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，抑郁症和应激性生活事件之间都有很强的联系，例如，应激性生活事件往往发生在抑郁症发作之前。因此，青春期青春期情感障碍和焦虑障碍发生率的性别差异与蓝斑-去甲肾上腺素(LC-NE)和下丘脑-垂体-肾上腺(HPA)轴等应激反应系统的成熟和性别分化相吻合也就不足为奇了。青春期的女孩对同伴的压力更敏感，这种增加的敏感性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情感障碍和焦虑症中改变的压力调节系统，人们知之甚少。在初步数据中，我们观察到成年雌性大鼠在青春期社交隔离后，成年后表现出对应激的神经内分泌高反应，并伴随着特定神经底物的变化。这些数据表明，青春期的社交隔离对成人的应激反应和与应激相关的神经底物具有持久的性别特异性影响。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。在情感性和焦虑症中，LC-NE系统调节从根本上被破坏的唤醒和注意过程。因此，青春期压力对这一系统的持久影响可能会导致成年后女性普遍存在的精神障碍。这一应用的中心假设是，青春期的社会隔离压力将在LC-NE系统中产生持久的变化，从而使成年雌性大鼠的LC-NE系统被张力激活(特定目标1)和/或对应激反应过度(特定目标2)。在这些特定的目标中，我们将记录未麻醉的成年自由活动雌性大鼠的LC活动。我们进一步假设CRF在调节LC活性中起关键作用。在具体目标3中，我们将检测为LC提供CRF传入输入的大脑区域中的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，拟议的实验将确定LC对压力的反应受女性青春期事件调节的潜在机制，从而增强我们对唤醒和注意过程潜在的神经机制的理解，这些过程是与压力相关的精神疾病的关键组成部分，女性表现出较高的发病率。 与公共健康相关：女性抑郁和焦虑的发生率比男性更高，这些更高的比率首次出现在青春期，抑郁和焦虑都可以由压力引发。在这项应用中，我们将使用雌性大鼠来研究青春期的社会压力如何改变神经系统的活动和功能，神经系统与应激相关的情感障碍有关。这些研究的结果将有助于我们理解女性压力与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.