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.

摘要 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、细胞和电路水平上确定神经元可塑性的新形式，以及这些大脑机制的生物学意义。对季节性情感障碍(SAD)的研究正在涌现出令人兴奋的线索，这是一种季节性抑郁症，涉及情绪低落和睡眠异常，导致高达6%的人口残疾。与治疗严重抑郁障碍(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5-羟色胺能回路。由于SAD在秋季/冬季有独特的、可预测的发病，而在春季/夏季有自发缓解，与MDD不同，这些疾病背后的神经回路机制不能完全重叠。季节性发作和情绪/睡眠异常的组合表明，昼夜节律和5-羟色胺能神经元系统之间的电路机制改变可能是SAD病理生理学的基础。我们已经获得了诱人的初步数据，指出一个双重的5-羟色胺能-谷氨酸能神经元亚群独特地位于一个解剖回路中，准备影响与昼夜节律/睡眠相关的行为，以及与运动、位置回避、冒险和积极应对策略有关的行为，所有这些都可能参与对季节性光周期的适应。具体地说，我们已经确定了这些特化的5-羟色胺能神经元表现出的一种新的神经递质可塑性：响应日照时间的变化，神经递质的部署以状态和轴突分支特有的方式变化。为了追求这种新颖的、非规范形式的神经元可塑性及其生物学意义，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，通过投影特异性基因敲除、睡眠监测和与任务相关的行为测量(目标1)；以及(2)操纵这些专门的5-羟色胺能神经元在光周期暴露期间的兴奋性，以使行为正常化--使用体内化学遗传学和体内钙成像的研究成为可能(目标2)。总而言之，这项创新的工作将揭示一种新的神经可塑性形式，涉及状态和分支特定神经递质的使用，并将阐明潜在的大脑机制，以适应类似季节性的光周期变化。