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：
10824467
负责人：
Brian George DIAS
金额：
$ 7.36万
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/10824467
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 FDA approved FOS gene Freezing Fright Future Genetic Goals Hippocampus Human Impairment Infusion procedures Label Learning 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 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 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 pharmacologic postsynaptic prevent receptor stress reduction 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.

项目摘要创伤后应激障碍（PTSD）是一种毁灭性的神经精神疾病，在此之后发展创伤。即使在没有创伤相关的刺激的恐惧的表达，即使他们没有更长的构成威胁是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在安全出现时不再威胁上下文，没有厌恶的结果。扩展学习中的这些定义是高度普遍的症状 PTSD和严重阻碍了生活质量。减少扩展学习定义的努力已重点放在了解杏仁核，前额叶皮层，海马和等区域的贡献该过程的灰色灰色。尽管这一重点取得了进步，但舍曲林和帕罗西汀是仅针对PTSD的FDA批准治疗。这些药物是5-羟色胺选择性再摄取抑制剂，抗抑郁药。因此，它们可以改善PTSD与情绪相关的症状，但不能直接解决学习 - 相关符号，例如扩展学习中的定义。有2400万美国人生活在PTSD中，有一个需要新的治疗选择来治疗扩展学习中的定义。多巴胺在扩展学习和增加甲化甲酯和MDMA等多巴胺水平的药物改善扩展学习。但是，这些药物并非特定于多巴胺能系统，可能导致药物滥用障碍部分是通过对腹侧对段区域多巴胺能细胞作用的作用。在这个提案，我们建议研究中丘脑核中多巴胺能细胞是否称为Zona Incerta （Zi）可以通过多巴胺介导的信号传导来减少扩展学习中的定义。为了检验这一假设，我们将将小鼠的听觉恐惧调节与药物，分子遗传学，病毒介导的电路结合起来追踪，光遗传学和化学方法论。更具体地说，我们将追踪 ZI中的多巴胺能细胞操纵这些细胞的活性和特异性多巴胺能的扰动功能在扩展训练期间的受体，同时检查这些操作对扩展的后果学习。此外，我们将研究这些多巴胺能细胞在暴露于压力 - 这是损害扩展学习的因素。我们工作的成功结果可能突出显示了ZI中多巴胺能细胞的新功能，以调节与恐惧相关的扩展学习。我们的结果可能通过表明刺激Zi占地多巴胺能细胞和在暴露疗法期间管理多巴胺受体激动剂可以改善扩展学习和减少涉及PTSD的不良适应性恐惧。