Social stress in adolescent females and the brain norepinephrine system.

描述（由申请人提供）：情感和焦虑相关障碍的性别差异是公认的，这些差异出现在青春期。在青少年和成年人中，抑郁症和压力性生活事件之间有很强的联系，例如，压力性生活事件通常发生在抑郁症发作之前。因此，压力反应系统（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和焦虑障碍发生率的性别差异相一致，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使女性更容易随着年龄的增长而发展为情感障碍。然而，人们对青春期的社会压力源如何影响情感障碍和焦虑障碍中改变的压力调节系统知之甚少。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对成年期应激的神经内分泌高反应性，并且伴随着特定神经基质的变化。这些数据表明，在青春期的社会隔离有持久的和性别特异性的影响，对成人的压力反应和压力相关的神经基板。在这里，我们建议研究青少年社会隔离应激对成年雌性大鼠LC-NE功能的影响。LC-NE系统介导唤醒和注意力过程，这些过程在情感和焦虑障碍中被根本性地破坏。因此，青春期压力对这一系统的持久影响可能导致成年女性中普遍存在的精神疾病。本申请的中心假设是，青春期期间社会隔离的压力将在LC-NE系统中产生持久的变化，使得其在成年雌性大鼠中被紧张性激活（特异性目的1）和/或对压力反应过度（特异性目的2）。在这些特定目的中，我们将记录未麻醉自由活动成年雌性大鼠的LC活性。我们进一步假设CRF在调节LC活性中的关键作用。在具体目标3中，我们将研究CRF mRNA在大脑区域提供CRF传入输入LC和CRF受体蛋白在LC中，以确定如何隔离在青春期改变CRF传入和受体在成年女性的LC。因此，拟议的实验将确定潜在的机制，LC对压力的反应是由女性青春期的事件来调节的，从而提高我们对唤醒和注意力过程的神经机制的理解，这些过程是压力相关精神疾病的关键组成部分，女性表现出更高的发病率。 公共卫生相关性：妇女抑郁和焦虑的比率高于男子，这些较高的比率首先出现在青春期，抑郁和焦虑都可能因压力而加剧。在这个应用程序中，我们将使用雌性大鼠来研究青春期的社会压力如何改变与压力相关的情感障碍有关的神经系统的活动和功能。这些研究的结果将有助于我们理解压力与女性抑郁和焦虑之间的关系。

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.