Examining Neurocircuit and Behavioral Effects in a Developmental Model for Indirect Pathway Hypofunction

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Project Summary I am an MD/PhD physician-scientist trained in psychiatry and neuroscience. My career goal is to become an independent neuroscience investigator devoted to a mechanistic understanding the long-term contributions of altered neurodevelopmental trajectories to neuropsychiatric disorders. I ultimately hope that discoveries made in my lab will generate new ways to assess risk factors during early life, as well as spur novel treatment and preventive approaches to neuropsychiatric disorders—in particular schizophrenia (SCZ), a devastating disorder in which development is thought to play an important but poorly understood role. I have designed a research plan that is integrated with my training objectives and career development plan, and will propel me towards scientific independence. Using the mouse as my model system, the questions I intend to address in this K08 proposal are centered on how striatal pathway-specific perturbations during basal ganglia (BG) circuit formation can shape developmental trajectories and alter the character of BG circuit computations with lasting behavioral consequences. Dysfunctions in dopamine (DA) signaling in the striatum and prefrontal cortex have long been associated with motivational and cognitive deficits in humans. In the striatum, increased expression of dopamine D2 receptors (D2Rs) in indirect pathway neurons have been implicated in the etiology of SCZ, but developmental mechanisms remain limited4-7. Mouse studies have shown that a non-pathway-specific developmental D2R overexpression led to behavioral deficits that were associated with altered DA signaling from the midbrain on striatum and prefrontal cortex16, 17, 20, 47. Meanwhile, early postnatal chemogenetic inhibition (with hM4D activation) of indirect pathway resulted in restructuring of corticostriatal synapses lasting for at least ten days19— suggesting a developmental window for corticostriatal wiring that may shape behaviors dependent on this circuitry. In this K08 proposal, I will address these questions with two Specific Aims. In Aim 1, I will test the hypothesis that transiently inhibiting striatal indirect pathway neurons during an early postnatal developmental window will result in decreased motivation and impaired cognitive performance in adult mice. I have developed a stereotaxic neonatal adaptor that improves regional targeting with viral vectors1. Preliminary data suggest a developmental effect on motivated behavior. In Aim 2, I will test the hypothesis that the developmental manipulation leads to persistent circuit-level changes affecting long-term DA release in adults, possibly by altering midbrain neuronal activity. I will record real-time striatal DA release dynamics in freely behaving mice by fiberphotometry (FP). To examine midbrain neuronal activity in vivo, I propose Ca2+ imaging experiments in freely behaving animals, using a virally-encoded Ca2+ indicator, GCaMP6f, in midbrain neurons. I will conduct this project at the New York State Psychiatric Institute and Columbia University under the mentorship team of Drs. Christoph Kellendonk, Peter Balsam, Mark Ansorge, René Hen, Joshua Berke, and Jonathan Javitch. Through the completion of the training goals delineated in this career development award proposal, I will be prepared to transition into scientific independence leading a research laboratory in an academic medical center.