Photoperiodic Programming of Serotonin Neurons

血清素神经元的光周期编程

• 批准号: 9922989
• 负责人: DOUGLAS G MCMAHON
• 金额: $ 40.51万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922989
• 关键词: Acute; Affective; Anxiety; Behavior; Behavioral; Biological Clocks; Bipolar Disorder; Brain; Brain region; Cell Nucleus; Cells; Development; Disease; Dorsal; Electrophysiology (science); Experimental Models; Fluorescent in Situ Hybridization; Gene Activation; Gene Expression Profiling; Gene Expression Regulation; Genes; Glutamates; Health; Human; In Situ Hybridization; Knockout Mice; Laboratories; Life; Light; Lighting; Major Depressive Disorder; Mediating; Mental Depression; Midbrain structure; Modeling; Molecular; Mood Disorders; Mus; Neonatal; Neuraxis; Neurons; Neurophysiology - biologic function; Neurosciences; Norepinephrine; Phenotype; Photoperiod; Play; Psyche structure; RNA; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Seasonal Affective Disorder; Serotonin; Signal Transduction; Synapses; Testing; Visual system structure; anxiety-like behavior; circadian; circadian pacemaker; critical period; dorsal raphe nucleus; electrical property; experimental study; fetal; multi-electrode arrays; neural circuit; neurobehavioral disorder; neurobiological mechanism; neurochemistry; neuromechanism; neurotransmission; noradrenergic; novel; photoperiodicity; postnatal development; prenatal; programs; relating to nervous system; transcription factor; transcriptome; transcriptome sequencing

PROJECT SUMMARY A fundamental question in neuroscience is how environmental signals may have long-lasting effects on neural circuits and neural function. The circadian clock and circadian photoperiod are associated with mood disorders, but the neurobiological mechanisms are unknown. Dysregulation of serotonin neurotransmission is implicated in neurobehavioral disorders, such as depression and anxiety, and alterations in the serotonergic phenotype of raphe neurons has dramatic effects on affective behaviors in rodents. The serotonergic dorsal raphe nuclei receive light input from the circadian visual system, as well as polysynaptic input from the biological clock nuclei, and dorsal raphe serotonin neurons respond acutely to tonic illumination with increased spike rate and to changes in the circadian light cycle with gene activation. Our laboratory has demonstrated that seasonal circadian photoperiods (winter –like “short days” vs. summer-like “long days”) can induce enduring changes in mouse dorsal raphe serotonin neurons - programming their spontaneous neural activity, and altering depression and anxiety-like behaviors. Here we seek to elucidate the mechanistic basis photoperiodic programming of serotonin neurons, focusing on electrophysiology, gene regulation and maternal-fetal vs neonatal developmental windows. We will examine neural mechanisms of photoperiodic programming of dorsal raphe serotonin neurons using both multi-electrode array and whole cell electrophysiology; altered gene regulation in serotonin neurons induced by photoperiodic programming using RT-PCR, RNA-seq gene expression analysis of FACS sorted serotonin neurons and RNA Scope in situ hybridization to determine the photoperiod programming transcriptome, and the gene network in serotonergic neurons driven by photoperiodic programming. We will test the hypothesis that the Pet-1 transcription factor is a critical node for photoperiodic programing and define critical periods for the enduring effects of photoperiod. Successful completion of these aims will reveal novel mechanisms by which a pervasive environmental signal – the daily light cycle – can influence the long-term function of brain serotonergic neurons and the behaviors they mediate.

项目总结 神经科学中的一个基本问题是环境信号如何对神经产生长期影响 电路和神经功能。生物钟和昼夜光周期与情绪紊乱有关， 但其神经生物学机制尚不清楚。5-羟色胺神经传递的失调与此有关 神经行为障碍，如抑郁和焦虑，以及5-羟色胺能表型的改变 中缝神经元对啮齿动物的情感行为有显著影响。5-羟色胺能中缝背核 接收来自昼夜节律视觉系统的光输入以及来自生物时钟的多突触输入 核团和中缝背侧5-羟色胺神经元对紧张性光照有强烈的反应，峰频率增加和 与基因激活的昼夜节律光周期的变化有关。我们的实验室已经证明了季节性的 昼夜光周期(冬天一样的“短白天”与夏天一样的“长白天”)可以诱导 小鼠中缝背侧5-羟色胺神经元--编程它们的自发神经活动，并改变 抑郁和类似焦虑的行为。在这里，我们试图阐明光周期的机理基础 5-羟色胺神经元的编程，重点是电生理、基因调控和母婴VS 新生儿发育窗口期。我们将研究光周期编程的神经机制 采用多电极阵列和全细胞电生理学的中缝背侧5-羟色胺神经元 RT-PCR、RNA-seq法研究光周期编程诱导5-羟色胺神经元基因调控 流式细胞仪分选5-羟色胺神经元基因表达分析及RNA原位杂交法检测 5-羟色胺能神经元的光周期编程转录组和基因网络 光周期编程。我们将测试Pet-1转录因子是关键节点的假设 光周期编程，并为光周期的持久效应定义关键周期。成功 这些目标的完成将揭示新的机制，通过这些机制，普遍存在的环境信号-每日 光周期-可以影响大脑5-羟色胺能神经元的长期功能及其行为 调停。