Neuroendocrine Mechanisms and Therapeutics in an Animal Model of PTSD

描述(由申请人提供)： 我们开发了一种创伤后应激障碍(PTSD)的动物模型，该模型基于不可避免的猫暴露和社会不稳定的组合。这种心理社会压力操作在大鼠身上产生了类似创伤后应激障碍的后遗症，包括高度焦虑、过度惊吓、记忆力受损、对急性应激源更强的心血管和激素反应，以及对12肾上腺素能受体拮抗剂育亨宾的夸大反应。这项拟议的研究将应用我们的创伤后应激障碍模型来研究可能阻止创伤后应激障碍样后遗症发展的治疗方法，了解创伤记忆形成和恢复的神经生物学基础，并研究创伤后应激障碍样后遗症背后的神经内分泌机制。以下三个问题涉及这项提案的具体目标。1)降低谷氨酸和CRF活性的药物治疗会阻止大鼠的PTSD样后遗症吗？研究表明谷氨酸和促肾上腺皮质激素释放因子(CRF)参与创伤记忆的形成和创伤后应激障碍的病理生理过程。针对这两个神经调节系统的药物治疗有可能改善PTSD患者存在的一系列复杂症状。我们假设，1)替尼普汀，一种稳定NMDA受体电流的抗抑郁剂；2)拉莫三嗪，一种降低谷氨酸水平的Na+通道阻滞剂；或3)CRH-1受体拮抗剂，将阻止心理应激大鼠PTSD样后遗症的发展。2)创伤性记忆形成和持续的机制是什么？创伤后应激障碍的显著特征是对创伤事件的病理性强烈记忆的建立和持续。我们将研究创伤后应激障碍模型中恐惧条件反射成分的形成和远程记忆提取所涉及的分子机制。具体地说，我们将研究捕食者诱导的恐惧条件反射对激活分子信号分子的影响，包括钙/钙调蛋白依赖激酶II(CaMKII)和cAMP反应元件结合蛋白(CREB)，以回应创伤经历，然后在几周后提醒那次经历。其次，我们将研究表观遗传可塑性，这可能是创伤记忆形成和长期持续的基础。具体地说，我们将评估心理社会压力对海马体、杏仁核和前额叶皮质BDNF基因甲基化的影响。3)大鼠的心理社会应激是否会导致类似创伤后应激障碍的神经内分泌活动异常？创伤后应激障碍涉及神经内分泌系统紊乱，包括基础糖皮质激素水平降低和糖皮质激素负反馈敏感性增加，以及CRF水平和糖皮质激素受体的变化。我们将评估我们的心理社会应激疗法是否在下丘脑、海马体和杏仁核的皮质酮反应、糖皮质激素受体和CRF水平上产生类似PTSD的表型。总体而言，这三种互补方法的目标是使用我们的创伤后应激障碍动物模型来洞察创伤后应激障碍的神经内分泌和机制特征，并开发更有效的治疗应激诱导的焦虑和情绪障碍的方法。临床意义：在战斗期间暴露于创伤应激的退伍军人有较高的焦虑症发病率，如创伤后应激障碍。我们对应激后遗症的病因以及如何有效地治疗应激相关的精神障碍还没有达到令人满意的认识。这项研究将加深我们对创伤记忆加工的神经生物学的理解，并有助于创伤后应激障碍的治疗方法的发展。

DESCRIPTION (provided by applicant): We have developed an animal model of post-traumatic stress disorder (PTSD) based on the combination of inescapable cat exposure and social instability. This psychosocial stress manipulation produces PTSD-like sequelae in rats, including heightened anxiety, exaggerated startle, impaired memory, greater cardiovascular and hormonal reactivity to an acute stressor and an exaggerated response to the 12-adrenergic receptor antagonist, yohimbine. The proposed research will apply our PTSD model to study therapeutics which may block the development of PTSD-like sequelae, to understand the neurobiological basis of traumatic memory formation and retrieval and to examine the neuroendocrine mechanisms which underlie PTSD-like sequelae. The following three questions address the specific aims of this proposal. 1) Will pharmacological treatments which reduce glutamate and CRF activity block PTSD-like sequelae in rats? Research has demonstrated the involvement of glutamate and corticotropin-releasing factor (CRF) in traumatic memory formation and in the pathophysiology of PTSD. Pharmacotherapy that will target these two neuromodulatory systems has the potential to ameliorate the complex cluster of symptoms present in people with PTSD. We hypothesize that treatment with 1) Tianeptine, an antidepressant which stabilizes NMDA receptor currents; 2) Lamotrigine, a Na+ channel blocker which reduces glutamate levels; or 3) a CRH-1 receptor antagonist, will block the development of PTSD-like sequelae in psychosocially stressed rats. 2) What are the mechanisms underlying the formation and persistence of traumatic memories? The hallmark feature of PTSD is the establishment and persistence of a pathologically intense memory of a traumatic event. We will examine molecular mechanisms involved in the formation and remote memory retrieval of the fear conditioning component of our PTSD model. Specifically, we will study the influence of predator-induced fear conditioning to activate molecular signalling molecules, including calcium/calmodulin- dependent kinase II (CaMKII) and cAMP-response element binding protein (CREB), in response to the traumatic experience and then, weeks later, to a reminder of that experience. Second, we will study epigenetic plasticity which may underlie the formation and long-term persistence of traumatic memories. Specifically, we will assess the effects of psychosocial stress on BDNF gene methylation in the hippocampus, amygdala and prefrontal cortex. 3) Does psychosocial stress in rats produce PTSD-like abnormalities in neuroendocrine activity? PTSD involves disturbances of neuroendocrine systems, including reduced basal glucocorticoid levels and increased glucocorticoid negative feedback sensitivity, as well as changes in CRF levels and glucocorticoid receptors. We will evaluate whether our psychosocial stress regimen produces a PTSD-like phenotype in corticosterone responses, glucocorticoid receptors and CRF levels in the hypothalmus, hippocampus and amygdala. Overall, the goal of these three complementary approaches is to use our animal model of PTSD to provide insight into the neuroendocrine and mechanistic features of PTSD and to develop more effective treatments of stress-induced anxiety and mood disorders. CLINICAL RELEVANCE: Veterans exposed to traumatic stress during combat have a high incidence of anxiety disorders, such as PTSD. We have yet to achieve a satisfactory understanding of the etiology of stress-induced sequelae and how to effectively treat stress-related mental disorders. This research will enhance our understanding of the neurobiology of traumatic memory processing and aid in the development of therapeutic treatments for PTSD.