Early life stress effects on threat-learning

摘要 ! 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%的人在童年时会经历至少一个重大的压力源，而这一单一的不利因素 事件使恐慌症、抑郁症或焦虑症的终生风险增加约30%。经历 三个或更多的早期生活压力源使与压力有关的病理学的终生风险加倍。仅焦虑症 美国人民每年花费约420亿美元，约占148美元的三分之一。 10亿美元用于心理健康。此外，根据世界卫生组织， 神经精神疾病在该国超过任何其他医疗条件，甚至两倍， 心血管疾病和焦虑症对全世界的精神健康构成最大威胁。在美国 近29%的人在一生中会患上某种形式的焦虑症。尽管有巨大的负担 对于与压力相关的疾病，关于病理学的神经生物学基础知之甚少 发展对许多人来说，后期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），威胁学习的部位，以及边缘下（IL）和边缘前（PL）皮质。 在控制饲养动物中的优雅工作表明，这些区域是晚熟的，并且在成年动物中 这些区域已经显示出对应力高度敏感。在最近的工作中，我们和其他人发现， ELS可以促使某些形式的威胁相关学习过早出现。然而，ELS的范围 对区域成熟、连通性和行为发展的影响尚不清楚。通过调查 发展过程中，我们有可能确定新的影响ELS的成熟和组装 为了了解改变关键神经发育事件的时间可能会如何影响大脑回路， 发展威胁评估和以后与压力有关的病理风险。在AIM 1中，我们将确定 应激遗传和成熟的组织学标志物的影响，包括BLA、IL和PL之间的连接。 在AIM 2中，我们将测试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驱动不对称的特定预测 皮质-边缘系统成熟，导致表达威胁相关神经元的能力发育中断。 学习，并对以后的情绪障碍风险产生影响。通过ELS的透镜， 这项工作的智力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育的影响。这里要解决的问题是 与广泛的科学受众有关，也对翻译的发展产生直接影响。 旨在确定因素介导的风险和恢复力的儿童和动物暴露在早期 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.