Sex-specific effects of chronic unpredictable stress on mitochondrial function in the HPA axis

Abstract

Background: Stress is a real or perceived threat that elicits physiological and behavioral responses via activation of innate response mechanisms like the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS). Mitochondria are dynamic organelles responsible for providing cellular energy and the synthesis and release of glucocorticoids from the adrenal glands in response to stress. Thus, mitochondria represent the first line of response to environmental challenges, however, the effects of chronic stress on mitochondrial function in the HPA axis, particularly with respect to sex differences, are relatively unexplored. Hypothesis: Chronic unpredictable stress (CUS) induces mitochondrial dysfunction in key brain regions within the HPA axis.Methods: Adult male and female C57Bl6/J mice were exposed to 28 consecutive days of CUS or handling (CON) with weekly weighing. During the last week of stress, anxiety-like behavior was evaluated using the elevated plus maze and open field tests and coping behavior was assessed using the forced swim test. Mice were euthanized and the brain and adrenal glands dissected, weighed, and mitochondrial function was assessed using high resolution respirometry in hypothalamus, amygdala, and adrenal tissues. Results: CUS exposure decreased total body weight gain by 53% (p=0.04) and increased anxiety-like behavior (p=0.01) in stressed males compared to controls but had no effect on female weight or anxiety-like behavior. Stressed males and females both exhibited 46% decreased latency to immobility in the forced swim test (p=0.0001). CUS induced significant sex-dependent decreases in mitochondrial respiration within key stress centers, with stressed males exhibiting decreased respiration in the amygdala (20%, p=0.05), and stressed females exhibiting decreased respiration in the hypothalamus (20%, p=0.004) and adrenal glands (17%, p=0.06). Co nclusions: The unique findings of this study identified sex dependent CUS effects on HPA axis mitochondrial function. These observations suggest targeting mitochondria as a therapeutic strategy against stress-related pathologies. This work was supported by a NIH grants P20GM109091 (F.H.), R01HL130972-01A1 (F.G.S.), R01HL5949 (F.G.S.), RO1DK132948 (C.W. & F.P.) and R01 MH129798 (SKW); VA grants: VISN7 RDA (F.H.), Merit awards: BX000168-10A1 (F.G.S.), BX005320 (F.G.S.), & BX002604 (M.J.R.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the abstract. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.