The Integrated Role of Vasopressin and Oxytocin Receptors in the Modulation of BNST Activity and Fear Processing

摘要：焦虑症是最常见的精神疾病，但还没有新的抗焦虑药物。 在过去的十年里被批准用于治疗。因此，有一个重大的未得到满足的需求，即开发新的 有效的药物疗法。在啮齿动物和人类的研究中，终纹床核(BNST)具有 形成了一个关键的大脑区域，将长期暴露在不确定威胁中转化为持续的恐惧。这个 BNST在患有焦虑症和创伤后应激障碍的患者中是过度活跃的。人类 影像研究显示BNST和中央杏仁核之间的功能连接增强 (CEA)在焦虑的个体中。在大鼠，BNST向CEA发出抑制性投射(BNSTàCEA)，但 在BNST如何与CEA相互作用以调节恐惧加工方面，存在着显著的知识差距。作为 CEA和BNST分别推动对可预测和不可预测威胁的恐惧反应，活动增加 BNSTàCEA神经元将倾向于对不可预测的威胁做出反应，并可以 高度警惕，人类焦虑症的一个重要标志。因此，抑制这一点的因素 BNSTàCEA的产物作为新的治疗靶点具有尚未开发的潜力。实验室的最新发现表明 其中一个靶点涉及BNST中的催产素受体(OTR)，因为OTR的激活抑制了BNSTàCEA 输出并促进对可预测威胁的恐惧(暗示恐惧)。相比之下，我们令人信服的初步数据 提示BNST中血管加压素1a受体(V1aR)的激活直接兴奋III型/促肾上腺皮质激素- 释放因子(CRF)神经元，它促进持续的恐惧反应。基于这一科学前提， 这一提议的中心假设是，通过抑制和兴奋BNSTàCEA神经元，OTR和V1aR 分别促进对可预测威胁和不可预测威胁的恐惧反应。这一创新的概念将是 使用尖端实验方法进行研究，包括化学遗传学和光遗传学 在最近建立的转基因大鼠模型(OTR-CRE、AVP-CRE、CRF-CRF-CRE)中对BNSTàCEA神经元的操作 Cre)。经过严格设计的行为和电生理实验将用 具体目标如下：1)确定V1aR和OTR在调节BNST活性中的整合作用 神经元，2)确定可预测的威胁和不可预测的威胁是否以不同的方式调节 BNSTàCEA神经元通过OTR和V1aR，3)确定BNSTàCEA神经元在调节恐惧中的作用 对可预测威胁与不可预测威胁的响应，以及OTR与V1aR的贡献。通过提炼 BNSTàCEA神经元活动的潜在机制，这一提议将对 了解处理可预测威胁与不可预测威胁的不平衡如何导致 过度警惕会导致焦虑症的发作。

SUMMARY: Anxiety disorders are the most common psychiatric conditions, yet no new anxiolytic drug has been approved for treatment in the last decade. Therefore, there is a significant unmet need to develop new effective pharmacotherapies. In rodent and human studies, the bed nucleus of the stria terminalis (BNST) has emerged as a key brain region translating prolonged exposure to uncertain threats into sustained fear. The BNST is hyperactive in patients suffering from anxiety disorders and post-traumatic stress disorder. Human imaging studies demonstrate an enhanced functional connectivity between the BNST and the central amygdala (CeA) in anxious individuals. In rats, the BNST sends inhibitory projection to the CeA (BNSTàCeA) but there is a significant knowledge gap on how the BNST interacts with the CeA to modulate fear processing. As the CeA and BNST drive fear responses to predictable and unpredictable threats, respectively, increased activity of the BNSTàCeA neurons will favor responses to the unpredictable threats and can precipitate hypervigilance, an important hallmark of anxiety disorders in humans. Therefore, the factors that inhibit this BNSTàCeA output have untapped potential as novel therapeutic targets. Recent findings from the lab show that one such target involves oxytocin receptors (OTR) in the BNST, as OTR activation inhibits BNSTàCeA output and facilitates fear to predictable threats (cued fear). In contrast, our compelling preliminary data indicate that activation of vasopressin 1a receptor (V1aR) in the BNST directly excites Type III/Corticotropin- releasing factor (CRF) neurons, which promote sustained fear responses. Based on this scientific premise, the central hypothesis of this proposal is that by inhibiting and exciting the BNSTàCeA neurons, OTR and V1aR facilitate fear responses to predictable vs. unpredictable threats, respectively. This innovative concept will be investigated using cutting-edge experimental approaches, including chemogenetic and optogenetic manipulations of BNSTàCeA neurons in recently developed transgenic rat models (OTR-Cre, AVP-Cre, CRF- Cre). Rigorously designed behavioral and electrophysiological experiments will test the hypothesis with the following specific aims: 1) Determine the integrated role of V1aR and OTR in modulating activity of BNST neurons, 2) Determine whether predictable vs. unpredictable threats differentially modulate activity of BNSTàCeA neurons via OTR and V1aR, 3) Determine the role of BNSTàCeA neurons in mediating fear responses to predictable vs. unpredictable threats, and the contribution of OTR vs. V1aR. By refining mechanisms underlying the activity of BNSTàCeA neurons, this proposal will have a positive impact on the understanding how an imbalance in processing of predictable vs. unpredictable threats can lead to a hypervigilance and precipitate the onset of anxiety disorders.