Adolescent trauma produces enduring disruptions in sleep architecture that lead to increased risk for adult mental illness

青少年创伤会对睡眠结构产生持久的破坏，从而导致成人精神疾病的风险增加

• 批准号: 10730872
• 负责人: Gregory I Elmer
• 金额: $ 42.49万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730872
• 关键词: Address; Adolescence; Adolescent; Adult; Adverse event; Affect; Affective; Anxiety; Arousal; Behavior; Behavioral; Bipolar Disorder; Categories; Cell Nucleus; Charge; Circadian Rhythms; Clinical; Cognitive; Data; Diagnostic; Disease; Drug abuse; Eating; Emotional; Environmental Risk Factor; Event; Exposure to; Genetic; Goals; Health; Homosynaptic Depression; Incidence; Individual; Individual Differences; Manic; Mediating; Mediation; Mediator; Mental Depression; Mental disorders; Midbrain structure; Neurobiology; Neurons; Obsessive-Compulsive Disorder; Output; Pathway interactions; Pattern; Play; Positioning Attribute; REM Sleep; Reporting; Risk; Role; Schedule; Schizophrenia; Series; Severities; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Stress; Symptoms; Teenagers; Tegmentum Mesencephali; Testing; Therapeutic; Trauma; Ventral Tegmental Area; adverse childhood events; adverse outcome; cognitive function; depressive symptoms; design; designer receptors exclusively activated by designer drugs; determinants of treatment resistance; drinking; emerging adult; experience; experimental study; functional disability; generalized anxiety; high risk; maladaptive behavior; negative affect; neuron development; non rapid eye movement; pediatric trauma; sex; sleep abnormalities; stress resilience; trauma exposure; virtual; young adult

Childhood trauma is one of the single greatest environmental factors known to increase risk for a broad range of adult psychiatric illnesses. The consequences of childhood trauma not only affect the risk for mental illness, but significantly alter symptom complexity and predict treatment resistance within a diagnostic category. It could be argued that sleep disturbance is the single greatest drive (others being eating, drinking, sex) known to increase risk for adult psychiatric illness. Sleep abnormalities co-occur with virtually all psychiatric illnesses and, like adolescent trauma, significantly worsens the trajectory, severity and complexity of the illness. Each component of sleep architecture contributes to cognitive, emotional and somatic health. For example, rapid-eye movement sleep (REM), plays a key role in processing affective, emotional information and is thought to be critically involved in ‘depotentiating’ the emotional charge of a stress event and ameliorating its autonomic arousal burden. A recent report strongly suggests that activation of the rostromedial tegmental nucleus (RMTg) can dramatically decrease REM sleep via its main output to the ventral tegmental area (VTA). This finding is intriguing since our lab recently implicated RMTg activation in mediating the maladaptive adult consequences of adolescent stress. RMTg activation and subsequent REM deficits during adolescence could have dramatic impact since sleep and circadian processes help drive and guide neuronal development. We will utilize adolescent exposure to an ethologically-relevant stress (live predator) to test the following hypotheses: 1) Adolescent exposure to ethologically-relevant stress results in enduring changes in component- specific sleep architecture that are associated with maladaptive behavior in adulthood, and 2) Adolescent stress- induced changes in RMTg function underly the changes in sleep architecture associated with maladaptive behavioral profiles in adulthood. The goal of AIM 1 is to determine if individual sleep profiles following adolescent stress are predictive of adult behavior in a panel of tests designed to assess depression and anxiety. We will characterize sleep architecture in adolescence and adulthood and then characterize behavior profiles in adulthood. We expect individual differences in sleep architecture following adolescent stress to be predictive of normal, maladaptive and stress-resilient adult behavioral profiles. The goal of AIM 2 is to test the functional role of the RMTg-VTA circuit in mediating disturbed sleep architecture and/or changes in adolescent stress-induced maladaptive behavior in adulthood. An intersectional chemogenetic (DREADD) approach will be used to specifically inhibit the RMTg-VTA circuit in order to test causal associations. Adolescent childhood trauma- induced sleep disturbance may be a primary factor in the trajectory towards adult mental illness. Investigating the specific alterations in sleep architecture and underlying neurobiology will help facilitate therapeutic discovery efforts.

儿童创伤是已知增加广泛风险的最大环境因素之一 成人精神病。童年创伤的后果不仅会影响精神疾病的风险，而且还会影响 但是，显着改变了症状的复杂性，并预测诊断类别内的治疗性耐药性。可以 被认为睡眠障碍是已知的最大动力（其他正在吃，喝，性别） 增加成人精神病的风险。睡眠异常与几乎所有精神病疾病共同发生， 像青少年的创伤一样，疾病的轨迹，严重程度和复杂性都显着恶化。每个 睡眠结构的组成部分有助于认知，情感和躯体健康。例如，快速眼 运动睡眠（REM），在处理情感，情感信息中起关键作用，被认为是 批判性地参与“驱逐”压力事件的情感指控并改善其自主神经 唤醒伯恩。最近的一份报告强烈表明，鼻膜细胞核（RMTG）的激活 可以通过其主要输出到腹侧对接区域（VTA）大大降低REM睡眠。这个发现是 自从我们的实验室最近实施了RMTG激活以来，很有趣 青少年应力。青少年期间的RMTG激活和随后的REM防御能力可能具有戏剧性 由于睡眠和昼夜节律的影响有助于推动和指导神经元发展。 我们将利用青少年暴露于与伦理学相关的压力（活掠食者）来测试以下 假设：1）青少年接触与伦理学相关的压力导致持久的成分变化 与成年后的适应不良行为相关的特定睡眠结构，以及2）青少年应力 - 在与不良适应性相关的睡眠体系结构变化下，RMTG功能的诱导变化 成年后的行为概况。目标1的目的是确定青少年之后的单个睡眠特征是否 压力可以预测成人行为，以评估抑郁症和动画。我们将 表征青少年和成年中的睡眠结构，然后在 成年。我们预计青少年压力后的睡眠结构中的个体差异可以预测 正常，适应不良和压力降低的成人行为特征。目标2的目标是测试功能角色 RMTG-VTA电路的介导干扰的睡眠结构和/或青少年应力诱导的变化 成年后的适应不良行为。交叉化学发生（Dreadd）方法将用于 青少年童年创伤 - 诱发睡眠障碍可能是成人精神疾病轨迹的主要因素。调查 睡眠体系结构和潜在神经生物学的具体改变将有助于促进治疗发现 努力。