There is a fundamental gap in understanding how the diversity of cortical cell types and connectivity patterns translates into functional dynamics of the circuits to support cognitive behaviors. This knowledge gap hampers our understanding of the dysfunctions of decision making and other debilitating cognitive abnormalities associated with most psychiatric illnesses, including addiction, major depression, and eating disorders. My long- term goal is to unravel the intricate link from genes to circuits and to systems and reveal the pathology, pathophysiology, and behavioral deficits involved in mental disorders at the level of specific circuits and their cellular constituents. This proposal aims to determine how the genome instructs the organization and function of the premotor cortex to support decision making. The premotor cortex in mice resembles those of the non-human primates and humans, illustrating their evolutionarily conserved role in higher-level cognitive functions. In addition, we have developed behavior paradigms in mice to permit the dissection of neural circuits underlying complex behaviors using the powerful molecular tools unavailable in many other species. The central hypothesis is that molecular signatures and connectivity patterns collectively drive premotor cortex neurons to acquire distinct functions to support decision making. This hypothesis has been formulated based on previous work and the preliminary data produced by the applicants. The rationale for the proposed research is that this study will provide a new target brain area together with specific cell types and pathways for understanding and treating the cognitive deficits implicated in psychiatric illnesses. This hypothesis will be tested by pursuing two specific aims: 1) Determine the function of the molecular cell types of the premotor cortex in decision making; and 2) Establish the functional role of the afferent inputs of the premotor cortex. Under the first aim, the neural responses of individual neurons will be mapped to their molecular identity by coupling in vivo imaging and spatial transcriptomics. Further, the molecular identity will be manipulated to determine their causal contribution to function. Next, the molecular identity and function of premotor cortex neurons defined by specific afferent inputs will be established by single-cell RNA sequencing and imaging during decision making. The functional role of these afferent inputs will be further characterized by pathway-specific optogenetic manipulations. This approach is innovative because it combines in vivo imaging with spatial transcriptomics and utilizes transplantation methods and the latest circuit mapping tools to reveal the novel, cognitive role of the premotor circuit in decision making. This proposed research is significant because it answers the long-standing question about the structure and function of cortical circuits: How do neurons of distinct identities connect and interact to produce network dynamics underlying higher-level cognition. Ultimately, such knowledge has the potential to reveal the specific cell types and brain pathways underlying decision making and to better understand, intervene, and treat dysfunctions of decision making that are prevalent in psychiatric illnesses.

Dysfunctions of decision making are core characteristics of various mental illnesses such as addiction, major depression and eating disorder. Here, we seek to develop and apply novel technologies in spatial single-cell omics and in vivo tracing and imaging to determine the neural basis of decision making. These studies will uncover fundamental insights into the brain mechanisms underlying the debilitating cognitive impairments associated with mental disorders and provide translational inroad for the intervention and treatment of these disorders.