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.