RMTg circuitry mediates psychiatric consequences of early life-threatening trauma

项目摘要 童年创伤的发生率高得令人无法接受。在最近的全国儿童健康调查中， 在健康方面，几乎一半的儿童经历过至少一种或多种类型的严重童年创伤， 三千五百万儿童童年创伤在成年后会产生巨大而昂贵的影响。童年创伤 增加患重度抑郁症（MDD）、广泛性焦虑、惊恐反应的风险， 强迫症（OCD）、躯体形式障碍、物质滥用和精神障碍。 童年创伤显著改变了治疗轨迹和结果。我们认为， 基础研究与临床效果的比例太低。此应用程序的目的是加速 我们认为，开发一种新的创伤模型可以提供稳健和相关的结果，并探索一种新的 关于精神疾病易感性增加的病因学假说。 我们将继续我们的研究在两个研究目标。目的1是为了进一步开发一种新的活体捕食者 模型（蛇）的主张，一个高度突出的，行为学相关的创伤将从事神经 系统的方式相关的精神疾病的研究。我们将系统地操纵时间， 青少年创伤暴露的数量，并在成年期进行大规模的生理， 行为和神经生物学特征表明跨越诊断界限的行为结构 (e.g.兴奋过度、快感缺乏、抑郁和焦虑）。神经激活模式将在关键评估 通过cFos激活模式的RMTg中心电路。丰富的行为和神经生物学学科 数据将进行多维标度和分类分析，以确定电路模式 与特定异常行为特征相关的参与。目标2将检验新的假设， 青少年暴露于行为学相关的创伤导致持久的行为和神经生物学 需要喙内侧被盖（RMTg）功能的中断。假设的角色组合， 涉及RMTg（威胁，恐惧，回避和负面影响），将其置于理想的情况下进行调解 早期创伤的破坏性后果和一些发现跨越诊断领域的核心症状。 我们将系统地抑制（RMTg导向的蝇蕈醇）或增强（RMTg导向的AMPA）RMTg功能 来验证我们的假设目标1中描述的类似分析将确定RMTg 抑制或增强分别抑制或抑制行为和神经生物学结果。 童年创伤和随后的情绪障碍的发展正在成为一个普遍的主题， 精神疾病临床前研究是唯一有资格系统地研究的后果， 早期创伤改善动物模型和我们对症状域的神经生物学理解 创伤的影响可以显着改善治疗策略，以帮助减轻个人和社会 负担

Project Summary Childhood trauma occurs at an unacceptably high rate. In the most recent National Survey of Children's Health, almost half of the children experienced at least one or more types of serious childhood trauma- nearly 35 million children. Childhood trauma has dramatic and costly effects in adulthood. Childhood trauma increases the risk of developing major depressive disorder (MDD), generalized anxiety, panic reaction, obsessive compulsive disorder (OCD), somatoform disorders, substance abuse and psychotic disorders. Childhood trauma significantly alters treatment trajectories and outcome for the worse. It is our contention that the ratio of basic research effort to clinical impact is too low. The purpose of this application is accelerate the development of a novel trauma model we believe delivers robust and relevant outcomes and to explore a novel hypothesis concerning the etiology of increased mental illness liability. We will pursue our studies in two research aims. Aim 1 is designed to further develop a novel live-predator model (snake) with the proposition that a highly salient, ethologically-relevant trauma will engage the nervous system in a manner relevant to studies of psychiatric disorders. We will systematically manipulate timing and number of adolescent trauma exposures and conduct large-scale mining in adulthood for physiological, behavioral and neurobiological profiles indicative of behavioral constructs that cross diagnostic boundaries (e.g. hyper arousal, anhedonia, depression and anxiety). Neural activation patterns will be assessed in key RMTg-centric circuitry via cFos activation patterns. A wealth of within subjects behavioral and neurobiological data will be subject to multidimensional scaling and categorical analysis to identify patterns of circuitry involvement associated with specific abnormal behavioral profiles. Aim 2 will test the novel hypothesis that adolescent exposure to ethologically-relevant trauma results in enduring behavioral and neurobiological disruptions that require rostral medial tegmentum (RMTg) function. The combination of roles hypothesized to involve the RMTg (threat, fear, avoidance and negative affect) place it in an ideal situation to mediate disruptive consequences of early trauma and some of the core symptoms found to cross diagnostic domains. We will systematically inhibit (RMTg-directed muscimol) or potentiate (RMTg-directed AMPA) RMTg function during trauma exposure to test our hypothesis. A similar analysis as described in Aim 1 will determine if RMTg inhibition or potentiation dampens or worsens, respectively, behavioral and neurobiological outcomes. Childhood trauma and the subsequent development of mood disorders is emerging as a pervasive theme in mental illness. Preclinical research is uniquely qualified to systematically investigate the consequences of early-life trauma. Improving animal models and our neurobiological understanding of the symptom domains impacted by trauma could significantly improve treatment strategies to help alleviate the individual and societal burden.