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

丘脑下对 PTSD 学习相关维度的调节。

• 批准号: 10253668
• 负责人: Brian George DIAS
• 金额: $ 27.01万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253668
• 关键词: Sub; thalamic; modulation; learning; related

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.]]

项目摘要 [[即使没有 更长的构成威胁是创伤后应激障碍（PTSD）的核心病理。这种适应不良的恐惧是 由于无法得知以前与创伤有关的刺激不再是 威胁。这些灭绝学习中的缺陷是PTSD的高度普遍维度，并且显着 阻碍生活质量。孤立或与药物治疗结合的认知行为疗法是 最广泛使用的治疗方法是挽救灭绝学习中的缺陷。这样的治疗有效 约有50％的治疗病例强调，有更有效地挽救缺陷 灭绝学习。实现这一目标的一种方法是首先了解如何促进灭绝学习 通过介导学习和神经电路的神经调节剂之间的相互作用，在 这样的学习。得知当先前与之相关的刺激时，不会发生厌恶结果 遇到创伤是灭绝学习的关键组成部分。多巴胺在信号中起着核心作用 这样的预测错误。多巴胺对灭绝学习的影响的大多数工作都集中在A10上 腹侧段区域（VTA）中多巴胺能细胞的簇。相反，其他独特的贡献 在哺乳动物大脑灭绝学习中进化保守的多巴胺能细胞簇是 未知。填补这一差距不仅会显着提高我们对多巴胺能影响的了解 灭绝学习，但一旦建立了这些贡献，我们就可以在多巴胺能细胞上进行分析 群集，可能导致灭绝学习缺陷并有可能识别新的分子扰动 药物治疗以挽救这些缺陷。我们和其他人发表的最新作品展示了一本小说 Zona Incerta（ZI）在与恐惧相关的行为中的作用，包括灭绝学习。受到存在的动机 在ZI中的A13多巴胺能细胞中，我们将在小鼠中的听觉恐惧调节与药理学， 分子遗传学，病毒介导的电路追踪，光遗传学和化学方法学，以测试 假设Zi中的A13细胞影响灭绝学习。更具体地说，我们将追踪连接性 Zi中多巴胺能细胞的作用，操纵其活性和特定多巴胺能受体的扰动功能 在灭绝训练期间，同时检查了这些操纵对规范的后果 灭绝学习。我们的工作将阐明临床上重要维度的基本神经生物学 PTSD（灭绝学习中的缺陷）。积极的结果将阐明研究电路如何调节 通过多巴胺的分子和生理功能进行规范性灭绝学习，同时能够营救 灭绝学习的缺陷。这项工作将使我们比较和对比压力引起的变化 整个大脑中多巴胺能细胞簇识别可能是独特的和共享的分子途径 针对减少灭绝学习的缺陷的目标。]]