Determining the nigrostriatal circuit basis of false auditory perceptions.

Project Summary/Abstract Auditory perception can become disrupted in disorders like autism and psychosis. Higher-order auditory pro- cessing occurs in the auditory thalamus and cortex. In turn, these areas project to the tail of the striatum (TS), where dopamine has been shown to modulate auditory processing and sound-guided decision-making. Given that dopamine transmission is disrupted in a wide range of neurological and psychiatric disorders that present with perceptual deficits, it is important to better understand the dopamine system's role in these deficits. Inhibiting dopamine projections to the TS has been shown to disrupt auditory discrimination, and activat- ing these projections induces false auditory perception in mice. Our group has shown that decreases and in- creases in dopamine transmission unbalance the activity levels of the striatum's principal output neurons: the D1- and D2-dopamine receptor-expressing spiny projection neurons (SPNs). The goal of this proposal is to un- derstand how excess dopamine causes false auditory perception and which striatal sub-regions and SPN types mediate these effects. To do this, we will use viral- and mouse-genetic approaches to selectively activate specific dopamine projections and record striatal dopamine transmission and D1- or D2-SPN Ca2+ activity. We will com- bine these tools with a recently established behavior for measuring auditory perception confidence (APC) in mice. Specifically, we will (1) determine the effects of selectively activating dopamine projections to the TS or dorsomedial striatum (DMS) to determine whether these two pathways differentially modulate the frequency and/or confidence of false auditory perceptions. Next (2) we will use miniature microscopes to image Ca2+ activity in striatal D1- and D2-SPNs activity under normal conditions and while selectively activating nigrostriatal dopa- mine projections during the APC task. Finally (3) we ask whether we can attenuate dopamine-driven false per- ceptions by chemogenetically manipulating D1-SPNs vs. D2-SPNs during the APC task. By detailing how specific dopamine sub-circuits influence auditory perception, our experiments will inform both the basic sensory and translational neuroscience fields. The work builds upon recent work from our labor- atory and has the potential to unveil new therapeutic strategies for diseases with prevalent sensory deficits like psychosis and autism. The fellowship ensures that I master the techniques associated with this proposal and receive world-class training in in vivo imaging and genetic targeting techniques, coding and data analysis, sci- entific communication, teaching and mentorship, and further knowledge of the basal ganglia and its implications in disease. My training plan also entails scientific outreach in the greater Chicago area and mentorship of under- graduate trainees. These activities are anchored by a strong co-mentorship team (Drs. Jones Parker and Raj Awatramani) and a vibrant research and academic environment at Northwestern University.