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

项目总结 创伤后应激障碍(PTSD)是一种破坏性的神经精神障碍，在 精神创伤。对以前与创伤有关的刺激的衰弱恐惧的表达，即使在它们不 更长的威胁是创伤后应激障碍的核心病理。这种不适应的恐惧是由于无法学习到 以前与创伤有关的刺激在SAFE中呈现时不再具有威胁性 而且没有任何令人反感的结果。这些消亡学习缺陷是一种非常普遍的症状 创伤后应激障碍和严重影响生活质量。减少灭绝学习缺陷的努力主要集中在 了解杏仁核、前额叶皮质、海马体和 中脑导水管周围灰质到这一过程。尽管在这方面取得了进展，舍曲林和帕罗西汀仍是 只有FDA批准的创伤后应激障碍的治疗方法。这些药物是5-羟色胺选择性再摄取抑制剂和 抗抑郁药。因此，它们可以改善创伤后应激障碍的情绪相关症状，但不能直接解决学习问题。 相关症状，如消亡学习障碍。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失性学习障碍。多巴胺在体内起着重要的作用 灭绝学习和增加多巴胺水平的药物，如哌醋甲酯和MDMA可以改善 灭绝学习。然而，这些药物并不是多巴胺能系统特有的，可能会导致 物质滥用障碍，部分是通过它们对腹侧被盖区的多巴胺能细胞的作用来实现的。在这 我们建议研究丘脑下部核团中的多巴胺能细胞是否存在于称为未确定带的区域。 (Zi)可以通过多巴胺介导的信号传递减少灭绝学习的缺陷。为了检验这一假设，我们将 将小鼠的听觉恐惧条件反射与药理学、分子遗传学、病毒介导的回路相结合 示踪、光遗传学和化学遗传学方法论。更具体地说，我们将跟踪 ZI中的多巴胺能细胞，操纵这些细胞的活动并扰乱特定的多巴胺能功能 消光训练中的受体，同时检查这些操作对消亡的影响 学习。此外，我们还将研究这些多巴胺能细胞对消亡训练后的反应 暴露在压力之下--这是损害消亡学习的一个因素。我们工作的成功成果可以 突出ZI中的多巴胺能细胞在调节与恐惧相关的消退学习中的新功能。我们的 结果可能会产生翻译影响，因为它表明刺激Zi定位的多巴胺能细胞和 在暴露治疗期间使用多巴胺受体激动剂可能会改善消退学习和 减少伴随着创伤后应激障碍的适应不良恐惧。

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.