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: 7797796
• 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 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797796
• 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

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. PUBLIC HEALTH RELEVANCE: Relevance of the Proposed Research to Veterans health Traumatic stress, which is commonly experienced during combat, can produce long-lasting emotional and mental disturbances, including depression and PTSD. Veterans with mood and anxiety disorders also have a high rate of hospitalization from secondary health-related problems, such as heart disease. Therefore, we need to conduct research to improve our understanding of the physiological basis of traumatic stress. To work toward achieving this goal the proposed research involves psychosocial stress in rats which produces PTSD-like responses at behavioral, pharmacological and physiological levels. This research will apply our established animal model of PTSD to improve our understanding of the neurobiological basis of the pathological effects of stress on brain and behavior to develop more effective pharmacotherapy for veterans with PTSD.

描述（由申请人提供）： 我们基于不可避免的猫暴露和社会不稳定的结合，开发了一种创伤后应激障碍（PTSD）的动物模型。这种社会心理压力操纵会在大鼠中产生PTSD样后遗症，包括焦虑症，夸张的惊吓，记忆力受损，对急性应激源的心血管反应性更大和激素反应性以及对12-肾上腺素能受体拮抗剂Yohimbine的夸张反应。拟议的研究将应用我们的PTSD模型来研究可以阻止PTSD样后遗症发展的治疗剂，以了解创伤性记忆形成和检索的神经生物学基础，并检查基于PTSD样序列的神经内分泌机制。以下三个问题涉及该提案的具体目的。 1）减少谷氨酸和CRF活性的药理治疗是否会阻塞大鼠PTSD样后遗症？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。针对这两个神经调节系统的药物疗法有可能改善PTSD患者中存在的复杂症状簇。我们假设用1）木激素（一种稳定NMDA受体电流的抗抑郁药）进行治疗。 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？ PTSD的标志性特征是对创伤事件的病理性记忆的建立和持久性。我们将检查参与我们PTSD模型的恐惧调节成分的形成和远程记忆检索涉及的分子机制。具体而言，我们将研究捕食者诱导的恐惧调节以激活分子信号分子的影响，包括钙/钙调蛋白 - 依赖性激酶II（CAMKII）和CAMP反应元件结合蛋白（CREB），以响应创伤经验，然后几周，以使这种经验的体验提高了这种经验。其次，我们将研究表观可塑性，这可能是创伤性记忆的形成和长期持久性的基础。具体而言，我们将评估心理压力对海马，杏仁核和前额叶皮质中BDNF基因甲基化的影响。 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干扰，包括降低的基础糖皮质激素水平和增加的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应激方案是否在皮质酮反应，糖皮质激素受体和下almus，海马和杏仁核中产生PTSD样表型。 总体而言，这三种互补方法的目的是使用我们的PTSD动物模型来洞悉PTSD的神经内分泌和机械特征，并开发出更有效的压力引起的焦虑和情绪障碍的治疗方法。临床相关性：战斗中暴露于创伤应力的退伍军人患有焦虑症的发病率很高，例如PTSD。我们尚未对压力诱导的后遗症的病因以及如何有效治疗与压力相关的精神疾病的病因达到令人满意的理解。这项研究将增强我们对创伤性记忆处理的神经生物学的理解，并有助于开发PTSD治疗治疗。 公共卫生相关性： 拟议的研究与在战斗中通常经历的退伍军人健康创伤压力的相关性可能会产生持久的情绪和心理障碍，包括抑郁症和PTSD。患有情绪和焦虑症的退伍军人也因继发性健康相关问题（例如心脏病）而患上住院率很高。因此，我们需要进行研究，以提高我们对创伤压力的生理基础的理解。为了实现这一目标，提出的研究涉及大鼠的心理压力，该大鼠在行为，药理和生理水平上产生类似PTSD的反应。这项研究将应用我们既定的PTSD动物模型，以提高我们对压力对大脑和行为的病理影响的神经生物学基础的理解，以开发PTSD退伍军人的更有效的药物治疗。