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.]]

项目概要 [[对先前与创伤相关的刺激表现出令人衰弱的恐惧，即使它们没有 不再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 由于无法了解到以前与创伤有关的刺激不再是造成的 威胁。这些消退学习的缺陷是 PTSD 的一个非常普遍的方面，并且显着 妨碍生活质量。单独的认知行为疗法或与药物疗法相结合的认知行为疗法是 挽救消退学习缺陷的最广泛使用的治疗方法。此类治疗有效 约 50% 的治疗病例，强调还有更有效地挽救缺陷的空间 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 通过介导学习的神经调节剂和在学习中发挥重要作用的神经回路之间的相互作用 这样的学习。了解当先前与相关的刺激相关时，不会发生令人厌恶的结果 遭遇创伤是消退学习的关键组成部分。多巴胺在信号传导中发挥核心作用 这样的预测错误。大多数关于多巴胺对消退学习影响的研究都集中在 A10 腹侧被盖区 (VTA) 的多巴胺能细胞簇。相比之下，其他不同的贡献 多巴胺能细胞簇在哺乳动物大脑中进化保守直至灭绝学习是 未知。填补这一空白不仅将显着提高我们对多巴胺能影响的认识 消退学习，而且一旦这些贡献被确定，我们就可以跨多巴胺能细胞进行分析 簇、分子扰动可能导致灭绝学习的缺陷并可能识别新的 药物疗法来挽救这些缺陷。我们和其他人最近发表的作品展示了一种新颖的 不确定带（ZI）在恐惧相关行为（包括灭绝学习）中的作用。因存在而受到激励 ZI 中的 A13 多巴胺能细胞，我们将把小鼠的听觉恐惧调节与药理学结合起来， 分子遗传学、病毒介导的回路追踪、光遗传学和化学遗传学方法来测试 ZI 中的 A13 细胞影响消退学习的假设。更具体地说，我们将跟踪连接性 ZI 中的多巴胺能细胞，操纵它们的活性并扰乱特定多巴胺能受体的功能 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。我们的工作将阐明基础神经生物学的临床重要维度 PTSD（消退学习缺陷）。积极的结果将揭示未被充分研究的电路如何调制 通过多巴胺的分子和生理功能进行规范性灭绝学习，同时能够拯救 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 跨越大脑中的多巴胺能细胞簇，以确定独特且共享的分子途径，这些途径可以 旨在减少灭绝学习的缺陷。]]