Influence of Chronic Stress on the Raphe Nucleus and Medial Prefrontal Cortex

描述(申请人提供)：5-羟色胺，或5-羟色胺(5-HT)，被认为可以调节情绪，并导致与压力相关的情绪障碍，如焦虑和抑郁。虽然焦虑症的病理生理机制仍有许多未知之处，但中缝背核(DR)和内侧前额叶皮质(MPFC)尤其重要。以往的研究表明，mPFC锥体细胞、DR GABA细胞和DR 5-HT细胞之间的解剖和功能联系，以及5-HT1A、5-HT2A和GABAA受体是该回路内细胞活动的重要调节因子。尽管DR-mPFC回路的每个组成部分都被认为与焦虑有关，但很少有研究准确地检验这些组成部分在焦虑行为模型中的变化方式。慢性社交失败是一种强大的压力源，它会产生焦虑和相关障碍中的许多行为和生理特征。一些研究已经检测了由于DR和mPFC内的长期社会失败而导致的神经元激活和蛋白表达的变化。然而，这些研究中很少有具体说明被分析细胞的神经化学特性，或者在他们的实验设计中考虑细胞的次区域分布。总体目标是了解慢性应激如何改变DR和mPFC中的细胞亚群调节5-羟色胺系统功能的方式。示踪研究和免疫组织化学将确定与mPFC相互联系的DR细胞亚群的分布。全细胞膜片钳电生理学将辨别这一亚群是否表现出不同的细胞特征，并在经历慢性社会失败的小鼠中受到不同的调节。假说是，社会失败选择性地改变了DR-mPFC回路中特定的膜特性和受体介导的反应，以增强对5-羟色胺细胞的负反馈。这一系列实验将有助于理解导致焦虑的细胞和分子机制，并有一天可能会突出药物开发的新靶点，或有助于改进现有的医疗方法。焦虑和相关的疾病被认为是由大脑5-羟色胺系统的变化所调节的，但这些变化是什么仍不清楚。这项研究中使用的技术允许测量血清素系统中特定细胞的变化，以确定它们在焦虑小鼠模型中的功能是否不同。通过识别导致焦虑行为的5-羟色胺系统成分，该项目可能有助于开发治疗人类焦虑的新药。

DESCRIPTION (provided by applicant): Serotonin, or 5-hydroxytryptamine (5-HT), is thought to regulate mood and contributes to stress-related, mood disorders such as anxiety and depression. Although much remains unknown about the pathophysiology of anxiety, the dorsal raphe (DR) and the medial prefrontal cortex (mPFC) are known to be particularly important. Previous studies have revealed anatomical and functional connectivity between the mPFC pyramidal cells, the DR GABA cells and the DR 5-HT cells, and the 5-HT1 A, 5-HT2A, and GABAA receptors are crucial mediators of the activity of cells within this circuit. Although each component of the DR-mPFC circuitry is thought to contribute to anxiety, few studies have precisely examined the way that these components are altered in a behavioral model of anxiety. Chronic social defeat is a potent stressor that produces many of the behavioral and physiological attributes seen in anxiety and related disorders. Some studies have examined the changes in neuronal activation and protein expression that occur as a result of chronic social defeat within the DR and mPFC. However, few of those studies specify the neurochemical identity of the analyzed cells or consider the subregional distribution of cells in their experimental design. The overall goal is to understand how chronic stress changes the way that subpopulations of cells in the DR and the mPFC modulate the function of the serotonin system. Tracing studies and immunohistochemistry will define the distribution of the subpopulation of DR cells that are interconnected with the mPFC. Whole-cell patch clamp electrophysiology will discern if this subpopulation exhibits distinct cellular characteristics and are differentially regulated in mice that experience chronic social defeat. The hypothesis is that social defeat selectively alters particular membrane properties and receptor-mediated responses within the DR-mPFC circuit to enhance negative feedback onto 5-HT cells. This line of experiments will contribute to an understanding of the cellular and molecular mechanisms that underlie anxiety and may one day highlight novel targets for drug development or help to refine existing methods of medical treatment. Anxiety and related disorders are thought to be mediated by changes in the serotonin system of the brain, but much remains unknown about what those changes are. The techniques used in this study allow for the measurment of changes in particular cells of the serotonin system to determine if they function differently in a mouse model of anxiety. By identifying components of the serotonin system that contribute to anxious behavior, this project may contribute to the development of novel drugs to treat human anxiety.