CORTICOTROPIN-RELEASING FACTOR-SEROTONIN INTERACTIONS

描述(申请人提供)：促肾上腺皮质激素释放因子(CRF)和 5-羟色胺能(5-羟色胺)-中缝背核(DRN)系统 独立地涉及对压力的急性反应和与压力相关的 精神障碍(如焦虑、抑郁)。在过去几年里， 我们提供的证据表明，这两个系统在解剖和功能上是 与对压力的反应有关。因此，我们证明了CRF调节DRN 急性脑损伤后前脑靶区神经元活动和5-羟色胺的释放 压力。此外，我们还证明，反复的压力会导致 DRN-5-HT系统对CRF和随后的应激的交叉适应。这个 这种竞争性更新的指导性假说是CRF对 DRN-5-羟色胺系统是行为肢体的某些组成部分。 急性应激反应和应激诱导的可塑性在这一功能中 慢性肾功能衰竭是与反复或慢性应激相关的精神症状的基础。 下面的目的是整合不同的方法来检验这一假设。目标1： 将使用体内微透析和电生理学来阐明特定的 选择性激活CRF-R1对神经元和神经化学的影响 DRN内的CRF-R2受体。目标2：将确定解剖基础 以及使用CRF影响DRN-5-HT系统的电路 免疫组织化学、原位杂交和电子显微镜观察。目标3： 将确定选择性激活CRF-R1与 DRN内的CRF-R2受体。目标4：将研究压力诱导的适应 DRN-5-HT系统关于a)CRF的作用，b)基础 机制和c)神经化学适应是否是行为的原因 适应(使用体内微透析、行为和受体 放射自显影)。我们之前的工作引入了创新的想法，即 CRF-5-HT相互作用是精神障碍的病理生理学焦点 也是新型精神治疗药物的靶子。拟议的研究将 从细胞到行为层面全面描述这些相互作用。 因此，它们将加强我们对压力在 精神病理学和指示治疗应激相关的新靶点 精神障碍。

DESCRIPTION (provided by applicant): Corticotropin-releasing factor (CRF) and the serotonergic (5-HT)-dorsal raphe nucleus (DRN) system have been independently implicated in the acute response to stress and in stress-related psychiatric disorders (e.g., anxiety, depression). During the last few years, we provided evidence that these two systems are anatomically and functionally linked in the response to stress. Thus, we demonstrated that CRF regulates DRN neuronal activity and 5-HT release in forebrain targets in response to acute stress. Moreover, we demonstrated that repeated stress results in cross-adaptation of the DRN-5-HT system to CRF and subsequent stress. The guiding hypothesis of this competing renewal is that CRF neuromodulation of the DRN-5-HT system underlies certain components of the behavioral limb of the acute stress response and that stress-induced plasticity in this function of CRF underlies psychiatric symptoms associated with repeated or chronic stress. The following AIMs integrate diverse approaches to test this hypothesis. AIM 1: will use in vivo microdialysis and electrophysiology to elucidate specific neuronal and neurochemical consequences of selectively activating CRF-R1 vs. CRF-R2 receptors within the DRN. AIM 2: will identify the anatomical substrates and circuitry by which CRF impacts on the DRN-5-HT system using immunohistochemistry, in situ hybridization and electron microscopy. AIM 3: will identify behavioral consequences of selectively activating CRF-R1 vs. CRF-R2 receptors within the DRN. AIM 4: will examine stress-induced adaptation of the DRN-5-HT system with regard to a) the role of CRF, b) the underlying mechanisms and c) whether neurochemical adaptation is causal to behavioral adaptation (using in vivo microdialysis, behavior and receptor autoradiography). Our previous work introduced the innovative idea that CRF-5-HT interactions are a pathophysiological focus of psychiatric disorders and a target of novel psychotherapeutic agents. The proposed studies will thoroughly characterize these interactions from a cellular to behavioral level. As such, they will enhance our understanding of the role of stress in psychopathology and indicate novel targets for the treatment of stress-related psychiatric disorders.