Photoperiodic Programming of Monoamine Brain Circuits

单胺脑回路的光周期编程

• 批准号: 10735447
• 负责人: Brad Alan Grueter
• 金额: $ 66.88万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735447
• 关键词: Acute; Affective; Animal Model; Antidepressive Agents; Anxiety; Automobile Driving; Behavior; Behavioral; Biological Clocks; Bipolar Disorder; Brain; Brain region; Cell Nucleus; Development; Disease; Dopamine; Dopamine D2 Receptor; Dorsal; Electrophysiology (science); Epidemiology; Exhibits; Experimental Models; Female; Glutamates; Goals; Human; Intervention; Ion Channel; Learning; Light; Long-Term Effects; Major Depressive Disorder; Measures; Mediating; Mental Depression; Mental Health; Midbrain structure; Molecular; Mood Disorders; Moods; Motivation; Mus; National Institute of Mental Health; Neurobiology; Neurons; Nucleus Accumbens; Output; Photoperiod; Play; Positive Valence; Potassium Channel; Psyche structure; Psychological reinforcement; Regulation; Reporting; Rewards; Role; Seasonal Affective Disorder; Seasons; Serotonin; Sex Bias; Shapes; Signal Transduction; Site; Synaptic plasticity; System; Transcriptional Regulation; Twin Multiple Birth; Ventral Tegmental Area; Visual System; anxiety-like behavior; base; channel blockers; circadian; circadian pacemaker; depressive symptoms; design; dorsal raphe nucleus; electrical property; experience; experimental study; hedonic; mRNA Expression; male; monoamine; mood regulation; motivated behavior; neural; neural circuit; neural network; neurobehavioral disorder; neurobiological mechanism; neuronal excitability; neurophysiology; novel; patch clamp; photoperiodicity; potassium channel protein TREK-1; programs; reuptake; sex; transmission process; uptake

PROJECT SUMMARY A fundamental question in neurobiology is how environmental signals – both developmental and ongoing– induce plasticity in neural circuits and networks to shape behavior. Circadian photoperiod, the proportion of daylight in a solar day, is a pervasive environmental signal that varies substantially with latitude and season, and drives acute and long-term effects on mood regulation in humans and in animal models. The associations of the molecular circadian clock and photoperiod with mood disorders are clear, but the neurobiological mechanisms remain incompletely understood. The serotonergic dorsal raphe nuclei (DRN) are a critical nexus for integrating circadian photoperiodic input with mood and reward. They receive light input from the circadian visual system and polysynaptic input from the biological clock nuclei and make widespread outputs, including to midbrain nuclei mediating motivation and reward through dopaminergic transmission. Seasonal photoperiods (winter–like “short days” vs. summer-like “long days”) induce enduring changes in mouse DRN serotonin neurons - programming their excitability and intrinsic electrical properties, their serotonin content, as well as anxiety and depressive-like behaviors. We have previously shown that the TREK-1 K+ channel mRNA expression is photoperiodically regulated in DRN 5- HT neurons, and therefore may play a key role in photoperiodic programming of serotonin excitability. A number of independent lines of evidence indicate that TREK-1 in DRN neurons impact mood regulation and mood disorders. We now also report intriguing sex-dependent photoperiodic regulation of dopamine uptake and release downstream of the DRN in the NAc of female mice, indicating photoperiodic impact on circuitry for motivation and reward that mirrors the reported female bias of Seasonal Affective Disorder (SAD) in humans. We propose as our overall hypothesis that DRN 5-HT neurons are a primary site of photoperiodic programing – in which transcriptional regulation of TREK-1 plays a key role in regulating neuronal excitability. In congruence with the NIMH RDOC paradigm, we envision photoperiod programing as an extended circuit for positive valence system behaviors in which the output of the programmed serotonergic DRN induces convergent drive by the DRN and VTA inputs to alter NAc function, driving changes in the output of reinforcement/motivated behaviors. We will further elucidate a mechanistic basis of photoperiodic programming of 5-HT neurons involving TREK-1, and downstream effects of this programming on positive valence systems, including NAc dopamine release and uptake, NAc synaptic plasticity, and NAc-driven motivation behavior. Completion of these Aims will enhance understanding of key neurobiological mechanisms underlying photoperiodic regulation of mood, motivation, and reinforcement.

项目总结 神经生物学中的一个基本问题是，环境信号--无论是发育的还是持续的--是如何 诱导神经回路和网络的可塑性来塑造行为。昼夜节光周期， 太阳日中的日光是一种普遍存在的环境信号，它随纬度和季节的变化而变化， 并在人类和动物模型中对情绪调节产生急性和长期的影响。协会 分子生物钟和光周期与情绪障碍的关系是清楚的，但神经生物学 机制仍然不完全清楚。 5-羟色胺能中缝背核(DRN)是整合昼夜节律光周期输入的重要神经网络 带着心情和回报。它们接受来自昼夜节律视觉系统的光输入和来自 生物钟核团和作出广泛的输出，包括向中脑核团介导的动机和 通过多巴胺能传递获得奖赏。季节性光周期(冬季般的“短日”与夏季的 “长时间”)诱导小鼠DRN 5-羟色胺神经元的持久变化-编程它们的兴奋性和 内在的电特性，它们的5-羟色胺含量，以及焦虑和抑郁样行为。我们 已有研究表明，DRN中Trek-1 K+通道基因的表达受光周期调控。 因此，它可能在5-羟色胺兴奋性的光周期编程中起关键作用。一个 多条独立的证据表明DRN神经元中的Trek-1影响情绪调节和 情绪障碍。我们现在还报告了耐人寻味的性别依赖性光周期调节多巴胺摄取 并在雌性小鼠NAC的DRN下游释放，表明光周期对 动机和奖励反映了季节性情感障碍(SAD)在人类中的女性偏见。 我们提出的总体假设是DRN 5-羟色胺神经元是光周期的主要部位 编程--其中Trek-1的转录调控在神经元调节中起关键作用 兴奋性。与NIMH RDoC范例一致，我们将光周期编程设想为一种 正价系统行为的扩展电路，其中程序化的5-羟色胺能输出 DRN通过DRN和VTA输入诱导汇聚驱动以改变NAC功能，从而驱动输出的改变 强化/激励行为。我们将进一步阐明光周期的机理基础。 涉及Trek-1的5-羟色胺神经元的编程以及该编程的下游效应 正价系统，包括NAC多巴胺的释放和摄取，NAC突触的可塑性，以及 NAC驱动的动机行为。这些目标的实现将增进对关键问题的理解 光周期调节情绪、动机和强化的神经生物学机制。