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

丘脑下对 PTSD 学习相关维度的调节。

基本信息

批准号：
10397476
负责人：
Brian George DIAS
金额：
$ 42.64万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
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/10397476
关键词：
Address American Amygdaloid structure Animals Antidepressive Agents Auditory Behavior Cell physiology Cells Complex DRD1 gene DRD2 gene Data Dimensions Disease Dopamine Dopamine Agonists Dopamine D2 Receptor Dopaminergic Cell Exposure to Extinction (Psychology)FDA approved FOS gene Freezing Fright Future Goals Hippocampus (Brain)Human Impairment Infusion procedures Label Learning Light Link Measures Mediating Methodology Mission Molecular Molecular Genetics Moods Mus National Institute of Mental Health Neurobehavioral Manifestations Neurons Outcome Paroxetine Pathology Pathway interactions Pharmaceutical Preparations Pharmacology Play Post-Traumatic Stress Disorders Prefrontal Cortex Prevention Process Public Health Quality of life RNA Interference Research Ritalin Role Selective Serotonin Reuptake Inhibitor Serotonin Agents Sertraline Shock Signal Transduction Site Stimulus Stress Structure of subthalamic nucleus Substance abuse problem Symptoms Synapses System Technology Testing Therapeutic Time Training Trauma Ventral Tegmental Area Viral Work abuse liability antagonist base conditioned fear conditioning design designer receptors exclusively activated by designer drugs dopamine system dopaminergic neuron ecstasy experience improved insight knock-down learning extinction midbrain central gray substance neural circuit neuropsychiatric disorder novel novel therapeutics optogenetics post-traumatic symptoms prevent receptor translational impact zona incerta

项目摘要

PROJECT SUMMARY Post-Traumatic Stress Disorder (PTSD) is a devastating neuropsychiatric disorder that develops after trauma. The expression of debilitating fear toward stimuli previously associated with trauma even after they no longer pose a threat is a core pathology of 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 when presented in safe contexts and with no aversive outcome. These deficits in extinction learning are a highly prevalent symptom of PTSD and significantly hamper quality of life. Efforts to reduce deficits in extinction learning have focused on understanding the contributions of regions like the amygdala, prefrontal cortex, hippocampus and periaqueductal gray to this process. Despite progress made from this focus, sertraline and paroxetine are the only FDA-approved treatments for PTSD. These drugs are serotonin selective reuptake inhibitors and antidepressants. As such they improve mood-related symptoms of PTSD but do not directly address learning- related symptoms like deficits in extinction learning. With 24 million Americans living with PTSD, there is a need for new therapeutic options to treat deficits in extinction learning. Dopamine plays an important role in extinction learning and drugs that increase dopamine levels like methylphenidate and MDMA improve extinction learning. However, these drugs are not specific to the dopaminergic system and could result in substance abuse disorders, in part, via their action on dopaminergic cells in the ventral tegmental area. In this proposal, we propose to study whether dopaminergic cells in a sub-thalamic nucleus called the zona incerta (ZI) can reduce deficits in extinction learning via dopamine-mediated signaling. To test this hypothesis, we will combine auditory fear conditioning in mice with pharmacological, molecular-genetic, viral-mediated circuit tracing, optogenetic and chemogenetic methodology. More specifically, we will trace the connectivity of dopaminergic cells in the ZI, manipulate the activity of these cells and perturb function of specific dopaminergic receptors during extinction training while examining the consequence of these manipulations on extinction learning. Additionally, we will examine how these dopaminergic cells respond to extinction training after exposure to stress – a factor that impairs extinction learning. Successful outcomes from our work could highlight a novel function for dopaminergic cells in the ZI in modulating fear-related extinction learning. Our results may have translational impact by suggesting that stimulating ZI-located dopaminergic cells and administering dopamine receptor agonists during exposure therapy may improve extinction learning and reduce maladaptive fear that accompanies PTSD.

项目概要创伤后应激障碍（PTSD）是一种破坏性的神经精神疾病，发生于创伤后应激障碍（PTSD）创伤：对先前与创伤相关的刺激表现出令人衰弱的恐惧，即使这些刺激没有发生。不再构成威胁是创伤后应激障碍的核心病理学，这种适应不良的恐惧是由于无法了解这一点而引起的。当以安全的方式呈现时，以前与创伤有关的刺激不再具有威胁性。这些消退学习的缺陷是一种非常普遍的症状。创伤后应激障碍（PTSD）并极大地妨碍了生活质量，减少灭绝性学习缺陷的努力重点是。了解杏仁核、前额皮质、海马体和尽管这一焦点取得了进展，但舍曲林和帕罗西汀仍是这一过程的关键。这些药物是 FDA 批准的唯一治疗 PTSD 的药物，这些药物是血清素选择性再摄取抑制剂和因此，它们可以改善 PTSD 的情绪相关症状，但不能直接解决学习问题。相关症状，如消退学习缺陷，有 2400 万美国人患有创伤后应激障碍 (PTSD)。需要新的治疗方案来治疗消退学习缺陷，多巴胺在其中发挥着重要作用。灭绝学习和增加多巴胺水平的药物（如哌醋甲酯和摇头丸）可以改善然而，这些药物并不是多巴胺能系统特有的，可能会导致药物滥用障碍部分是通过其对腹侧被盖区多巴胺能细胞的作用而产生的。提案中，我们建议研究丘脑下核（称为未定带）中的多巴胺能细胞是否（ZI）可以通过多巴胺介导的信号传导减少消退学习的缺陷。为了检验这一假设，我们将进行测试。将小鼠的听觉恐惧调节与药理学、分子遗传、病毒介导的回路相结合追踪、光遗传学和化学遗传学方法更具体地说，我们将追踪它们的连接性。 ZI 中的多巴胺能细胞，操纵这些细胞的活性并扰乱特定多巴胺能细胞的功能灭绝训练期间的受体，同时检查这些操作对灭绝的影响此外，我们将研究这些多巴胺能细胞在消退训练后如何反应。暴露于压力——这是损害我们工作取得成功的一个因素。强调 ZI 中的多巴胺能细胞在调节与恐惧相关的消退学习方面的新功能。结果可能会产生翻译影响，表明刺激位于 ZI 的多巴胺能细胞和在暴露疗法期间给予多巴胺受体激动剂可能会改善消退学习和减少适应创伤后应激障碍的适应不良恐惧。