Early life stress effects on threat-learning

《摘要》 好了！ 早期生活压力(ELS)显著增加了情绪障碍和情感病理的风险。六十- 4%的人会在童年经历至少一个显著的压力源，而这个单一的不利因素 这一事件会使患恐慌症、抑郁症或焦虑症的终生风险增加约30%。体验 三个或三个以上的早期生活应激源会使压力相关疾病的终生风险增加一倍。仅焦虑症 美国人每年花费约420亿美元，约占总数148美元的三分之一 在心理健康上花费了10亿美元。此外，根据世界卫生组织的数据，疾病对 这个国家的神经精神障碍超过了任何其他疾病，甚至是美国的两倍 心血管疾病和焦虑症是全世界精神健康的最大威胁。在美国 近29%的人会在一生中患上某种形式的焦虑症。尽管有巨大的负担 在应激相关的障碍中，人们对病理的神经生物学基础知之甚少。 发展。对许多人来说，后来情绪障碍的根源可能在于发育的改变和长期的 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)，威胁学习的场所，以及下缘(IL)和前额叶(PL)皮质。 在控制饲养动物方面的优雅研究表明，这些区域是成熟较晚的成年动物。 这些区域已被证明对压力高度敏感。在最近的研究中，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早熟出现。然而，ELS的程度 对区域成熟、连通性和行为发育的影响尚不清楚。通过调查 在发育过程中，我们有可能发现ELS对成熟和组装的新影响 并了解改变关键神经发育事件的时间可能如何影响 未来应激相关病理学的威胁评估和风险的发展。在目标1中，我们将确定 应激对成熟的遗传和组织标志的影响，包括BLA、IL和PL之间的连通性。 在目标2中，我们将检验ELS改变威胁相关学习的发展概况的假设 出现类似焦虑的行为。在AIM 3中，我们将测试ELS驱动不对称的具体预测 皮质-边缘成熟，导致表达威胁相关能力的发育中断 学习，以及对后来的情绪困扰的风险。透过ELS的镜头，宽阔的 这项工作的学术意义在于它有望揭示导致病理风险的机制。 以及环境对大脑和行为发育的影响。这里要解决的问题是 与广泛的科学受众相关，并对翻译的发展产生直接影响 旨在确定影响儿童和动物早期接触的风险和复原力的因素的规划 逆境。

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.