Basal ganglia circuit mechanisms for threat coping

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Project Summary/Abstract Avoiding potential threats before experiencing disastrous events is critical for survival, yet excessive avoidance may lead to maladaptive conditions such as withdrawal or missing rewarding events. Abnormalities in threat- coping may underlie psychiatric conditions including post-traumatic stress disorder and anxiety disorders. Recent studies have shown a critical role for the sensory part of the striatum, the posterior tail of the striatum (TS), in avoidance of a potential threat. These studies have indicated that TS-projecting dopamine neurons are activated by salient threatening stimuli, and animals avoid activation of these neurons. The role of the TS in threat avoidance has been pursued further using a foraging paradigm (“Monster task”) in which mice are presented with a potential threat (a moving monster) while they forage for a reward. In this task, although mice never experienced physical harm, they exhibited three stages of threat-response: initial reactive avoidance, gradually-acquired proactive avoidance, and eventual overcoming of the threat to obtain reward. Lesions of TS-projecting dopamine neurons impaired threat avoidance. Further, preliminary results indicate that, in the TS, medium spiny neurons in direct and indirect pathways (dMSNs and iMSNs) facilitate threat avoidance and overcoming, respectively. Building on these observations, the goal of this project is to elucidate the neural mechanisms by which TS and associated circuits of the basal ganglia function to regulate progression of threat-coping. Aim 1 will test the hypothesis that dopamine in TS represents threat prediction error and regulates threat-coping by dual modes of functioning, acute and learning-based actions. To this end, dopamine release in TS will be monitored using fiber photometry or manipulated optogenetically during the Monster task. Aim 2 will examine the striatal circuit mechanisms by which dopamine regulates threat-coping. The specific hypotheses to be tested are that (1) the balance between dMSNs and iMSNs determines the behavioral output (threat avoidance vs. overcoming), and that (2) phasic dopamine signals modulate the balance between these opponent circuits through both acute and learning-based mechanisms. Finally, Threat-coping can involve at least two distinct processes: action selection (choosing to approach or avoid) and/or changes in sensory processing (adjusting the salience of a potentially threatening stimulus). Aim 3 will aim to identify pathways downstream of TS which are involved in these processes. Specifically, this aim will test the hypotheses that (1) the integration of dMSN and iMSN activities occurs in the substantia nigra pars lateralis (SNL) which then regulates avoidance behavior, and that (2) the TS-globus pallidus-thalamic reticular nucleus pathway modulates sensory representation in lateral geniculate nucleus to attend or overcome a monster threat. Overall, this study will elucidate a role for novel neural circuits (TS and associated basal ganglia pathways) in three stages of threat-coping, initial reactive avoidance, proactive avoidance, and overcoming of the threat.