The role of long-range inhibitory neurons in cortical circuits

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Project Summary Cortical activity changes dramatically upon changes in behavioral state of an animal with different behavioral states, such as sleep and wake, having profound impact on cortical processing. The circuitry responsible for sensing behavioral state and modifying cortical activity to generate cortical states remains unknown. However, inhibitory neurons (INs) have been recently implicated in this role. Interestingly, both dysregulation of behavioral states and disruptions in INs are hallmarks of major neuropsychiatric disorders. Here, I propose that a specific sub type of inhibitory neuron in the cortex plays a role in the generation of low-frequency oscillations, a hallmark of multiple cortical states. I propose that the long-range inhibitory neurons of the cortex play a crucial role in the generation of low-frequency oscillations. Long-range inhibitory neurons are highly distinct from other cell types in the cortex both in terms of their morphology and gene expression. While other INs in the cortex project locally, long-range inhibitory neurons project across many millimeters, in the mouse, and across cortical areas. Previous studies of the connectivity of these cells have been hampered by the necessity to slice tissue and fill cells to generate morphologies limiting our knowledge of these cells. In my first aim, I plan to address these issues using tissue clearing and light sheet microscopy to determine the postsynaptic areas targeted by these cells. I will compliment this with 2-photon recordings of the activity of these cells performed across behavioral states to determine the activity patterns affecting downstream areas. In my second aim, I will perform in vivo function characterizations of long-range inhibitory neurons using optogenetics and electrophysiology. Ex-vivo studies suggest that long-range inhibitory neurons are active during slow wave sleep, a period of low-frequency oscillations. I will perform in vivo extracellular electrophysiology while using optogenetic tools to manipulate the activity of long-range inhibitory neurons. I will use excitatory opsins with frequency modulated stimulation and an inhibitory opsin. I will measure the responses of single units and network oscillations to this stimulation. I will perform manipulations in long-range inhibitory neurons and other neuronal types to show specificity of results testing the hypothesis that these cells regulate the generation of low-frequency oscillations. Together these two aims provide the first in vivo characterizations of the activity of long-range inhibitory neurons. When completed, I will be able to relate the connectivity, morphology, and activity patterns of this cell type to understand the role of this cell type in cortical circuits.