State-dependent and branch-specific neurotransmitter usage in a serotonergic/glutamatergic neural circuit regulating adaptation to seasonal photoperiod

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Summary Changes in our surrounding environment are perceived and then encoded in the brain, leading to physiological and behavioral responses that involve substantial remodeling in the structure and function of specialized neural circuits. Such plasticity is adaptive and even life sustaining. Our research seeks to identify novel forms of neuronal plasticity at the molecular, cellular, and circuit level, and the biological significance of such brain mechanisms. Exciting clues are emerging from studies of Seasonal Affective Disorder (SAD), a type of seasonal depression involving low mood and sleep abnormalities that disable up to 6% of the population. Like for Major Depressive Disorder (MDD), the first-line treatment for SAD includes Selective Serotonin Reuptake Inhibitors (SSRIs), thus implicating serotonergic circuitry. Because SAD has a distinctive, predictable onset in the fall/winter and a spontaneous remission in the spring/summer, unlike MDD, the neural circuit mechanisms underlying these disorders must not be fully overlapping. The combination of seasonal onset and mood/sleep abnormalities suggests the hypothesis that altered circuit mechanisms between circadian and serotonergic neuronal systems might underlie SAD pathophysiology. We have garnered enticing preliminary data that points to a dual serotonergic-glutamatergic neuron subset uniquely positioned in an anatomical circuit poised to influence circadian/sleep-related behaviors and behaviors related to locomotion, place-avoidance, risk-taking, and active coping strategies, all of which may be engaged in adaptations to seasonal photoperiods. Specifically, we have identified a novel form of neurotransmitter plasticity exhibited by these specialized serotonergic neurons: in response to changes in the amount of daylight, the deployment of neurotransmitter changes in a state- and axon branch-specific manner. In pursuit of such a novel, non-canonical form of neuronal plasticity and its biological significance, we propose to (1) determine the role of neurotransmitter plasticity in photoperiod behavioral adaptation, as explored using projection-specific gene knock-out, sleep monitoring, and task-related behavioral measurements (Aim 1); and (2) manipulate the excitability of these specialized serotonergic neurons during photoperiod exposure to normalize behavior – studies made possible using in vivo chemogenetics coupled with in vivo calcium imaging (Aim 2). Collectively, this innovative work will inform on a novel form of neuronal plasticity involving state- and branch-specific neurotransmitter usage and will illuminate brain mechanisms underlying behavioral and physiological adaptations to photoperiod changes akin to seasonality.