Two-photon analysis of circuit-level mechanisms of schizophrenia biomarkers

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 DESCRIPTION (provided by applicant): Research into the biological substrate of schizophrenia (SZ) over the past several decades has focused on identifying empirical markers of the disorder which are more proximal to etiological processes than the phenomenological symptomology on which the diagnosis is based. Such biomarkers suggest fundamental disruptions in sensory cortical processing, carry the potential to explain phenomenological and higher order cognitive aspects of the disorder, and provide a critical translational strategy for targeted clinical intervention. Despite some encouraging leads, we still do not understand the pathophysiology behind most biomarkers, or how the measures themselves relate to the essential computations of the cerebral cortical circuit, limiting their utility as translational tols and theoretical benchmarks. Recent advances in transgenic and optical imaging in mice provide exciting new tools with which these specific questions can be answered. The proposed project will use cutting-edge two-photon optical imaging and photostimulation methods to identify the microcircuit level substrate of two established oscillatory biomarkers of SZ: alpha and gamma-band synchronization in visual cortex. Specifically, we will use chronic ketamine exposure in mice to generate a model of disordered sensoricortical processing and measure spontaneous and visually evoked oscillatory dynamics in V1 with dense microelectrode recordings. We will then (AIM1) employ state-of-the-art fast 3D 2- photon Ca2+ imaging to measure the multicellular activity of cortical microcircuits in vivo, describing how oscillatory biomarkers relate to the patterned activity of local cell assemblies and to the function of specific inhibitory interneuron subpopulations with demonstrated disease relevance. Based on these findings, we will then (AIM2) employ optogenetic manipulation of cortical cells in the same imaging/stimulation context to assess casual links between oscillatory biomarkers of SZ, circuit dynamics, and the function of local inhibitory interneuron populations. These studies will yield i) key biomechanistic information for interpreting measures in humans, helping to mature them from biomarkers to clinical assays, and ii) potentially novel insights into how these measures and the psychotic states they mark (e.g. SZ) relate to the emergent patterns of neural activity and their associated network-level dynamics. Moreover, the proposed work will build directly on my graduate work on sensory biomarkers of psychotic disturbance by identifying the cortical substrate of these measures and expanding my expertise into the visual domain, animal research, two-photon optical imaging and photostimutlation with optogenetics. This training will position me to pursue follow-up studies in genetic mouse models of SZ and which further explore the behavioral/perceptual consequences of disrupted microcircuit dynamics, sensory modalities other than vision, and intervention strategies based on these bioassays.