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.

项目概要 神经生物学的一个基本问题是环境信号——无论是发育的还是持续的——如何 诱导神经回路和网络的可塑性来塑造昼夜节律光周期，即昼夜节律的比例。 太阳日中的日光是一种普遍的环境信号，随纬度和季节变化很大， 并对人类和动物模型的情绪调节产生急性和长期的影响。 分子生物钟和光周期与情绪障碍的关系是明确的，但神经生物学 机制仍不完全清楚。 血清素能中缝背核 (DRN) 是整合昼夜节律光周期输入的关键纽带 他们接收来自昼夜节律视觉系统的光输入和来自多突触的输入。 生物钟核并产生广泛的输出，包括调节动机和的中脑核 通过多巴胺能传递进行奖励。季节性光周期（冬季“短日”与夏季“ “漫长的日子”）诱导小鼠 DRN 血清素神经元的持久变化 - 编程它们的兴奋性和 内在的电特性、血清素含量以及焦虑和抑郁样行为。 之前已经表明 TREK-1 K+ 通道 mRNA 表达在 DRN 5- 中受到光周期调节 因此，HT 神经元可能在血清素兴奋性的光周期编程中发挥关键作用。 大量独立证据表明 DRN 神经元中的 TREK-1 影响情绪调节和 我们现在还报道了有趣的性别依赖性光周期调节多巴胺摄取。 并在雌性小鼠 NAc 中的 DRN 下游释放，表明光周期对电路的影响 动机和奖励反映了人类季节性情感障碍（SAD）中女性的偏见。 作为我们的总体假设，我们提出 DRN 5-HT 神经元是光周期的主要位点。 编程 – TREK-1 的转录调控在调节神经元中起着关键作用 与 NIMH RDOC 范式一致，我们将光周期编程设想为一种 用于正价系统行为的扩展电路，其中编程的血清素能的输出 DRN 通过 DRN 和 VTA 输入诱导收敛驱动，以改变 NAc 功能，从而驱动输出变化 我们将进一步阐明光周期的机制基础。 涉及 TREK-1 的 5-HT 神经元编程，以及该编程对下游的影响 正价系统，包括 NAc 多巴胺释放和摄取、NAc 突触可塑性和 NAc 驱动的动机行为的完成将增强对关键的理解。 情绪、动机和强化的光周期调节的神经生物学机制。