Sub-thalamic modulation of learning-related dimensions of PTSD.

项目摘要 [[The对先前与创伤相关的刺激表现出使人衰弱的恐惧，即使在他们没有 创伤后应激障碍（PTSD）的核心病理学。这种适应不良的恐惧是 由于无法了解以前与创伤有关的刺激不再是 威胁。这些缺失是PTSD的一个非常普遍的维度， 影响生活质量。认知行为疗法单独或与药物治疗相结合， 最广泛使用的治疗方法来挽救灭绝学习的缺陷。这些治疗方法有效， 大约50%的治疗病例，强调有空间更有效地挽救赤字， 灭绝学习实现这一目标的一种方法是首先了解灭绝学习是如何促进的 通过调节学习的神经调质和在学习中起重要作用的神经回路之间的相互作用， 这样的学习。学习到当先前与之相关的刺激发生时， 是灭绝学习的关键组成部分。多巴胺在信号传导中起着核心作用 这种预测误差。大多数关于多巴胺对消退学习影响的研究都集中在A10上。 腹侧被盖区（VTA）的多巴胺能细胞簇。与此相反，其他不同的贡献 在哺乳动物大脑中进化保守的多巴胺能细胞簇， 未知填补这一空白不仅将大大推进我们对多巴胺能影响的认识， 消退学习，而且一旦这些贡献建立，我们可以分析整个多巴胺能细胞， 集群，分子扰动，可能会导致灭绝学习的缺陷，并可能识别新的 药物治疗来挽救这些缺陷。我们和其他人最近发表的研究表明， 在恐惧相关的行为中，包括灭绝学习中的作用。由于存在 我们将联合收割机将小鼠听觉恐惧条件反射与药理学， 分子遗传学，病毒介导的电路跟踪，光遗传学和化学遗传学方法来测试 假设ZI中的A13细胞影响消退学习。更具体地说，我们将跟踪连接 的多巴胺能细胞，操纵他们的活动和干扰功能的具体多巴胺能受体 在灭绝训练期间，同时检查这些操纵对规范和破坏的后果， 灭绝学习我们的工作将阐明临床重要维度的基础神经生物学 PTSD（Deficits in Extraction Learning）积极的结果将揭示如何充分研究电路调制 通过多巴胺的分子和生理功能进行规范性消退学习，同时能够挽救 灭绝学习的缺陷。这项工作将使我们能够比较和对比压力引起的变化 在大脑中的多巴胺能细胞群中，以确定独特和共享的分子途径， 旨在减少灭绝学习中的缺陷。

PROJECT SUMMARY [[The expression of debilitating fear toward stimuli previously associated with trauma even after they no longer pose a threat is a core pathology of Post-Traumatic Stress Disorder (PTSD). Such maladaptive fear is caused by an inability to learn that the stimuli that had been previously linked to trauma are no longer threatening. These deficits in extinction learning are a highly prevalent dimension of PTSD and significantly hamper quality of life. Cognitive Behavioral Therapy in isolation or in combination with pharmacotherapies are the most widely used treatments to rescue deficits in extinction learning. Such treatments are effective in approximately 50% of treated cases, emphasizing that there is room to more effectively rescue deficits in extinction learning. One way to achieve this objective is to first understand how extinction learning is facilitated by interactions between neuromodulators that mediate learning and neural circuitry that play important roles in such learning. Learning that an aversive outcome does not occur when a stimulus previously associated with trauma is encountered is a key component of extinction learning. Dopamine plays a central role in signaling such prediction errors. Most work on the influence of dopamine on extinction learning has focused on the A10 cluster of dopaminergic cells in the ventral tegmental area (VTA). In contrast, the contributions of other distinct clusters of dopaminergic cells that are evolutionarily conserved in the mammalian brain to extinction learning is unknown. Filling this gap will not only significantly advance our knowledge of dopaminergic influences on extinction learning, but also once these contributions are established, we can analyze across dopaminergic cell clusters, molecular perturbations that may cause deficits in extinction learning and potentially identify new pharmacotherapy to rescue these deficits. Recent work published by us and others have demonstrated a novel role for the zona incerta (ZI) in fear-related behavior, including extinction learning. Motivated by the presence of A13 dopaminergic cells in the ZI, we will combine auditory fear conditioning in mice with pharmacological, molecular-genetic, viral-mediated circuit tracing, optogenetic and chemogenetic methodology to test the hypothesis that A13 cells in the ZI influence extinction learning. More specifically, we will trace the connectivity of dopaminergic cells in the ZI, manipulate their activity and perturb function of specific dopaminergic receptors during extinction training, while examining the consequence of these manipulations on normative and disrupted extinction learning. Our work will illuminate basic neurobiology underlying a clinically important dimension of PTSD (deficits in extinction learning). Positive results will shed light on how an understudied circuit modulates normative extinction learning via molecular and physiological function of dopamine, while being able to rescue deficits in extinction learning. This work will position us to compare and contrast stress-induced changes across dopaminergic cell clusters in the brain to identify unique and shared molecular pathways that could be targeted to reduce deficits in extinction learning.]]