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，影响着数百万人 国际吧PTSD患者经历持续的恐惧和痛苦的创伤事件记忆 对认知行为疗法如暴露疗法有抵抗力。这种抑制控制的丧失 对临床干预提出了重大挑战并且可能部分由杏仁核的过度兴奋性驱动， 这是一个储存恐惧记忆的大脑区域。尽管我们知道大脑的活动 区域和恐惧调节，在我们理解杏仁核功能障碍是如何发生的方面， 电路产生病理性恐惧，在理解基于电路的发现如何在 啮齿类动物转化为人类疾病。我的长期目标是更好地理解细胞和分子 神经回路中潜在的恐惧调节功能受到急性创伤的影响，并利用这一信息， 开发针对人类类似回路的新疗法。本建议的总体目标是 三方面：1）在小鼠中建立表达神经肽的杏仁核抑制性神经元的因果作用 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 类似人类杏仁核中的细胞类型。基于我们先前的发现，CST+神经元在 PTSD，我的中心假设是创伤性事件损害了细胞和分子的抑制功能， 杏仁核基底外侧复合体（BLA）中的CST+神经元，其与消退密切相关 学习（暴露疗法的心理学基础），这最终导致不受管制， PTSD患者的病理性恐惧这项研究的基本原理是，一旦因果关系 CST+神经元功能和创伤诱导的缺陷之间的关系， CST+神经元的类似物可以促进特异性靶向这些神经元的新疗法的开发。 细胞本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）研究损害灭绝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，和3）映射创伤影响的BLA细胞类型， 使用下一代测序技术结合先进的计算技术， 接近。这种方法是创新的，因为它提出了因果联系创伤引起的恐惧赤字 抑制新疾病相关细胞类型，同时还鉴定和定位创伤易感细胞 人类大脑中的高分辨率类型，这是以前没有做过的。拟议的研究是 重要的是，因为这些结果有望促进我们对神经回路的理解， 恐惧抑制，以及提供细胞类型特异性治疗靶向治疗的潜在途径 恐惧和焦虑导致的精神障碍很可能，选择性靶向神经元细胞类型将证明， 有效地减少患有这些疾病的个体的并发症并改善其生活质量。