Photoperiodic Programming of Monoamine Brain Circuits

项目摘要 神经生物学的一个基本问题是环境信号--包括发育和持续的-- 在神经回路和网络中诱导可塑性以塑造行为。昼夜光周期， 太阳日中的日光是随纬度和季节显著变化的普遍环境信号， 并对人类和动物模型的情绪调节产生急性和长期影响。的关联 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 机制仍然不完全清楚。 中缝背核（DRN）是整合昼夜光周期输入的关键神经元 心情和奖励。它们接收来自昼夜节律视觉系统的光输入和来自昼夜节律视觉系统的多突触输入 生物钟核团，并作出广泛的输出，包括中脑核团介导的动机， 通过多巴胺能传递的奖赏。季节性光周期（类似冬季的“短日”与类似夏季的“短日”） “长日”）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， 内在的电特性，它们的血清素含量，以及焦虑和抑郁样行为。我们 先前已经表明TREK-1 K+通道mRNA的表达在DRN 5中受到光周期性调节， HT神经元，因此可能发挥关键作用，在光周期编程的5-羟色胺兴奋性。一 许多独立的证据表明，DRN神经元中的TREK-1影响情绪调节， 情绪障碍我们现在也报告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的DRN下游释放，表明光周期对 动机和奖励，反映了人类季节性情感障碍（SAD）的女性偏见。 我们提出我们的总体假设，DRN 5-HT神经元是光周期的主要网站 编程-其中TREK-1的转录调节在调节神经元细胞中起关键作用。 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，其中编程的负能的输出 DRN通过DRN和VTA输入引起会聚驱动，以改变NAc功能，从而驱动输出的变化 强化/动机行为。我们将进一步阐明光周期的机制基础 涉及TREK-1的5-HT神经元的编程，以及这种编程对 正价系统，包括NAc多巴胺释放和摄取，NAc突触可塑性， NAC驱动的动机行为。完成这些目标将提高对关键的理解， 光周期调节情绪、动机和强化的神经生物学机制。

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.