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

描述（由申请人提供）：重度抑郁症是最常见的情绪障碍，但在过去的20年里，在临床治疗方面没有取得重大进展。大多数抗抑郁药物影响单胺类神经递质系统，其中血清素（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。患者的结构和功能成像研究显示，在情绪障碍中，该区域的体积变化和过度活跃是一致的。在动物身上进行的研究也表明，mPFC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，对人类和动物的mPFC进行深部脑刺激（DBS）也产生了类似抗抑郁的效果。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向中缝背核（DRN）发送投射，而DRN包含了大脑中最多的5-羟色胺神经元。然而，DRN是异质的，这些投射实际上似乎汇聚在GABA能神经元上，这表明这些GABA神经元可能作为5-羟色胺感觉控制的过滤器。此外，我们的实验室和其他人也表明，DRN GABA神经元主要是在对各种压力源做出反应时激活的，这也表明了这一群体的失调是如何导致情绪障碍的。本研究的目的是证明mPFC-DRN通路中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，并使我能够更好地表征该回路的细胞结构。第二个目标将使用电生理和形态学技术来评估社会压力在mPFC-DRN通路的各种细胞成分中诱导的适应性。在第三个目标中，我将使用光遗传学工具来剖析抑郁症社会失败模型中mPFC-DRN通路中特定神经群体的行为影响。总之，这些目标将使我们更好地了解情绪障碍背后的神经回路，并可能导致更有效和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. PUBLIC HEALTH RELEVANCE: The proposed project will explore the functional cytoarchitecture of the pathway between the medial prefrontal cortex and the dorsal raphe nucleus and its role in depression-like behaviors. This work will investigate the physiological adaptations and behavioral contributions of specific neural populations that compose this circuit. Results from this work will contribute to the development of more effective and efficient antidepressant strategies.