| Yhteenveto: | <p>Neuronal oscillations are a prominent feature of motor cortical local field potentials (LFPs) and abnormalities in oscillatory activity have been linked to several disorders. Theta-modulated gamma-frequency pulses of alternating current stimulation are known to modulate motor learning in humans; however, it is unclear how these frequencies modulate motor cortical activity at the cellular microcircuit level.</p>
<p>Here, we aimed to develop a method for bidirectionally modulating theta and gamma coupled oscillations in the motor cortex using closed-loop optogenetic stimulation of parvalbumin (PV)-expressing inhibitory interneurons or excitatory pyramidal neurons. To achieve this, motor cortical LFPs were recorded in PV-Cre and RBP4-Cre (retinol-binding-protein-4) mice, in which these neurons were transfected with Channelrhodopsin-2 (ChR2). Using our recently developed phase-tracking system (OscillTrack), blue-light pulses were delivered at four phases of the ongoing motor cortical theta oscillation in awake, head-fixed mice. Optogenetic stimulation was delivered over a quarter of the theta cycle, either as a continuous pulse, a burst of three pulses at gamma frequency (75Hz), or a burst of three pulses where the gamma rhythmicity was slightly altered – random gamma.</p>
<p>Both continuous and gamma stimulation significantly modulated motor cortical theta power in a phase-dependent manner compared to controls, with continuous stimulation of excitatory cells leading to strongest modulation. Phase-dependent amplification during stimulation of excitatory vs inhibitory neurons was offset by 90°, in line with predictions from computational models of excitatory and inhibitory circuits. These effects did not occur when previously recorded closed-loop stimulation patterns were replayed to the mice, suggesting that the effects on theta power were not due to the stimulation patterns alone, but rather due to the real-time interaction with underlying theta phase. While gamma oscillations were broadly modulated by all stimulation types for excitatory neurons, the strongest effect was induced by gamma stimulation, leading to a clear 75Hz peak. These results were not dependent on the phase of theta oscillation targeted.</p>
<p>These findings demonstrate that phase-dependent modulation of theta power can be mediated by stimulation of excitatory or inhibitory neurons, and that the effect of specific stimulation phases is likely to be the result of interactions between these populations. Moreover, theta phase-dependent optogenetic stimulation of excitatory, but not inhibitory, neurons could be a more effective method of driving cortical gamma power. This approach can be used to inform the development of brain stimulation methods to modulate these activities in humans.</p>
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