Early life stress effects on threat-learning

早期生活压力对威胁学习的影响

• 批准号: 10291325
• 负责人: Kevin George Bath
• 金额: $ 39.98万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-23 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291325
• 关键词: Address; Adolescent; Adult; Adverse event; Affective; American; Amygdaloid structure; Anatomy; Animals; Anxiety; Anxiety Disorders; Area; Automobile Driving; Bathing; Behavior; Behavioral; Brain; Cardiovascular Diseases; Caring; Cell Proliferation; Cell physiology; Cells; Child; Child Abuse; Childhood; Country; Development; Developmental Course; Developmental Process; Diagnostic; Emotional; Emotional Disturbance; Environment; Evaluation; Event; Exposure to; Extinction (Psychology); Female; Freezing; Fright; Genetic; Goals; Growth; Hippocampus (Brain); Histologic; Human; Impaired cognition; Impairment; Individual; Interneurons; Label; Learning; Life; Long-Term Effects; Measures; Medial; Mediating; Medical; Mental Depression; Mental Health; Methods; Modeling; Molecular Genetics; Mus; Neurobiology; Panic Disorder; Pathologic; Pathology; Plant Roots; Post-Traumatic Stress Disorders; Prefrontal Cortex; Regulation; Research; Risk; Role; Site; Stress; Structure; Techniques; Teenagers; Testing; Trauma; Work; World Health Organization; anxiety-like behavior; base; behavior measurement; behavioral outcome; burden of illness; cellular development; classical conditioning; cortico-limbic circuits; cost; depressive symptoms; early life adversity; early life stress; endophenotype; experience; insight; lens; lifetime risk; male; mature animal; mouse model; neurobiological mechanism; neurodevelopment; neuron development; neuropsychiatric disorder; novel; optogenetics; pediatric trauma; pup; relating to nervous system; resilience; response; stem; stress related disorder; stressor

ABSTRACT' ! Early life stress (ELS) significantly increases the risk for emotional disturbance and affective pathology. Sixty- four percent of individuals will experience at least one significant stressor in childhood, and this single adverse event increases the lifetime risk for panic disorder, depression, or anxiety disorders by ~30%. Experiencing three or more early life stressors doubles the lifetime risk for stress-related pathology. Anxiety disorders alone cost the American people approximately $42 billion a year, which is approximately one third of the total $148 billion spent on mental health. Further, according to the World Health Organization, the burden of disease for neuropsychiatric disorders on the country exceeds that of any other medical condition, even doubling that of cardiovascular disease, and anxiety disorders pose the greatest threat to mental health worldwide. In the U.S. nearly 29% of people will develop some form of anxiety disorder in their lifetime. Despite the enormous burden of stress-related disorders, relatively little is known regarding the neurobiological underpinnings of pathology development. For many, the roots of later emotional disturbance may lie in altered development and long term functioning of cortico-limbic circuits that regulate emotional reactivity and threat evaluation, including the basolateral amygdala (BLA), the site of threat learning, and the infralimbic (IL) and prelimbic (PL) cortices. Elegant work in control reared animals have shown that these regions are late maturing and in adult animals these regions have been shown to be highly sensitive to stress. In recent work, we and other have found that ELS can drive precocious emergence of some forms of threat-associated learning. However, the extent of ELS effects on regional maturation, connectivity, and behavioral development are still not known. By investigating developmental process, we have the potential to identify novel effects of ELS on the maturation and assembly of this brain circuit, and to understand how altering timing of key neurodevelopmental events may impact the development of threat assessment and risk for later stress-related pathology. In AIM 1, we will determine the effects of stress genetic and histological markers of maturation, including connectivity between BLA, IL and PL. In AIM 2 we will test the hypothesis that ELS alters the developmental profile of threat associated learning and emergence of anxiety-like behavior. In AIM 3, we will test the specific prediction that ELS drives asymmetrical cortico-limbic maturation, resulting in a developmental disruption in the ability express threat-associated learning, with implications for risk for later emotional disturbance. Through the lens of ELS, the broad intellectual significance of this work is in its promise for informing the mechanisms driving risk for pathology and the impact of the environment on brain and behavioral development. The questions addressed here are relevant to a broad scientific audience and also have immediate impact on the development of translational programming aimed at identifying factors mediating risk and resilience in children and animals exposed to early adversity.

抽象的' ！ 早期生活压力（ELS）显着增加情绪障碍和情感病理的风险。六十- 百分之四的人在童年时期会经历至少一种重大压力源，而这一单一不利因素 事件会使一生中患恐慌症、抑郁症或焦虑症的风险增加约 30%。体验中 三个或三个以上的早期生活压力源会使终生患压力相关病理的风险加倍。单独焦虑症 美国人民每年损失约 420 亿美元，约占 148 美元总额的三分之一 十亿美元用于心理健康。此外，据世界卫生组织称，疾病负担 该国的神经精神疾病超过任何其他疾病，甚至是其他国家的两倍 心血管疾病和焦虑症对全球心理健康构成最大威胁。在美国 近 29% 的人一生中会患上某种形式的焦虑症。尽管背负着巨大的负担 对于与压力相关的疾病，人们对病理学的神经生物学基础知之甚少 发展。对于许多人来说，后来情绪困扰的根源可能在于发展和长期的改变。 调节情绪反应和威胁评估的皮质边缘回路的功能，包括 基底外侧杏仁核（BLA），威胁学习的部位，以及边缘下（IL）和边缘前（PL）皮质。 对对照饲养动物的优雅研究表明，这些区域在成年动物中晚熟 这些区域已被证明对压力高度敏感。在最近的工作中，我们和其他人发现 ELS 可以推动某些形式的威胁相关学习的提前出现。然而，ELS 的范围 对区域成熟度、连通性和行为发展的影响仍不清楚。通过调查 发育过程中，我们有潜力识别 ELS 对成熟和组装的新影响 的大脑回路，并了解改变关键神经发育事件的时间可能如何影响 发展威胁评估和后期压力相关病理学的风险。在 AIM 1 中，我们将确定 应激遗传和成熟组织学标记的影响，包括 BLA、IL 和 PL 之间的连接。 在 AIM 2 中，我们将检验以下假设：ELS 改变威胁相关学习的发展概况 出现类似焦虑的行为。在AIM 3中，我们将测试ELS驱动非对称的具体预测 皮质边缘成熟，导致表达威胁相关能力的发育障碍 学习，对以后情绪困扰的风险有影响。通过 ELS 的镜头，广泛的 这项工作的学术意义在于它有望为病理学风险驱动机制提供信息 以及环境对大脑和行为发展的影响。这里解决的问题是 与广大科学受众相关，并对转化研究的发展产生直接影响 旨在确定影响早期暴露于环境的儿童和动物的风险和复原力的因素的规划 逆境。