Long-range inhibitory neuron circuit organization and cortical function

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Project Summary Cortical activity is highly dependent on behavioral state of an animal with different states, such as sleep and wake, having profound impact on cognition and cortical processing. At the brain level, behavioral states (such as sleep and wakefulness) are associated with distinct patterns of cortical activity (or cortical states), that are well captured by oscillatory activity measured with EEG and/or LFP. Recent work shows that cortical states regulate processing of local neuronal information as well as the communication between brain areas, and despite this important function, relatively little is known about the circuits underlying these distinct states of network activity. Inhibitory neurons (INs), though they make up a minority of cells in the cortex, are well positioned to regulate cortical state. While the vast majority INs in the cortex project locally, there is a subtype of cortical IN that projects over a long distances in stark contrast to other INs. These cells arborize densely throughout the cortex, can span over different cortical regions, and are remarkably unique in terms of gene expression and morphology. Even though they constitute a very small portion of INs, they are evolutionarily conserved, suggesting that these cells play an important role in brain function. Their massive axonal arborization suggests that these cells can coordinate the activity of many downstream cells. Though this IN cell type is completely unique in its morphology and potential role in cortical circuits, we do not understand its function, though, I hypothesize it is crucial for regulating synchronized slow cortical rhythms. Here we will use new intersectional genetic tools in the mouse, to gain access to this distinct neuronal type and to interrogate the in vivo functional role of SST/nNOS INs in cortical circuits. The long projections and dense cortical arborizations of SST/nNOS cells make them a good candidate to synchronize activity across large areas. Furthermore, ex-vivo studies suggest that long-range inhibitory neurons are likely to be active during periods of highly synchronized brain of slow wave sleep (SWS). This state is characterized by a slow oscillation between UP and DOWN states that is tightly synchronized across millimeter distances in the cortex. While many believe transitions between UP and DOWN states arise solely from interactions between pyramidal cells, recent work suggests that an unknown mechanism exists to initiate the sharp and synchronous DOWN state transition across millimeter areas. I hypothesize that the activity pf SST/nNOS cells is critical for the generation of slow cortical rhythms and the transition from UP to DOWN states.