Mechanisms of panic and PTSD vulnerability

恐慌和创伤后应激障碍（PTSD）脆弱性的机制

基本信息

批准号：
9760272
负责人：
Katherine Miles Johnston McMurray
金额：
$ 6.37万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9760272
关键词：
Acidosis Acids Amygdaloid structure Anxiety Area Attenuated Behavior Behavioral Brain Brain region Carbon Dioxide Cell Death Comorbidity Complement Data Development Disease Dose Extinction (Psychology)Freezing Fright Functional disorder Genes Genetic Goals Human Hypothalamic structure Inhalation Lateral Mediating Mediation Mental disorders Modeling Molecular Mus Neuroanatomy Neurobiology Neurons Operative Surgical Procedures Outcome Panic Panic Attack Panic Disorder Pathway interactions Patient-Focused Outcomes Patients Phenotype Physiology Post-Traumatic Stress Disorders Regulation Role Severities Site Statistical Models Structure of terminal stria nuclei of preoptic region Subfornical Organ Symptoms T-Cell Receptor T-Lymphocyte Techniques Testing Training Trauma Veterans Viral Work common symptom conditioned fear designer receptors exclusively activated by designer drugs individual variation individualized medicine innovation insight nerve supply neural circuit new therapeutic target novel predictive marker prevent response sensor stressor

项目摘要

Project Summary/Abstract Panic disorder (PD) and post-traumatic stress disorder (PTSD) are prevalent, highly comorbid and debilitating psychiatric disorders. Comorbidity is associated with worse patient outcomes, yet little is known regarding the pathophysiology of these conditions. Emerging evidence suggests shared vulnerability factors and underlying mechanisms. One common predictor of vulnerability may be CO2 sensitivity. Low dose CO2 inhalation triggers acidosis and represents a homeostatic stressor which evokes fear. In PD patients, CO2 inhalation reliably induces panic attacks. In veterans, pre-deployment CO2 sensitivity predicted trauma-induced PTSD symptoms. Thus, sensitivity to this homeostatic stressor may predict vulnerability to develop PTSD in response to later trauma. The goal of this project is to investigate the underlying mechanisms and neurocircuitry contributing to shared vulnerabilities and comorbidity of PD and PTSD. Our lab recently found long-term deficits on fear extinction, a common symptom in PTSD patients, in CO2 exposed mice. Individual variability in CO2 responsivity correlated with later extinction deficits supporting a predictive role for CO2 sensitivity on long-term fear outcomes. Our lab previously identified the subfornical organ (SFO) as a key site regulating CO2-evoked fear responses via activation of acid-sensing receptor T-cell Death-associated gene 8 (TDAG8). Genetic deletion of TDAG8 reduced CO2-evoked freezing. TDAG8 expression correlated with PD severity in humans and CO2-evoked freezing in mice. Thus, TDAG8 expression within SFO may regulate sensitivity to CO2 and promote vulnerability to fear extinction deficits. The SFO projects to brain regions associated with fear and anxiety, such as the infralimbic cortex (IL). IL activation was significantly reduced both immediately following CO2 and in mice showing delayed fear extinction deficits and additionally, correlated with fear behaviors. Together, these data suggest that IL activity may mediate the effects of CO2 sensitivity on fear extinction deficits. The objective of this F32 proposal is to elucidate the circuitry and molecular mechanisms by which CO2 sensitivity (homeostatic threat) results in long-term fear extinction deficits (external threat). Direct SFO to IL innervation and the role of SFO TDAG8 in CO2-evoked fear suggest engagement of SFO-IL circuits and upstream SFO TDAG8 chemosensory mechanisms in long term fear extinction deficits evoked by homeostatic threat, CO2. Aim 1 will test the hypothesis that IL hypoactivation via SFO afferents is necessary and sufficient for CO2-evoked long-term deficits on fear extinction. Aim 2 will test the hypothesis that SFO TDAG8 expression regulates CO2 sensitivity and fear extinction deficits through dysregulating fear and homeostatic regulatory brain regions. Results from these studies will identify novel neural circuits regulating fear outcomes and identify predictive markers relevant to PD and PTSD. This will ultimately aid in the development of novel and tailored treatments to better treat or prevent PD and PTSD.

项目概要/摘要恐慌症 (PD) 和创伤后应激障碍 (PTSD) 十分普遍，共病率很高且使人衰弱精神疾病。合并症与较差的患者预后相关，但人们对合并症知之甚少。这些病症的病理生理学。新出现的证据表明存在共同的脆弱性因素和潜在的机制。脆弱性的一种常见预测因素可能是二氧化碳敏感性。低剂量二氧化碳吸入触发因素酸中毒，代表一种引起恐惧的稳态应激源。在 PD 患者中，二氧化碳吸入可靠诱发惊恐发作。在退伍军人中，部署前的二氧化碳敏感性可以预测创伤引起的创伤后应激障碍 (PTSD) 症状。因此，对这种稳态压力源的敏感性可能会预测因以后的反应而发展为创伤后应激障碍（PTSD）的脆弱性。创伤。该项目的目标是研究潜在的机制和神经回路 PD 和 PTSD 的共同弱点和合并症。我们的实验室最近发现恐惧造成的长期缺陷灭绝是创伤后应激障碍（PTSD）患者的常见症状，在二氧化碳暴露的小鼠中。 CO2 的个体差异响应性与后期灭绝缺陷相关，支持 CO2 敏感性的长期预测作用恐惧结果。我们的实验室之前确定穹窿下器官 (SFO) 是调节 CO2 诱发的关键部位通过激活酸敏感受体 T 细胞死亡相关基因 8 (TDAG8) 产生恐惧反应。遗传 TDAG8 的缺失减少了 CO2 引起的冻结。 TDAG8 表达与人类 PD 严重程度相关和二氧化碳引起的小鼠冻结。因此，SFO 内的 TDAG8 表达可能调节对 CO2 和增加对恐惧灭绝缺陷的脆弱性。 SFO 投射到与恐惧和恐惧相关的大脑区域焦虑，例如边缘下皮质（IL）。 IL 激活立即显着减少二氧化碳和小鼠表现出延迟的恐惧消退缺陷，此外，还与恐惧行为相关。总之，这些数据表明 IL 活性可能介导 CO2 敏感性对恐惧消退的影响赤字。该 F32 提案的目的是阐明其电路和分子机制二氧化碳敏感性（稳态威胁）会导致长期的恐惧消退缺陷（外部威胁）。直接 SFO 至 IL 神经支配和 SFO TDAG8 在 CO2 引起的恐惧中的作用表明 SFO-IL 回路的参与和上游 SFO TDAG8 化学感应机制在稳态引起的长期恐惧消退缺陷中的作用威胁，二氧化碳。目标 1 将检验以下假设：通过 SFO 传入的 IL 低激活是必要且充分的二氧化碳引起的恐惧灭绝的长期赤字。目标 2 将检验 SFO TDAG8 表达的假设通过调节恐惧和稳态调节来调节二氧化碳敏感性和恐惧消退缺陷大脑区域。这些研究的结果将确定调节恐惧结果的新神经回路，并确定与 PD 和 PTSD 相关的预测标记。这最终将有助于开发新颖且量身定制的更好地治疗或预防 PD 和 PTSD 的治疗方法。