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.

项目摘要 神经生物学中的一个基本问题是环境信号（无论是发育还是正在进行）如何 诱导神经元和网络的可塑性以塑造行为。昼夜节律光周期，比例 太阳日的日光是一个普遍存在的环境信号，随纬度和季节而变化很大， 并驱动对人类和动物模型中情绪调节的急性和长期影响。协会 具有情绪障碍的分子昼夜节律时钟和光周期很明显，但是神经生物学 机制仍然不完全理解。 血清素能背raphe核（DRN）是整合昼夜节律光周期输入的关键联系 有心情和回报。他们从昼夜节目的视觉系统和多突触输入中收到明亮的输入 生物钟核并发出宽度的输出，包括中脑核介导动机和 通过多巴胺能传播奖励。季节性光周期（冬季 - 类似“短日”与夏季 “漫长的日子”）引起鼠标DRN 5-羟色胺神经元的持久变化 - 编程他们令人兴奋的和 内在的电性能，其5-羟色胺含量以及焦虑和抑郁样行为。 以前已经表明，在DRN 5-中，Trek-1 K+通道mRNA表达受到光的调节 HT神经元，因此可能在血清蛋白令人兴奋的光周期编程中起关键作用。一个 独立的证据线数量，表明DRN神经元中的TREK-1会影响情绪调节和 情绪障碍。现在，我们还报告了多巴胺摄取的有趣的性别依赖性光周期调节 并在雌性小鼠的NAC中释放DRN的下游，表明光周期对电路的影响 动机和奖励反映了人类中季节性情感障碍（SAD）的女性偏见。 我们提出的总体假设是DRN 5-HT神经元是光周期的主要部位 编程 - TREK-1的转录调节在调节神经元中起关键作用 兴奋性。为了与NIMH RDOC范式一致，我们将Photoperiod编程设想为 正价系统行为的延长电路，其中编程的Seratonergic的输出 DRN影响DRN和VTA输入的收敛驱动以更改NAC功能，从而推动输出的变化 强化/动机行为。我们将进一步阐明光周期的机械基础 5-HT神经元的编程涉及Trek-1，以及该编程的下游效果 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。这些目标的完成将增强对关键的理解 情绪，动机和增强的光周期调节的神经生物学机制。