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 感知周围环境的变化，然后在大脑中编码，从而导致物理和行为反应，涉及专门神经元电路的结构和功能进行大量重塑。这种可塑性是适应性的，甚至是维持生命。我们的研究试图在分子，细胞和电路水平以及这种大脑机制的生物学上鉴定新形式的神经元可塑性形式。令人兴奋的线索来自对季节性情感障碍（SAD）的研究，这是一种季节性抑郁症，涉及情绪低落和睡眠异常，最多可使人口6％。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（SSRIS），因此是隐式血清素能回路。由于SAD在秋季/冬季具有独特的，可预测的发作，并且在春季/夏季具有赞助缓解，因此与MDD不同，这些疾病背后的神经元电路机制不得完全重叠。季节性发作和情绪/睡眠异常的结合表明，昼夜节律和塞拉顿素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，该数据指向双重的血清能神经元的神经元子集，该子集唯一地定位在一个被毒害的解剖回路中，以影响昼夜节律/与睡眠相关的行为和行为和与机车，避免，避免，冒险，冒险，冒险，冒险和活跃策略相关的pontersod ponters的photors gentering nepersod nepersod neperion nepersod nepersod nepersod nepersod nepersod of neperiations neperiations neperiations。具体而言，我们已经确定了这些专业的塞拉顿能神经元所表现出的一种新型的神经递质可塑性形式：为了响应日光的变化，在状态和轴突分支特异性方式中的神经递质的部署变化。为了追求这种新颖的，非典型的神经递质可塑性及其生物学意义，我们建议（1）使用投射特异性的基因敲除，睡眠监测和与任务相关的行为测量（AIM 1）确定神经递质可塑性在光周期适应中的作用； （2）在光周期暴露于正常化的行为期间操纵这些专门的血清素能神经元的兴奋 - 研究可以使用体内化学遗传学与体内钙成像相结合（AIM 2）。总的来说，这项创新的工作将为一种新型的神经元可塑性提供信息，涉及国家和分支特异性的神经递质使用情况，并将阐明对光周期的行为和物理适应性的脑机制，类似于季节性。