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

总结 我们周围环境的变化被感知，然后在大脑中编码，导致生理和行为反应，涉及专门神经回路的结构和功能的实质性重塑。这种可塑性是适应性的，甚至是维持生命的。我们的研究试图在分子，细胞和电路水平上识别神经元可塑性的新形式，以及这些大脑机制的生物学意义。令人兴奋的线索出现在对季节性情感障碍（SAD）的研究中，SAD是一种季节性抑郁症，涉及情绪低落和睡眠异常，使多达6%的人口残疾。与重度抑郁症（MDD）一样，SAD的一线治疗包括选择性5-羟色胺再摄取抑制剂（SSRI），因此涉及多巴胺能回路。因为SAD在秋季/冬季有一个独特的、可预测的发作，而在春季/夏季有一个自发的缓解，与MDD不同，这些疾病背后的神经回路机制一定不完全重叠。季节性发作和情绪/睡眠异常的组合表明，昼夜节律和多巴胺能神经元系统之间的电路机制的改变可能是SAD病理生理学的基础。我们已经获得了诱人的初步数据，指出一个独特的双能-能神经元亚群位于一个解剖电路中，可以影响昼夜节律/睡眠相关的行为以及与运动、避地、冒险和积极应对策略相关的行为，所有这些都可能参与对季节性光周期的适应。具体来说，我们已经确定了一种新的形式的神经递质可塑性表现出这些专门的神经元：在响应日光量的变化，部署的神经递质的变化，在状态和轴突分支特定的方式。为了探索神经元可塑性的新的、非典型的形式及其生物学意义，我们提出：（1）确定神经递质可塑性在光周期行为适应中的作用，如使用投射特异性基因敲除、睡眠监测和任务相关行为测量（Aim 1）;和（2）在光周期暴露期间操纵这些特化的多巴胺能神经元的兴奋性以使行为正常化-使用体内化学遗传学结合体内钙成像（Aim 2）使研究成为可能。总的来说，这项创新工作将提供一种新形式的神经元可塑性，涉及状态和分支特异性神经递质的使用，并将阐明行为和生理适应类似于季节性的光周期变化的大脑机制。

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.