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

描述(申请人提供)：重度抑郁症是最普遍的情绪障碍，但在过去的20年里，在临床治疗方面没有取得重大的治疗进展。大多数抗抑郁药物策略影响单胺类神经递质系统，5-羟色胺(5-羟色胺)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质(MPFC)与抑郁症及其治疗有关。对患者的结构和功能成像研究表明，在情绪障碍中，这一区域的体积变化和过度活动是一致的。在动物身上进行的研究也表明，mPFC中的神经可塑性变化也可能与对应激源和类似抑郁的行为的脆弱性和弹性有关。此外，对人类和动物的mPFC进行脑深部刺激(DBS)都会产生一种抗抑郁药样的效果。有趣的是，DBS需要一个完整的5-羟色胺系统才能产生这种效果。以前的工作表明，mPFC向中缝背核(DRN)发送投射，中缝背核包含大脑中最大的5-羟色胺神经元群。然而，DRN是异质性的，这些投射实际上似乎汇聚在GABA能神经元上，这表明这些GABA神经元可能在5-羟色胺的感觉控制中起着过滤器的作用。此外，我们的实验室和其他实验室还表明，DRN GABA神经元主要是在对各种应激源做出反应时激活的，这也表明这一群体的调节失调可能会导致情绪障碍。这项建议的目的是表明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，使我能够更好地描述这一回路的细胞结构。第二个目标将使用电生理和形态技术来评估社会应激在mPFC-DRN通路的不同细胞成分中诱导的适应。在第三个目标中，我将使用光遗传学工具来剖析抑郁症社会失败模型中mPFC-DRN通路中特定神经群体的行为影响。总而言之，这些目标将提供对情绪障碍背后的回路的更好理解，并可能导致更有效和更高效的抗抑郁策略的开发。 公共卫生相关性：拟议的项目将探索内侧前额叶皮质和中缝背核之间通路的功能细胞结构及其在抑郁样行为中的作用。这项工作将研究组成这一回路的特定神经群体的生理适应和行为贡献。这项工作的结果将有助于开发更有效和高效的抗抑郁药物策略。

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.