Many neural programs that shape behavior become established during adolescence. Adverse events at this age can have enduring consequences for both adolescent and adult mental health. Here we show that repeated social stress at different stages of adolescent development differentially affects rat behavior and neuronal activity. Early-adolescent (PND 28, EA), mid-adolescent (PND 42, MA), and adult (PND 63) rats were subjected to resident-intruder social stress (7 days) and behavior was examined 24-72 h later. In EA rats selectively, resident-intruder stress increased proactive responses in the defensive burying and forced swim tests. In adult rats, resident-intruder stress decreased burying behavior regardless of whether the animal was stressed as an adult or during early adolescence. Because the locus coeruleus (LC)-norepinephrine system has been implicated in proactive defense behaviors, LC neuronal activity was quantified in separate cohorts. Stressed EA rats had elevated spontaneous LC discharge rates and diminished responses to sensory stimuli compared to controls. Microinjection of a CRF antagonist into the LC selectively inhibited neurons of stressed EA rats, suggesting that EA social stress induces tonic CRF release onto LC neurons, shifting the mode of discharge to an activated state that promotes active defensive behaviors. In all adult groups, resident-intruder stress resulted in an increased phasic response to sensory stimuli with no change in spontaneous rates. Mid-adolescence was a transition period during which social stress did not affect behavior or LC activity. The results suggest that social stress interacts with the brain norepinephrine system to regulate defensive strategies in an age-dependent manner.

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Early life events influence vulnerability to psychiatric illness. This has been modelled in rats and it has been demonstrated that different durations of maternal separation shape adult endocrine and behavioural stress reactivity. One system through which maternal separation may act is the locus coeruleus (LC)–norepinephrine system that regulates emotional arousal. Here we demonstrate that different durations of maternal separation have distinct effects on LC physiology and dendritic morphology. Rat pups were separated from the dam for 15 min/d (HMS-15) or 180 min/d (HMS-180) from post-natal days 2–14. Others were either undisturbed (HMS-0) or were vendor-purchased controls. LC characteristics were compared at age 22–35 d using whole-cell recordings in vitro. Cells were filled with biocytin for morphological analysis. LC neurons of HMS-180 rats were tonically activated compared to HMS-15 and control rats, with firing rates that were 2-fold higher than these groups. Corticotrophin-releasing factor (CRF) application did not further activate LC neurons of HMS-180 rats but increased LC firing rate in HMS-0 and control rats. LC neurons of HMS-15 rats were resistant to excitation by CRF. Maternal separation also affected LC dendritic morphology. LC dendrites of HMS-15 rats exhibited less branching and decreased total dendritic length, an effect that could decrease the probability of contacting limbic afferents that terminate in the pericoerulear region. This effect may provide a structural basis for an attenuated magnitude of emotional arousal. Together, these results demonstrate long-term consequences of early life events on the LC–norepinephrine system that may shape adult behaviour.

Exposure to psychological trauma is the precipitating factor for PTSD. In addition, a history of chronic or traumatic stress exposure is a predisposing risk factor. We have developed a Chronic plus Acute Prolonged Stress (CAPS) treatment for rats that models some of the characteristics of stressful events that can lead to PTSD in humans. We have previously shown that CAPS enhances acute fear responses and impairs extinction of conditioned fear. Further, CAPS reduced the expression of glucocorticoid receptors in the medial prefrontal cortex. In this study we examined the effects of CAPS exposure on behavioral stress coping style, anxiety-like behaviors, and acute stress reactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Male Sprague-Dawley rats were exposed to CAPS treatment, consisting of chronic intermittent cold stress (4°C, 6hrs/day, 14 days) followed on day 15 by a single 1-hr session of sequential acute stressors (social defeat, immobilization, swim). After CAPS or control treatment, different groups were tested for shock probe defensive burying, novelty suppressed feeding, or evoked activation of adrenocorticotropic hormone (ACTH) and corticosterone release by an acute immobilization stress. CAPS resulted in a decrease in active burying behavior and an increase in immobility in the shock probe test. Further, CAPS-treated rats displayed increases in the latency to feed in the novelty suppressed feeding test, despite an increase in food intake in the home cage. CAPS treatment also reduced the HPA response to a subsequent acute immobilization stress. These results further validate CAPS treatment as a rat model of relevance to PTSD, and together with results reported previously, suggest that CAPS impairs fear extinction, shifts coping behavior from an active to a more passive strategy, increases anxiety, and alters HPA reactivity, resembling many aspects of human PTSD.

Organizations that fund research to address global development challenges are increasingly interested in measuring the social and economic outcomes of research. However, traditional metrics for measuring research outputs are often insufficient for capturing the outcomes targeted by international assistance organizations. To address this, the Center for Development Research (CDR), part of the U.S. Global Development Lab at the United States Agency for International Development (USAID), has designed a new tool: the Program and Policy Change (PPC) framework for tracking and quantifying the influence of research on program and policy change in international development. The framework draws on existing conceptual frameworks of evidence uptake and the literature on policy change. This article describes the design of the PPC framework and presents the results of applying the framework to two USAID research programs. The benefits of the framework include applicability across research sectors, focus on evidence-informed policy at various levels of geographical influence, and inclusion of a numeric scoring system that enables quantification of outcomes.

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The research goal was to determine whether social stress differentially impacts on behavior and brain physiology during critical windows in adolescent development. Early adolescent (EA), mid‐adolescent (MA) and adult rats were exposed to 7 days of a social stressor, the resident‐intruder paradigm. Social stress had divergent effects on behavior in EA and adult rats, promoting active coping behaviors in EA rats and decreasing active coping behaviors in adult rats as determined by the defensive burying test and response to swim stress. Mid‐adolescent rats exposed to social stress showed no changes in the behavioral endpoints. Effects of social stress in EA rats was not mimicked by chronic restraint stress. Because the locus coeruleus (LC)‐norepinephrine system has been implicated in certain active coping behaviors, LC neuronal activity was recorded in EA rats exposed to social stress and matched controls. LC spontaneous firing rates were higher in EA rats exposed to social stress. Moreover, intra‐LC infusion of the CRF antagonist, DPheCRF12‐41, inhibited LC neurons of stressed rats but not controls. These data suggest that exposure to social stress in early adolescence promotes tonic secretion of CRF into the LC to activate this system. This CRF‐induced activation of the LC‐norepinephrine system may underlie the promotion of active‐coping behaviors noted in socially stressed EA rats.MH058250