Neural substrates of extinction deficits in pathological fear

病理性恐惧中消退缺陷的神经基础

• 批准号: 10999104
• 负责人: Michael Totty
• 金额: $ 6.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-15 至 2027-01-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10999104
• 关键词: Neural; substrates; extinction; deficits; pathological

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.

创伤后应激障碍 (PTSD) 是一种常见的精神疾病，影响数百万人 全世界。患有创伤后应激障碍 (PTSD) 的人会经历持续的恐惧和对创伤事件的痛苦记忆 通常对暴露疗法等认知行为治疗有抵抗力。这种抑制控制的丧失 对临床干预提出了重大挑战，部分原因可能是杏仁核过度兴奋， 已知储存恐惧记忆的大脑区域。尽管已知大脑活动之间存在关联 区域和恐惧调节，我们对杏仁核功能障碍如何理解存在根本差距 电路会产生病态的恐惧，并且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了解细胞和分子如何 恐惧调节的神经回路功能受到急性创伤的影响，并利用这些信息 开发针对人类类似电路的新疗法。该提案的总体目标是 三重：1）在小鼠中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 人类杏仁核中的类似细胞类型。根据我们之前的研究结果，表明 CST+ 神经元 PTSD，我的中心假设是创伤事件损害了抑制性的细胞和分子功能 杏仁核基底外侧复合体 (BLA) 中的 CST+ 神经元，与消退密切相关 学习（暴露疗法的心理基础），这最终会导致不受监管， PTSD 患者的病理性恐惧。拟议研究的基本原理是，一旦因果关系 在小鼠中建立了 CST+ 神经元功能与创伤引起的缺陷之间的关系，从而识别出人类 CST+神经元的类似物可以促进专门针对这些神经元的新型疗法的开发 细胞。该提案的中心假设将通过追求三个具体目标进行测试：1）确定 BLA 是否 CST+神经元通过抑制编码恐惧的BLA活性在小鼠恐惧消退中发挥因果作用 神经元，2) 研究损害消退学习的创伤如何影响分子和细胞 BLA 神经元（包括 CST+ 神经元）的功能，以及 3）绘制受创伤影响的 BLA 细胞类型图 使用下一代测序结合先进的计算将小鼠连接到人脑 接近。这种方法是创新的，因为它提出将创伤引起的恐惧缺陷因果联系起来 抑制新型疾病相关细胞类型，同时识别和绘制创伤易感细胞图谱 以高分辨率在人脑中进行打字，这是以前从未做过的。拟议的研究是 意义重大，因为结果预计将增进我们对底层神经回路的理解 恐惧抑制，并为细胞类型特异性治疗靶向治疗提供潜在途径 基于恐惧和焦虑的疾病。神经元细胞类型的选择性靶向可能会证明 有效减少这些疾病患者的症状并改善其生活质量。