Top-Down Control of Serotonergic Circuits in Depressive-Like Behaviors

描述（由申请人提供）：重性抑郁症是最普遍的情绪障碍，但在过去的20年里，在开发临床治疗方面没有重大的治疗进展。大多数抗抑郁药策略影响单胺神经递质系统，5-羟色胺（5-HT）是最常见的靶点。然而，最近有越来越多的临床和临床前证据表明内侧前额叶皮层（mPFC）与抑郁症及其治疗有关。对患者的结构和功能成像研究揭示了心境障碍患者该区域的一致体积变化和过度活跃。在动物中进行的研究也表明，mPFC中的神经可塑性变化也可能与对压力源和抑郁样行为的脆弱性和弹性有关。此外，人类和动物的mPFC的脑深部刺激（DBS）产生了抗抑郁样作用。有趣的是，DBS需要一个完整的5-HT系统才能产生这种效果。先前的研究表明，mPFC将投射发送到中缝背核（DRN），其中包含大脑中最大的5-HT神经元群。然而，DRN是异质性的，这些投射实际上似乎会聚在GABA能神经元上，这表明这些GABA能神经元可能充当对5-HT的感觉控制的过滤器。此外，我们的实验室和其他实验室还表明，DRN GABA神经元主要是在应对各种压力时被激活的，这也表明这一人群的失调可能导致情绪障碍。该提案的目标是表明由mPFC-DRN通路中的DRN GABA能神经元介导的神经可塑性适应影响抑郁样行为和抗抑郁反应。我的第一个具体目标是对mPFC-DRN通路进行神经解剖学和功能解剖，这将使我能够更好地描述该回路的细胞结构。第二个目标将使用电生理学和形态学技术来评估mPFC-DRN通路的各种细胞组分中由社会应激诱导的适应。在第三个目标中，我将使用光遗传学工具来剖析抑郁症社交失败模型中mPFC-DRN通路中特定神经群体的行为影响。总之，这些目标将提供一个更好的了解电路的基础情绪障碍，并可能导致更有效和更高效的抗抑郁策略的发展。

DESCRIPTION (provided by applicant): Major depression is the most prevalent mood disorder, yet there has not been major therapeutic progress in developing clinical treatments in the past 20 years. Most antidepressant strategies affect monoamine neurotransmitter systems with serotonin (5-HT) as the most common target. Recently, though, there has been a growing body of clinical and preclinical evidence that implicate the medial prefrontal cortex (mPFC) in depression and its treatment. Structural and functional imaging studies in patients have revealed consistent volume changes and hyperactivity of this region in mood disorders. Studies performed in animals have also shown that the neuroplastic changes in the mPFC may also be related to vulnerability and resiliency to stressors and depression-like behaviors. Additionally, deep brain stimulation (DBS) of the mPFC in both humans and animals produced an antidepressant-like effect. Interestingly, an intact 5-HT system was required for DBS to produce this effect. Previous work has shown that the mPFC sends projections to the dorsal raphe nucleus (DRN), which contains the largest population of 5-HT neurons in the brain. However, the DRN is heterogeneous and these projections actually appear to converge on GABAergic neurons, which suggests that these GABA neurons may act as filters of sensory control over 5-HT. Additionally, our lab and others have also shown that DRN GABA neurons are primarily activated in response to a variety of stressors, which would also suggest how dysregulation of this population might lead to mood disorders. The goal of this proposal is to show that neuroplastic adaptations mediated by DRN GABAergic neurons in the mPFC-DRN pathway affect depressive-like behaviors and antidepressant response. My first specific aim is to perform a neuroanatomical and functional dissection of the mPFC-DRN pathway and will allow me to better characterize the cellular architecture of this circuit. The second aim will use electrophysiological and morphological techniques to evaluate the adaptations induced by social stress in various cellular components of the mPFC-DRN pathway. In the third aim I will use optogenetic tools to dissect the behavioral impact of specific neural populations in the mPFC-DRN pathway in the social defeat model of depression. Together, these aims will provide a better understanding of the circuitry that underlies mood disorders and could lead to the development of more effective and efficient antidepressant strategies.