhibition Excitatory Drive +++++ + +++ Early in phase, Inhibition at highest

5. Summary 1.rhythmic network inhibition interacts with excitatory input to pyramidal cells 2.amplitude values converted into phase values – in the gamma cycle more excited cells fire earlier

6. Investigating the Gamma Oscillation with Optogenetics Cardin et al. 2009 – an overview Cardin et al. 2009 – an overview – Tested barrel cortex in mice in vivo processes information from the rodent whiskers processes information from the rodent whiskers Primary sensory area (S1) Primary sensory area (S1) Detailed & orderly, equivalent to fingers on the hand – high acuity Detailed & orderly, equivalent to fingers on the hand – high acuity – Light-driven activation of interneurons & pyramidal neurons. Electrophysiological recordings Electrophysiological recordings – Relevant Findings Integral role of fast spiking interneurons in gamma oscillations Integral role of fast spiking interneurons in gamma oscillations Evidence of amplitude to spike timing recoding Evidence of amplitude to spike timing recoding

7. Light-sensitive ChR2 Light-sensitive ChR2 – activated by ~470 nm blue light Interneurons Interneurons – targeted to FS-PV + interneurons Fast Spiking Fast Spiking Parvalbumin expressed only in IN Parvalbumin expressed only in IN Excitatory neurons Excitatory neurons – Targeted to αCamKII Expressed only in EX Expressed only in EX : bacteriorhodopsin Chlamydomonas ChR2: bacteriorhodopsin Chlamydomonas reinhardtii channelrhodopsin-2 ( FS-PV +: parvalbumin-positive fast-spiking ChR2-mCherry: AAV DIO ChR2-mCherry

8. Findings

9. Fast Spike activation generates gamma oscillations And LFP band

10. Natural gamma oscillations require FS activity Single light pulses during epochs of natural and evoked gamma Shifted the phase of gamma oscillations that were Single light pulses during epochs of natural and evoked gamma Shifted the phase of gamma oscillations that were 1.spontaneously occurring 2.evoked by midbrain reticular formation stimulation – activation by the light pulse significantly increased the duration of the ongoing gamma cycle – Oscillations largely eliminated by blocking AMPA and NMDA receptors despite high levels of evoked FS FS stimulation during naturally occurring gamma Increased duration of the ongoing gamma cycle

11. Evoked gamma phase regulates sensory processing Synaptic inputs arriving at peak of inhibition – Should have diminished response Inputs arriving at the opposite phase in gamma – Should have large response. To test : Stimulated FS cells at 40 Hz to establish gamma recorded the responses of RS cells to a single whisker deflection Deflection presented at one of five phases relative to a single gamma cycle Timing of whisker-induced RS action potentials relative to light- evoked inhibition and the gamma cycle had a significant impact on – Amplitude – Timing – precision of the sensory-evoked responses of RS cells

12. Evoked gamma phase regulates sensory processing Gamma oscillations decreased the amplitude of the RS sensory response at three phase points – consistent with the enhanced level of overall inhibition in this state Precision of sensory-evoked spikes was significantly enhanced in a gamma-phase dependent manner

13. Conclusions Data directly support the fast-spiking-gamma hypothesis Provides the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation – first causal demonstration of cortical oscillations induced by cell-type-specific activation Demonstrates gated sensory processing in a temporally specific manner

14. References Cardin, J. A., Carlen, M., Meletis, K., Knoblich, U., Zhang, F., Deisseroth, K., et al. (2009). Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature, 459(7247), 663-667. Fries, P., Nikolic, D., & Singer, W. (2007). The gamma cycle. Trends in Neurosciences, 30(7), 309-316.

15. Light-sensitive ChR2 Light-sensitive ChR2 – Cre-dependent expression of ChR2 ChR2-mCherry ChR2-mCherry – activated by ~470 nm blue light Interneurons Interneurons – targeted to FS-PV + interneurons Fast Spiking Fast Spiking P Parvalbumin expressed only in IN – Injected into PV-Cre knock-in mice – PV-Cre/FS mice Excitatory neurons Excitatory neurons – Injected into αCamKII-Cre mice – inducing recombination in excitatory neurons – αCamKII-Cre/RS mice : bacteriorhodopsin Chlamydomonas ChR2: bacteriorhodopsin Chlamydomonas reinhardtii channelrhodopsin-2 ( FS-PV +: parvalbumin-positive fast-spiking ChR2-mCherry: AAV DIO ChR2-mCherry