PROJECT SUMMARY/ABSTRACT This exploratory project is a collaboration between Huntington's disease (HD) researchers and BRAIN tool developers and will utilize novel interventional tools for changing neural circuit dynamics to causally link brain activity to behavior in the context of HD. Almost 30 years after identifying the genetic mutation causing this debilitating neurodegenerative disease, treatments remain limited to managing late-stage symptoms of motoric, psychiatric, and cognitive deficits. Findings from patients and mouse models of HD point to pre-symptomatic imbalances in neuronal circuit activity, well before any overt symptoms are observed. This project will explore modulating specific microcircuits in the HD brain using tools developed under the BRAIN initiative. Our central hypothesis is that manipulating the firing activity within selected microcircuits before the onset of symptoms by chemogenetic inhibition and/or excitation of key target populations will slow HD disease progression. A crucial early event in HD is the pathological increase in the overall excitatory output from cortex onto striatum. Underlying mechanisms could be enhanced excitability of cortical pyramidal neurons (PNs) and/or decreased inhibition by cortical parvalbumin interneurons (PVs) that provide the main inhibitory drive onto PNs. Stimulating PVs offers a physiologically relevant approach, as it restores this critical input while preserving other modulating synaptic inputs to the PNs (Aim 1). A second, and more direct, correction is to decrease the firing of the PNs themselves (Aim 2). Finally, a third approach will convert excitatory synapses into inhibitory ones at the PN terminals which would directly reduce the hyperactivity of specific striatal neurons during the prodromal phase of the disease process (Aim 3). Our major goal will be to determine which of the three key entry points provides the most efficacious strategy for preventing or delaying and mitigating the behavioral deficits in the R6/2 transgenic mouse model of HD. For manipulation of neuronal activity this project will utilize the bioluminescent optogenetic (BL- OG) platform that employs light emitting luciferases to activate light sensing opsins, including the recently developed ‘interluminescence’ approach that enables controlling synaptic transmission by expressing the light emitter and sensor in pre- and post-synaptic partners, respectively. To achieve our goals, we are combining expertise in circuit manipulation tool development and HD mouse model behavioral research towards a more refined understanding of the brain mechanisms underlying complex behaviors. At the same time our project will drive translational progress toward potential novel therapeutic purposes. In addition to the impact on HD research our results are expected to have a significant impact on approaching other neurodegenerative diseases that show circuit imbalances.