Modulation of the BNST activity by oxytocin - role in stress, fear and anxiety.

联系PD/PI：Dabrowska，Joanna 摘要：压力可引发包括广泛性焦虑症在内的精神障碍 (GAD)和创伤后应激障碍。目前可用的药物疗法对 焦虑症--因此，迫切需要找到能够缓解焦虑的新方法。 应激诱导的神经元活动异常会导致焦虑的长期变化，因此 压力敏感脑区产生这些效应的机制可能会为治疗提供新的见解。在……里面 啮齿动物和人类的研究表明，终纹床核(BNST)已成为大脑的一个关键区域 将压力转化为焦虑的持续变化。重复胁迫增加了BNST输出的活性 产生应激激素促肾上腺皮质激素释放因子(CRF)的神经元。这与一种 焦虑、恐惧和高度警惕是压力引起的精神障碍的特征。因此，该组织的活动 GAD患者BNST升高。因此，调节BNST产量的因素有 作为新的治疗靶点的未开发的潜力。我们建议，这样的目标之一可能是吸引当地 抑制中间神经元，加强对BNST输出神经元的抑制。催产素(OT)已被证明可以 抑制压力反应和减少焦虑，但这些OT作用的部位或细胞靶点仍然存在 不清楚。BNST神经元表达OT受体并接受来自下丘脑室旁核的OT传入 下丘脑(PVN)。我们的初步数据表明，催产素激活了脑内抑制性中间神经元的一个子集。 BNST。基于这一前提，这项提案的主要目标是确定是否通过激活 抑制性中间神经元，OT抑制BNST的输出，从而减轻焦虑。这一点的中心假设是 建议是催产素通过激活中间神经元来改善应激诱导的焦虑样行为。 对BNST输出(CRF)神经元的抑制控制。这一创新的概念将使用切割- 边缘实验方法，包括OT启动子驱动的抑制性DREADD表达(Designer 受体)选择性地抑制投射中催产素的释放 从PVN到BNST(OTPVN BNST通路)。严格设计的实验结合了行为学和 电生理测量将检验中心假设，具体目的如下：1)确定 催产素在BNST对雌雄大鼠焦虑和恐惧调节中的作用 OT对雄性和雌性大鼠BNST神经元活动的调节作用。实现这些目标将填补 通过确定OT在BNST中的作用来改善压力的影响，从而显著地认识到差距。我们 预计通过完善我们对中央OT影响的理解，这项提议将对 揭示压力引起的精神障碍的神经生物学机制。 项目摘要/摘要第6页

Contact PD/PI: Dabrowska, Joanna SUMMARY: Stress can precipitate the onset of psychiatric disorders, including generalized anxiety disorder (GAD) and posttraumatic stress disorder. Currently available pharmacotherapies have limited efficacy in anxiety disorders - hence there is an urgent need to identify new approaches that can ameliorate anxiety. Stress-induced abnormalities in neuronal activity lead to long-lasting changes in anxiety, hence targeting the mechanisms underlying these effects in stress-sensitive brain regions may provide new insight for treatment. In rodent and human studies, the bed nucleus of the stria terminalis (BNST) has emerged as a key brain region translating stress into sustained changes in anxiety. Repeated stress increases the activity of BNST output neurons, which produce the stress hormone corticotropin-releasing factor (CRF). This parallels a state of anxiety, fear and hypervigilance, hallmarks of stress-induced mental disorders. Accordingly, activity of the BNST is elevated in patients suffering from GAD. Therefore, the factors that regulate BNST output have untapped potential as novel therapeutic targets. We propose that one such target may be engaging local inhibitory interneurons to strengthen inhibition of BNST output neurons. Oxytocin (OT) has been shown to inhibit the stress response and reduce anxiety, but the sites or cellular targets of these OT actions remain unclear. BNST neurons express OT receptors and receive OT input from the paraventricular nucleus of the hypothalamus (PVN). Our preliminary data indicate that OT activates a subset of inhibitory interneurons in the BNST. Based on this premise, the main objective of this proposal is to establish whether by activating the inhibitory interneurons, OT inhibits BNST output and thus reduces anxiety. The central hypothesis of this proposal is that OT ameliorates stress-induced anxiety-like behavior by engaging interneurons that provide inhibitory control over BNST output (CRF) neurons. This innovative concept will be investigated using cutting- edge experimental approaches, including OT promoter-driven expression of inhibitory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to selectively suppress the release of OT in the projection from the PVN to the BNST (OT PVN BNST pathway). Rigorously designed experiments combining behavioral and electrophysiological measures will test the central hypothesis with the following specific aims: 1) Determine the role of OT in the BNST in the regulation of anxiety and fear in male and female rats and 2) Determine the role of OT in regulating the activity of BNST neurons in male and female rats. Accomplishing these Aims will fill a significant knowledge gap by establishing the role of OT in the BNST in ameliorating the effects of stress. We expect that by refining our understanding of central OT effects this proposal will have a positive impact on uncovering the mechanisms underlying the neurobiology of stress-induced psychiatric disorders. Project Summary/Abstract Page 6