The role of nigrostriatal and striatal cell subtype signaling in behavioral impairments related to schizophrenia

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Project Summary/Abstract In psychotic disorders, excess nigrostriatal (NS) dopamine signaling is linked to hallucinations, delusions, and disorganized thought—positive symptoms that respond to antipsychotic drugs. By contrast, the prevalent negative and cognitive symptoms in these disorders are largely unresponsive to treatment. Antipsychotic drugs are thought to work by blocking D2 dopamine receptors (D2Rs), which are highly expressed in the striatum. This observation and the fact that increasing brain-wide dopamine (via amphetamine treatment) improves cognition fueled the dogma that excess dopamine is not involved in cognitive and negative symptoms. However, in patients with schizophrenia, dopamine is selectively increased in the striatum (not throughout the brain). Moreover, the striatum also expresses D1 dopamine receptors (D1Rs), which are not targeted by current antipsychotics. Therefore, dopamine may contribute to negative and cognitive symptoms through striatal D1R signaling, but this idea has never been directly tested. The goal of the proposed research is to determine whether striatal D1R- and D2R-expressing spiny projection neurons (SPNs) differentially contribute to dopamine-driven deficits in social and cognitive function. To do this, I developed an approach to mimic the pathway-specific excess in dopamine observed in schizophrenia by selectively expressing the excitatory cation channel TRPV1 in SNc dopamine neurons of Trpv1 knockout mice. Systemically treating these mice with the TRPV1 agonist capsaicin increases dopamine release in the dorsal striatum but not prefrontal cortex (PFC) as measured by dLight fluorescence using in vivo fiber photometry. Selectively driving NS dopamine transmission in this way increases locomotion, but also disrupts social interaction and working memory, behavioral proxies for negative and cognitive symptoms. Here I propose to expand on these findings with the following specific aims: (1) In Aim 1, I will use the TRPV1-based approach with miniature microscopes to image Ca2+ activity in D1- or D2-SPNs under normal and hyperdopaminergic conditions to determine how altered activity in each SPN type contributes to deficits in social and cognitive behavior. (2) In Aim 2, I will use the TRPV1-based approach with chemogenetic manipulations of D1R- or D2R-expressing SPNs to causally link their activity to specific changes in behavior caused by selectively driving striatal dopamine release. By defining the roles of striatal D1- and D2-SPNs in dopamine-driven changes in behavioral constructs related to the symptoms of schizophrenia, my experiments have the potential to identify novel therapeutic strategies for psychosis that more comprehensively address its symptoms. Under this fellowship, I plan to receive training in in vivo imaging and electrophysiology recording techniques, coding and data analysis, grant and manuscript writing, teaching and mentorship, and further knowledge of basal ganglia-related dysfunction and psychiatric disease. My training goals, dedication to progressing science research and diversity in academia, strong mentorship team, and the vibrant academic environment at Northwestern ensure I will reach success as an NRSA fellow.