Neuroimaging Cholinergic Mechanisms of Fear Extinction in PTSD

项目总结 创伤后应激障碍(PTSD)是一种严重的公共卫生负担严重的衰弱障碍。然而， 目前的药物治疗明显不理想。α7烟碱型乙酰胆碱受体(NAChR)是 创伤后应激障碍治疗的显著分子靶点。乙酰胆碱调节恐惧学习和记忆过程 在创伤后应激障碍患者中，α7nAChR密度在临床前模型中因慢性应激而降低。 尽管有这些令人信服的证据，但α7nAChRs在人类创伤后应激障碍的病理生理学中的作用并不完全 明白了。为了解决这一差距，这项提议将表征α7nAChR对行为和神经的贡献 暴露在创伤中的参与者的恐惧学习标记代表了创伤后应激障碍的所有严重程度。vbl.使用 [18F]ASEM，一种针对α7 nAChRs的正电子发射断层扫描放射配基，我们获得了令人兴奋的结果 初步数据显示，与严重程度相关的创伤后应激障碍患者α7nAChR活性较低 创伤后应激障碍症状群。此外，杏仁核中α7nAChR可获得性较低对应于较弱 杏仁核和腹内侧前额叶皮质的功能连接，这是支撑 害怕学习过程。在这些令人兴奋的数据的激励下，这个项目的主要目标是 α7nAChR在创伤后应激障碍的恐惧消退学习和回路中的作用。为了实现这一目标，我们将招聘80名 创伤暴露的参与者在创伤后应激障碍症状的全维度范围内进行了抽样。全 参与者将接受[18F]ASEM PET扫描，并参与一项既定的恐惧逆转任务 并行功能磁共振成像(FMRI)。所获取的数据将用于寻址三个 明确的目标。目标1将确定创伤后应激障碍患者的α7nAChR可用性是否低于创伤暴露 控制，以及哪些创伤后应激障碍症状群严重程度与较低的α7nAChR可用性相对应。目标2将 确定杏仁核中α7nAChR的低可获得性是否预示着恐惧消退期间学习能力下降。目标 3将确定杏仁核中α7nAChR的可用性降低是否预示着在 恐惧消失了。最终的分析将确定杏仁核α7nAChR的可用性是否介导了 杏仁核-vmPFC连接与恐惧消退学习的比率，评估这些受体的一种机制 创伤后应激障碍中潜在的被破坏的恐惧消退回路。这些发现将确定α7nAChR在 活人恐惧消退的病理生理学及其脑回路，为未来治疗发展提供信息 以解决慢性创伤后应激障碍症状背后的恐惧消退障碍。

PROJECT SUMMARY Post-traumatic stress disorder (PTSD) is a deeply debilitating disorder with severe public health burden. Yet, current pharmacological treatments are glaringly suboptimal. The α7 nicotinic acetylcholine receptor (nAChR) is a salient molecular target for PTSD therapeutics. Acetylcholine regulates fear learning and memory processes that are impaired in people with PTSD, and α7 nAChR density is reduced by chronic stress in preclinical models. Despite this compelling evidence, the role of α7 nAChRs in the pathophysiology of PTSD in humans is not fully understood. To address this gap, this proposal will characterize α7 nAChR contributions to behavioral and neural markers of fear learning in trauma-exposed participants representing the full spectrum of PTSD severity. Using [18F]ASEM, a positron emission tomography (PET) radioligand specific to α7 nAChRs, we obtained exciting preliminary data indicating lower α7 nAChR availability in people with PTSD that is associated with the severity of PTSD symptom clusters. Further, lower α7 nAChR availability in amygdala corresponded to weakened functional connectivity of the amygdala and ventromedial prefrontal cortex, which is a key circuit that underpins fear learning processes. Motivated by these exciting data, the primary objective of this project is to characterize α7 nAChR contributions to fear extinction learning and circuitry in PTSD. To achieve this goal, we will recruit 80 participants with trauma exposure sampled across the full dimensional spectrum of PTSD symptoms. All participants will be scanned with [18F]ASEM PET and participate in an established fear reversal task with concurrent functional magnetic resonance imaging (fMRI). The acquired data will be used to address three Specific Aims. AIM 1 will determine if people with PTSD have lower α7 nAChR availability than trauma exposed controls, and which PTSD symptom cluster severities correspond to lower α7 nAChR availability. AIM 2 will determine if lower α7 nAChR availability in amygdala predicts impaired learning rates during fear extinction. AIM 3 will determine if lower α7 nAChR availability in amygdala predicts weaker vmPFC-amygdala connectivity during fear extinction. A final analysis will determine if amygdala α7 nAChR availability mediates the relationship of amygdala-vmPFC connectivity with fear extinction learning rates, assessing these receptors a mechanism underlying disrupted fear extinction circuits in PTSD. The findings will determine α7 nAChR roles in the pathophysiology of fear extinction and its brain circuits in living people, informing future therapeutic development to address fear extinction impairments that underlie chronic PTSD symptoms.