Coordination of M1 projection neuron subtypes by oscillations

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PROJECT SUMMARY/ABSTRACT Motor acts such as reaching often rely upon the primary motor cortex (M1) for their execution. Oscillatory activities in M1 accompany motor actions, with the dominant electroencephalographic correlate of those actions being event-related desynchronization (ERD), a loss of low frequency power during movement onsets. Intracerebral recordings in humans, monkeys, and rodents have found that ERD co-occurs with movement associated gamma oscillations in M1. Gamma has received increased attention as a therapeutic target because it is altered in several movement disorders and affected by transcranial stimulation. However, the microcircuitry and function of gamma oscillations in M1 are not well studied. Given the abundance of specialized projection neurons in M1, it is crucial to understand how they are coordinated by gamma in normal subjects. In other cortical circuits, gamma oscillations depend on the interaction between principal cells (PNs) and fast-spiking interneurons (FSIs). In M1, projection-specific PN subtypes differ in their connectivity with FSIs, suggesting that they are differentially regulated by gamma. This project seeks to understand how gamma oscillations during reaching orchestrate three major classes of PNs in M1: pyramidal tract, corticostriatal, and corticothalamic. In Aim 1, local field potentials and single unit activity in M1 are recorded during a skilled reaching task in rats. Extracellular spike waveform characteristics will be used to identify FSIs, while PNs will be classified with antidromic stimulation. Paw kinematics will be tracked to measure reaching. For each PN subtype, we will characterize entrainment to gamma, coordination with FSIs, and reaching correlates. Aim 2 dissects the circuit mechanisms underlying any projection-specific differences in gamma entrainment. For each pair of PN subtypes, one will be made to selectively express the excitatory opsin ChroME, while the other will be labeled with GFP. In M1 brain slices, whole-cell patch clamp recordings will be made from both populations during gamma induced by optogenetic ramp stimuli. This will reveal the ability for the opsin-bearing population to induce local gamma, and how sensitive the GFP population is to it. Voltage clamp recordings will reveal the relative contributions of EPSCs and IPSCs to these rhythms, further illuminating circuit mechanisms. Lastly, Aim 3 assesses the behavioral importance of gamma entrainment. During the reaching task closed-loop optogenetic modulation of each of the PN subtypes will be delivered to bias their spiking either in- or out-of-phase with ongoing M1 gamma. The effect this has on gamma amplitude, behavioral performance, and the unstimulated projection PNs, will be determined. Altogether, these aims offer a comprehensive characterization of how M1 gamma coordinates the output microcircuitry, clarifies its physiology, and tests its behavioral relevance. Those insights are necessary for deepening our understanding of oscillatory activities in M1 and motor disordes, and perfecting future therapies.