Neuroendocrine Mechanisms and Therapeutics in an Animal Model of PTSD

PTSD 动物模型的神经内分泌机制和治疗方法

• 批准号: 8195928
• 负责人: David Mark Diamond
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195928
• 关键词: AMPA Receptors; Acetylation; Acute; Address; Adrenergic Antagonists; Adverse effects; Affect; Amygdaloid structure; Animal Model; Anticonvulsants; Antidepressive Agents; Anxiety; Anxiety Disorders; Area; Attenuated; BDNF gene; Behavior; Behavioral; Biological; Biological Assay; Brain; CRF receptor type 1; Calcium; Calmodulin; Cardiovascular system; Chromatin; Cognitive; Cognitive deficits; Complex; Corticosterone; Corticotropin-Releasing Hormone; Cyclic AMP-Responsive DNA-Binding Protein; DNA Methylation; Development; Disease model; Effectiveness; Emotional; Endocrine system; Epigenetic Process; Epinephrine; Etiology; Event; Exhibits; Feedback; Felis catus; Fright; Functional disorder; Funding; Glucocorticoid Receptor; Glucocorticoids; Glutamates; Goals; Health; Heart Diseases; Hippocampus (Brain); Histone H3; Hormonal; Hospitalization; Human; Hydrocortisone; Hypothalamic structure; Immune system; Incidence; Individual; Laboratories; Learning; Link; Measures; Medical Research; Memory; Mental Depression; Mental Health; Mental disorders; Metabolic; Methylation; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Molecular; Mood Disorders; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Paper; Pharmacological Treatment; Pharmacotherapy; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Psyche structure; Psychosocial Stress; Rattus; Receptor Activation; Reducing Agents; Regimen; Regulation; Research; Retrieval; Signal Transduction; Signaling Molecule; Stress; Symptoms; System; Testing; Therapeutic; Therapeutic Studies; Tissues; Trauma; Veterans; Work; Yohimbine; base; brain behavior; cardiovascular disorder risk; channel blockers; clinical efficacy; combat; conditioned fear; corticosterone receptor; effective therapy; emotional trauma; experience; high risk; hypothalamic-pituitary-adrenal axis; improved; insight; lamotrigine; mRNA Expression; meetings; memory process; memory retrieval; physical conditioning; population health; programs; public health relevance; receptor; research study; response; social; stressor; therapeutic development; tianeptine

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 ¿2-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.

我们已经建立了一种基于结合的创伤后应激障碍（PTSD）动物模型 不可避免的猫暴露和社会不稳定。这种社会心理压力操纵产生类似PTSD的 大鼠的后遗症，包括动画增强，夸张的惊吓，记忆力受损，心血管较大和 对急性应激源的激素反应性和对2-肾上腺素受体拮抗剂的反应， Yohimbine。拟议的研究将应用我们的PTSD模型来研究治疗，这可能会阻止 PTSD样后遗症的发展，以了解创伤性记忆形成的神经生物学基础 并检索并检查基于PTSD样后遗症的神经内分泌机制。 以下三个问题涉及该提案的具体目的。 1）会减少谷氨酸和CRF活性阻滞PTSD样后遗症的药物治疗 老鼠？研究表明，谷氨酸和皮质激素释放因子（CRF）参与 创伤性记忆形成和PTSD的病理生理学。药物治疗将针对这两个 神经调节系统有可能改善人们中存在的复杂符号簇 与PTSD。我们假设用1）木氨酸（一种稳定NMDA的抗抑郁药）进行治疗 接收器电流； 2）Lamotrigine，一种Na+通道阻滞剂，可降低谷氨酸水平；或3）CRH-1 受体拮抗剂将阻止心理压力大鼠中PTSD样后遗症的发展。 2）创伤记忆的形成和持久性的基础是什么？这 PTSD的Hallmark特征是对一个病理强烈记忆的建立和持久性 创伤事件。我们将检查涉及的分子机制和远程记忆 检索我们PTSD模型的恐惧调节成分。具体来说，我们将研究 捕食者引起的恐惧调节以激活分子信号分子，包括钙/钙调蛋白 - 依赖性激酶II（CAMKII）和CAMP响应元件结合蛋白（CREB），响应于 创伤经验，然后几周后，提醒人们。其次，我们将研究表观遗传学 可塑性可能是创伤记忆的形成和长期持久性的基础。具体来说，我们 将评估社会心理应激对海马，杏仁核中BDNF基因甲基化的影响 前额叶皮层。 3）大鼠的社会心理压力是否在神经内分泌活性中产生PTSD样异常？ PTSD 涉及神经内分泌系统的灾难，包括降低碱性糖皮质激素水平并增加 糖皮质激素负反馈敏感性以及CRF水平和糖皮质激素受体的变化。我们 将评估我们的社会心理压力方案是否在皮质酮中产生类似PTSD的表型 下丘，海马和杏仁核的反应，糖皮质激素受体和CRF水平。 总体而言，这三种完整方法的目的是使用我们的动物模型PTSD提供 深入了解PTSD的神经内分泌和机械特征，并开发更有效的治疗方法 压力引起的动画和情绪障碍。 临床相关性： 在战斗中暴露于创伤应力的退伍军人患有焦虑症的高度，例如PTSD。 我们尚未达到满意的厂房对压力引起的后遗症病因的理解以及如何 有效治疗与压力有关的精神障碍。这项研究将增强我们对 创伤性记忆加工的神经生物学和有助于创造PTSD治疗治疗的神经生物学。