Mechanisms of panic and PTSD vulnerability

项目总结/摘要 惊恐障碍（PD）和创伤后应激障碍（PTSD）是一种普遍存在的、高度共病的、使人衰弱的疾病 精神疾病合并症与更差的患者结局相关，但关于合并症的发生率知之甚少。 这些条件的病理生理学。新出现的证据表明，共同的脆弱性因素和潜在的 机制等脆弱性的一个常见预测因素可能是对二氧化碳的敏感性。低剂量CO2吸入触发 酸中毒，代表一种引起恐惧的稳态应激源。在PD患者中，CO2吸入可靠 会引发恐慌症在退伍军人中，部署前CO2敏感性预测创伤诱导的PTSD症状。 因此，对这种稳态压力源的敏感性可能预示着在应对后期应激时发展为PTSD的脆弱性。 外伤这个项目的目标是研究潜在的机制和神经回路有助于 共同的脆弱性和PD和PTSD的共病。我们的实验室最近发现， 在暴露于CO2的小鼠中，PTSD患者的常见症状是消退。CO2的个体变异性 响应度与后期灭绝赤字相关，支持长期CO2敏感性的预测作用。 害怕结果。我们的实验室以前确定穹窿下器官（SFO）是调节CO2诱发的 通过激活酸敏感受体T细胞死亡相关基因8（TDAG 8）的恐惧反应。遗传 TDAG 8的缺失减少了CO2诱发的冻结。TDAG 8表达与人类PD严重程度相关 和CO2诱发的小鼠冻结。因此，SFO内的TDAG 8表达可能调节对CO2的敏感性， 促进对恐惧灭绝缺陷的脆弱性。SFO投射到与恐惧相关的大脑区域， 焦虑，如边缘下皮层（IL）。IL激活显著降低， 二氧化碳和小鼠表现出延迟的恐惧消退缺陷，此外，与恐惧行为相关。 总之，这些数据表明，IL活性可能介导了CO2敏感性对恐惧消退的影响 赤字这个F32提案的目的是阐明电路和分子机制， 二氧化碳敏感性（稳态威胁）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 TDAG 8在CO2诱发的恐惧中的作用表明SFO-IL回路的参与， 稳态诱发的长期恐惧消退缺陷的上游SFO TDAG 8化学感受机制 威胁，二氧化碳。目的1将检验通过SFO传入的IL低激活是必要和充分的假设 二氧化碳引起的长期恐惧消退的缺陷。目的2将检验SFO TDAG 8表达与SFO TDAG 8表达相关的假设。 调节CO2敏感性和恐惧灭绝赤字通过失调的恐惧和稳态调节 大脑区域。这些研究的结果将确定新的神经回路调节恐惧的结果， 与PD和PTSD相关的预测标志物。这将最终有助于开发新颖和定制的 更好地治疗或预防PD和PTSD。

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.