Social stress in adolescent females and the brain norepinephrine system.

描述（由申请人提供）：情感障碍和焦虑相关障碍发生率的性别差异是公认的，这些差异出现在青春期。例如，在青少年和成年人中，抑郁和压力生活事件之间有很强的联系，压力生活事件通常在抑郁发作之前发生。因此，应激反应系统如蓝斑-去甲肾上腺素（LC-NE）和下丘脑-垂体-肾上腺（HPA）轴的成熟和性别分化与青春期情感障碍和焦虑障碍发生率的性别差异的出现是一致的，这并不奇怪。青春期女孩对同伴压力更敏感，这种敏感性的增加可能会使女性随着年龄的增长更容易患上情感障碍。然而，关于青春期的社会压力源如何影响在情感和焦虑障碍中改变的压力调节系统，我们知之甚少。在初步数据中，我们观察到成年雌性大鼠在青春期社会隔离后表现出神经内分泌对应激的高反应性，并伴有特定神经基质的变化。这些数据表明，青春期的社会隔离对成人应激反应和与应激相关的神经基质具有持久和性别特异性的影响。本研究拟研究青春期社会隔离应激对成年雌性大鼠LC-NE功能的影响。LC-NE系统介导的唤醒和注意过程在情感和焦虑障碍中被根本破坏。因此，青春期压力对该系统的持久影响可能导致成年女性普遍存在的精神疾病。本应用的中心假设是，青春期社会隔离的压力会在成年雌性大鼠的LC-NE系统中产生持久的变化，从而使其被紧张性激活（特异性目标1）和/或对压力反应过度（特异性目标2）。在这些特定目的中，我们将记录未麻醉的自由活动的成年雌性大鼠的LC活动。我们进一步假设了CRF在调节LC活性中的关键作用。在Specific Aim 3中，我们将检查向LC提供CRF传入输入的脑区域中的CRF mRNA和LC中的CRF受体蛋白，以确定青春期隔离如何改变成年女性LC中的CRF传入和受体。因此，我们提出的实验将确定女性青少年时期事件调节应激反应的潜在机制，从而增强我们对觉醒和注意过程的神经机制的理解，这些神经机制是女性表现出更高比率的压力相关精神疾病的关键组成部分。

DESCRIPTION (provided by applicant): Gender differences in rates of affective and anxiety-related disorders are well-established and these differences emerge in adolescence. In both adolescents and adults, there is a strong link between depression and stressful life events with a stressful life event often preceding an episode of depression, for example. So, it is not surprising that the maturation and sexual differentiation of stress-responsive systems such as the locus coeruleus-norepinephrine (LC-NE) and hypothalamic-pituitary-adrenal (HPA) axis coincides with the emergence of gender differences in rates of affective and anxiety disorders in adolescence. Adolescent girls are more sensitive to peer stress and this increased sensitivity may make females more vulnerable to developing affective disorders as they age. However, little is known about how social stressors in adolescence can impact stress-regulatory systems that are altered in affective and anxiety disorders. In preliminary data, we observed that adult female rats exhibited neuroendocrine hyperresponsiveness to stress in adulthood after adolescent social isolation and there were concomitant changes in specific neural substrates. These data suggest that social isolation during adolescence has enduring and sex-specific effects on adult stress reactivity and on stress-related neural substrates. Here, we propose to study the effects of adolescent social isolation stress on adult LC-NE function in female rats. The LC-NE system mediates arousal and attentional processes that are fundamentally disrupted in affective and anxiety disorders. Therefore, an enduring effect of adolescent stress on this system could contribute to psychiatric disorders that are prevalent in females in adulthood. The central hypothesis of this application is that the stress of social isolation during adolescence will produce an enduring change in the LC-NE system such that it is tonically activated (Specific Aim 1) and/or hyperresponsive to stress (Specific Aim 2) in adult female rats. In these Specific Aims, we will record LC activity in unanesthetized freely moving adult female rats. We further hypothesize a key role for CRF in regulating LC activity. In Specific Aim 3, we will examine CRF mRNA in brain regions providing CRF afferent inputs to the LC and CRF receptor protein in the LC to determine how isolation during adolescence changes CRF afferents and receptors in the LC in adult females. Thus, the proposed experiments will identify potential mechanisms by which LC responsivity to stress are regulated by events in adolescence in females thereby enhancing our understanding of the neural mechanisms underlying arousal and attentional processes that are key components of stress-related psychiatric illness that are exhibited in higher rates by females. PUBLIC HEALTH RELEVANCE: Women have higher rates of depression and anxiety than men and these higher rates are first seen in adolescence and both depression and anxiety can be precipitated by stress. In this application, we will use female rats to examine how social stress in adolescence changes activity and function in a neural system that has been implicated in stress-related affective disorders. The results of these studies will help our understanding of the relationship between stress and depression and anxiety in women.