RMTg circuitry mediates psychiatric consequences of early life-threatening trauma

RMTg 回路介导早期危及生命的创伤的精神后果

• 批准号: 9436843
• 负责人: Gregory I Elmer
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9436843
• 关键词: Adolescent; Adult; Affect; Anhedonia; Animal Model; Antidepressive Agents; Anxiety; Arousal; Basic Science; Behavior; Behavioral; Categories; Cell Nucleus; Chemosensitization; Child; Child health care; Childhood; Classification; Clinical; Cognition; Conceptions; Data; Development; Diagnosis; Diagnostic; Disease; Dorsal; Drug abuse; Early-life trauma; Etiology; Event; Exposure to; Female; Foundations; Fright; Future; Goals; Gray unit of radiation dose; Habenula; Incidence; Individual; Intervention; Investigation; Laboratories; Lead; Lesion; Life; Major Depressive Disorder; Male Adolescents; Medial; Mediating; Mental Depression; Mental disorders; Methods; Mining; Modeling; Mood Disorders; Moods; Muscimol; National Institute of Mental Health; Nature; Nervous system structure; Neurobiology; Obsessive-Compulsive Disorder; Outcome; Panic; Patients; Pattern; Physiological; Play; Positioning Attribute; Post-Traumatic Stress Disorders; Psychotic Disorders; Rattus; Reaction; Recording of previous events; Research; Risk; Role; Schedule; Schizophrenia; Series; Sleep; Snakes; Somatoform Disorders; Statistical Methods; Stress; Structure of terminal stria nuclei of preoptic region; Substance abuse problem; Surveys; Symptoms; Tegmentum Mesencephali; Testing; Therapeutic; Time; Trauma; behavioral construct; clinically relevant; cost; design; experience; generalized anxiety; improved; individualized medicine; interest; negative affect; novel; pediatric trauma; postnatal; pre-clinical research; relating to nervous system; traumatic event; treatment strategy

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.

项目摘要 童年创伤的发生率不高。在最近的全国儿童调查中 健康，几乎一半的孩子经历了至少一种或多种类型的严重童年创伤 - 几乎 3500万儿童。童年创伤在成年中具有巨大的昂贵影响。童年创伤 增加发生重大抑郁症（MDD），普遍焦虑，恐慌反应， 强迫症（OCD），躯体形式疾病，药物滥用和精神病。 童年创伤显着改变了治疗轨迹和结果。我们的论点是 基础研究工作与临床影响的比率太低。此应用的目的是加速 我们认为开发一种新颖的创伤模型，我们可以提供强大和相关的结果并探索小说 关于增加精神疾病责任的病因的假设。 我们将以两个研究目标进行研究。 AIM 1旨在进一步开发新颖的现场培训者 模型（蛇）的主张是，高度显着，与伦理学的创伤会引起紧张感 与精神疾病研究有关的方式。我们将系统地操纵时机和 青少年创伤的数量并在成年期进行大规模开采，以进行生理， 行为和神经生物学概况指示了跨诊断边界的行为结构 （例如，超级唤醒，抗抑郁症和焦虑）。神经激活模式将在密钥中进行评估 通过CFOS激活模式以RMTG为中心的电路。主体内部的财富行为和神经生物学 数据将受到多维缩放和分类分析的约束，以识别电路的模式 与特定异常行为概况相关的参与。 AIM 2将检验新的假设 青少年暴露于与伦理学相关的创伤导致持久的行为和神经生物学 需要主内侧段（RMTG）功能的破坏。假设的角色的结合 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 早期创伤和一些核心症状的破坏性后果被发现跨越诊断领域。 我们将系统地抑制（RMTG定向的Muscimol）或Potentiate（RMTG定向AMPA）RMTG功能 在创伤期间暴露于检验我们的假设。与AIM 1所述的类似分析将确定RMTG是否 抑制或增强分别抑制或恶化，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普遍的主题 精神疾病。临床前研究具有独特的资格，可以系统地研究 早期创伤。改善动物模型以及我们对症状领域的神经生物学理解 受创伤的影响可以大大改善治疗策略，以帮助减轻个人和社会 负担。