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

项目摘要 创伤后应激障碍（PTSD）是一种毁灭性的神经精神障碍， 外伤对先前与创伤相关的刺激的衰弱性恐惧的表达，即使在他们没有 是创伤后应激障碍的核心病理这种适应不良的恐惧是由于无法学习， 以前与创伤有关的刺激在安全的环境中不再具有威胁性， 背景和没有令人厌恶的结果。这些灭绝学习的缺陷是一种非常普遍的症状， 创伤后应激障碍，严重影响生活质量。减少灭绝学习缺陷的努力集中在 了解杏仁核、前额叶皮层、海马体等区域的作用， 中脑导水管周围的灰质。尽管从这一重点取得了进展，舍曲林和帕罗西汀是 只有FDA批准的治疗创伤后应激障碍的药物这些药物是5-羟色胺选择性再摄取抑制剂， 抗抑郁药因此，它们改善了PTSD的情绪相关症状，但并不直接解决学习问题- 相关的症状，如灭绝学习的缺陷。有2400万美国人患有创伤后应激障碍， 需要新的治疗选择来治疗消退学习的缺陷。多巴胺在 消退学习和增加多巴胺水平的药物，如哌甲酯和MDMA， 灭绝学习然而，这些药物不是特异性的多巴胺能系统，并可能导致 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。在这 建议，我们建议研究是否多巴胺能细胞在一个丘脑下核所谓的神经节 (ZI)可以通过多巴胺介导的信号减少消退学习的缺陷。为了验证这个假设，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、病毒介导回路相结合 示踪、光遗传学和化学遗传学方法。更具体地说，我们将跟踪 在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神经元的功能。 受体在灭绝训练，同时检查这些操纵灭绝的后果 学习此外，我们将研究这些多巴胺能细胞如何应对灭绝训练后， 暴露于压力-一个因素，削弱灭绝学习。我们工作的成功成果可以 强调了ZI中多巴胺能细胞在调节恐惧相关的消退学习中的新功能。我们 结果可能有翻译的影响，表明刺激ZI-定位多巴胺能细胞， 在暴露疗法期间施用多巴胺受体激动剂可以改善消退学习， 减少伴随PTSD的适应不良恐惧。

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.