Rhythms of the Brain Tuesday, November 30, 2010 Timothy Leonard

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

2. Background/Theory The gamma cycle (Fries, Nikolic, & Singer, 2007) • rhythmic network inhibition interacts with excitatory input to pyramidal cells • amplitude values converted into phase values • in the gamma cycle more excited cells fire earlier • Functional Consequences • 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 inhibitoryinterneurons 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 provide the major excitatory drive to the interneurons • 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. • The whole network is inhibited and the next gamma cycle starts anew. • 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 Level of Inhibition Excitatory Drive Time +++++ + +++ Early in phase, Inhibition at highest

5. Summary • rhythmic network inhibition interacts with excitatory input to pyramidal cells • 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 • Tested barrel cortex in mice in vivo • processes information from the rodent whiskers • Primary sensory area (S1) • Detailed & orderly, equivalent to fingers on the hand – high acuity • Light-driven activation of interneurons & pyramidal neurons. • Electrophysiological recordings • Relevant Findings • Integral role of fast spiking interneurons in gamma oscillations • Evidence of amplitude to spike timing recoding

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

8. Findings

9. Fast Spike activation generatesgammaoscillations There should be a selective peak in LFP when FS cells are driven in the gamma range. • 20-80 Hz (optical stimulation) of FS cells resulted in significant amplification of LFP power in that same frequency band • 8-24 (optical stimulation) Hz activation of RS cells resulted in significant amplification of LFP power in that same frequency band • Gamma by FS - lower frequencies by RS • no effect on LFP power when • FS cells at 8 Hz (optical stimulation) • RS stimulation at 40 Hz (optical stimulation) 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 • spontaneously occurring • 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 despitehigh levels of evoked FS • FS stimulation during naturally occurring gamma • Increased duration of the ongoing gamma cycle • Stimulation of the midbrainreticular formation (RF) led to increased gamma activity • light pulse was given during an ongoing gamma oscillation • prolonging the ongoing gamma cycle and shifting the phase of the following cyclesrelative to the pre-light oscillation

11. Evoked gamma phase regulates sensory processing • 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 • 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

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