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

状态依赖性和分支特异性神经递质在血清素能/谷氨酸能神经回路中的使用调节对季节性光周期的适应

• 批准号: 10666427
• 负责人: Susan M. Dymecki
• 金额: $ 21.19万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10666427
• 关键词: Affect; Affective; Agitation; Anatomy; Animals; Axon; Behavior; Behavioral; Binding; Biological; Biological Models; Brain; Brain Stem; Brain region; Cell Nucleus; Chronic; Circadian Dysregulation; Circadian Rhythms; Complex; Coping Skills; Coupled; Darkness; Data; Depressed mood; Development; Disease; Environment; Exhibits; Exposure to; Failure; Fire - disasters; Functional disorder; Genes; Genetic; Glutamates; Goals; Hour; House mice; Human; Involutional Depression; Knowledge; Laboratory mice; Length; Life; Light; Location; Locomotion; Major Depressive Disorder; Mammals; Mediating; Mental Depression; Molecular; Monitor; Moods; Motor Activity; Mus; Neuronal Plasticity; Neurons; Neurotransmitters; Organism; Phase; Photoperiod; Physiological; Physiological Adaptation; Physiology; Play; Polysomnography; Population; Positioning Attribute; Research; Risk Taking; Role; SLC17A8 gene; Schedule; Seasonal Affective Disorder; Seasons; Selective Serotonin Reuptake Inhibitor; Septofimbrial Nucleus; Serotonin; Signal Transduction; Signaling Molecule; Sleep; Sleep Wake Cycle; Spontaneous Remission; Stimulus; Stress and Coping; Structure; Structure of paraventricular nucleus of thalamus; Sunlight; Synaptic Vesicles; System; Testing; Time; Viral; Work; behavior measurement; behavioral response; behavioral study; circadian; day length; experience; experimental study; falls; genetic manipulation; in vivo; in vivo calcium imaging; innovation; insight; knockout gene; neural; neural circuit; neurochemistry; neuronal cell body; neuronal circuitry; neurotransmission; novel; raphe nuclei; response; segregation; sleep abnormalities; suprachiasmatic nucleus; translational potential

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.

概括 我们周围环境的变化被大脑感知并编码，从而导致生理和行为反应，这些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。季节性情感障碍 (SAD) 是一种季节性抑郁症，涉及情绪低落和睡眠异常，会导致人丧失能力。与重度抑郁症 (MDD) 一样，SAD 的一线治疗包括选择性血清素再摄取抑制剂 (SSRI)，因此涉及血清素能回路，因为 SAD 在秋季/冬季有一个独特的、可预测的发作。与春季/夏季的自发缓解不同，这些疾病的神经回路机制不能完全重叠，季节性发作和情绪/睡眠异常的组合。提出了这样的假设：昼夜节律和血清素神经系统之间的回路机制的改变可能是 SAD 病理生理学的基础。与运动、回避地方、冒险和积极应对策略相关的行为，所有这些都可能与季节性的适应有关具体来说，我们发现了这些特殊的血清素能神经元表现出一种新型的神经递质可塑性：为了响应日光量的变化，神经递质的部署以状态和轴突分支特异性的方式发生变化。神经元可塑性的一种新颖的、非规范的形式及其生物学意义，我们建议（1）确定神经递质可塑性在光周期行为适应中的作用，正如使用投射特异性基因所探索的那样敲除、睡眠监测和任务相关的行为测量（目标 1）；以及（2）在光周期暴露期间操纵这些特殊的血清素神经元的兴奋性以使其行为正常化——利用体内化学遗传学与体内钙成像相结合的研究成为可能（目标 2）这项创新工作将揭示一种涉及状态和分支特异性神经递质使用的新型神经元可塑性，并将阐明类似光周期变化的行为和生理适应的大脑机制。到季节性。