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Neuroimaging Cholinergic Mechanisms of Fear Extinction in PTSD

PTSD 恐惧消退的神经影像学胆碱能机制

基本信息

批准号：
10734244
负责人：
Ansel Hillmer
金额：
$ 83.55万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734244
关键词：
Acetylcholine Address Amygdaloid structure Anti-Anxiety Agents Arousal Basic Science Behavioral Brain Brain region Chronic Post Traumatic Stress Disorder Chronic stress Computer Models Data Development Dimensions Disease Evaluation Exhibits Extinction Fright Functional Magnetic Resonance Imaging Functional disorder Future Goals Hippocampus Human Image Impairment Individual Learning Link Maps Measures Mediating Molecular Target Neurosciences Nicotinic Receptors Participant Persons Pharmacological Treatment Pharmacotherapy Positron-Emission Tomography Post-Traumatic Stress Disorders Pre-Clinical Model Prefrontal Cortex Process Public Health Receptor Signaling Reporting Role Sampling Sampling Studies Scanning Severities Symptoms Therapeutic Translating acetylcholine receptor agonist alpha-bungarotoxin receptor anxious cholinergic clinical development clinically relevant diagnostic criteria human study improved learning extinction meetings memory process multidisciplinary multimodality neural neural circuit neuroimaging neuronal circuitry physiologic model pre-clinical radioligand receptor receptor density recruit response symptom cluster therapeutic development trauma exposure

项目摘要

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.

项目总结