Neural substrates of extinction deficits in pathological fear

创伤后应激障碍(PTSD)是一种影响数百万人的常见精神疾病 全世界。患有创伤后应激障碍的人会经历持续的恐惧和痛苦的创伤事件记忆 这些人往往对暴露疗法等认知行为疗法有抵抗力。这种抑制性控制的丧失 对临床干预构成了重大挑战，部分原因可能是杏仁核的过度兴奋， 大脑中储存恐惧记忆的区域。尽管已知的大脑活动之间的联系 区域和恐惧调节，我们对杏仁核功能障碍的理解存在一个根本性的差距 电路产生病理性恐惧，在理解基于电路的发现如何在 啮齿动物会转化为人类疾病。我的长期目标是更好地理解细胞和分子 恐惧调节的神经回路功能受到急性创伤的影响，并利用这一信息 开发针对人类类比电路的新疗法。这项提议的总体目标是 三个方面：1)在小鼠身上建立表达神经肽的杏仁核抑制神经元的因果作用 皮质抑素(CST+)在恐惧消退中的作用，2)确定这种细胞类型如何受到急性创伤的影响，以及3)确定 人类杏仁核中类似的细胞类型。根据我们之前的发现，CST+神经元在 创伤后应激障碍，我的中心假说是创伤事件会损害抑制性神经递质的细胞和分子功能。 杏仁核基底外侧复合体(BLA)中与灭绝密切相关的CST+神经元 学习(暴露疗法的心理基础)，这最终导致不受监管， 创伤后应激障碍患者的病理性恐惧。提出这项研究的理由是，一旦因果关系 在小鼠中建立了CST+神经元功能和创伤诱导的缺陷之间的关系，识别出人类 CST+神经元的类似物可以促进专门针对这些神经元的新疗法的开发 细胞。这项提议的中心假设将通过追求三个具体目标来检验：1)确定血乳酸是否 CST+神经元通过抑制编码恐惧的BLA的活性在小鼠恐惧消退中起因果作用 神经元，2)研究损伤消亡学习的创伤如何影响分子和细胞 BLA神经元的功能，包括CST+神经元，以及3)从 使用下一代测序和高级计算相结合的方法将老鼠移植到人脑 接近了。这种方法是创新的，因为它提出了将创伤导致的恐惧缺陷之间的因果联系 抑制一种新的疾病相关细胞类型，同时识别和定位创伤敏感细胞 人类大脑中的类型具有高分辨率，这是以前从未做过的。拟议的研究是 意义重大，因为这一结果有望促进我们对潜在的神经电路的理解 抑制恐惧，以及为针对细胞类型的治疗靶向治疗提供潜在途径 以恐惧和焦虑为基础的精神障碍。对神经细胞类型的选择性靶向很可能证明 在减少症状和改善患有这些疾病的个人的生活质量方面有效。

Posttraumatic stress disorder (PTSD) is a common psychiatric condition that affects millions of people worldwide. Individuals with PTSD experience persistent fear and distressing memories of traumatic events that are often resistant to cognitive-behavioral treatments like exposure therapy. This loss in inhibitory control poses a major challenge to clinical interventions and may be driven in-part by hyperexcitability of the amygdala, a brain region known to store fear memories. Despite the known associations between activity in this brain region and fear regulation, there is a fundamental gap in our understanding of how dysfunction in amygdala circuits generates pathological fear, and an even larger gap in understanding how circuit-based findings in rodents translate to human disease. My long-term goal is to better understand how cellular and molecular function in neural circuits underlying fear regulation is affected by acute trauma, and to use this information to develop novel therapeutics targeting analogous circuits in humans. The overall objective of this proposal is three-fold: 1) establish, in mice, a causal role of amygdala inhibitory neurons that express the neuropeptide cortistatin (CST+) in fear extinction, 2) determine how this cell type is impacted by acute trauma, and 3) identify analogous cell types in the human amygdala. Based on our previous findings implicating CST+ neurons in PTSD, my central hypothesis is that traumatic events impair the cellular and molecular function of inhibitory CST+ neurons in the basolateral complex of the amygdala (BLA), which are critically involved in extinction learning (the psychological basis of exposure therapy), and that this ultimately results in unregulated, pathological fear in individuals with PTSD. The rationale for the proposed research is that, once causal links between CST+ neuron function and trauma-induced deficits are established in mice, identifying human analogs of CST+ neurons can facilitate development of novel therapeutics that specifically target these cells. The central hypothesis of this proposal will be tested by pursuing three specific aims: 1) determine if BLA CST+ neurons play a causal role in fear extinction in mice by suppressing the activity of fear-encoding BLA neurons, 2) investigate how trauma that impairs extinction learning also impacts the molecular and cellular function of BLA neurons, including CST+ neurons, and 3) map trauma-impacted BLA cell types from the mouse to the human brain using next-generation sequencing coupled with advanced computational approaches. This approach is innovative because it proposes to causally link trauma-induced deficits in fear suppression to a novel, disease-associated cell type while also identifying and mapping trauma-susceptible cell types in the human brain with high resolution, which has not been done before. The proposed research is significant because the results are expected to advance our understanding of the neural circuitry underlying fear suppression, as well as provide potential avenues for cell type-specific therapeutic targeting for treatment of fear- and anxiety-based disorders. It is likely that selective targeting of neuronal cell types will prove efficacious in reducing symptomology and improving the quality of life for individuals living with these disorders.