Gestational witness stress impacts postpartum brain, behavior, and cardiovascular health in Wistar female rats

Background: Maternal mortality in the United States is the highest of any industrialized country and is increasing at an alarming rate, with cardiovascular disease (CVD) and mental health as leading causes. A bidirectional relationship exists between CVD and postpartum mental health, including postpartum depression (PPD), where PPD patients exhibit a 70% increased risk of developing CVD in the 5 years after delivery compared with mothers without PPD. Stress exposure is a risk factor for both PPD and CVD. Moreover, partner-associated violence and trauma are common social stressors experienced during pregnancy and most significantly associated with maternal morbidity. Mitochondria are dynamic organelles that are crucial in energy production, inflammation, and the stress response. We have previously identified a role for brain mitochondrial function in postpartum behavioral health; however, mechanisms that link psychosocial stress-induced CVD and PPD are virtually unknown. The objective of this study was to examine the effects of gestational psychosocial stress on postpartum cardiac and neurological health. Hypothesis: Gestational witness stress will decrease mitochondrial function in the prefrontal cortex in association with cardiac stress and PPD-relevant behaviors in postpartum female rats. Methods: Time-mated adult female Wistar rats and virgin females were separated into stress and control groups. Virgin females were yoked to pregnant counterparts for all experimental manipulations. Stressed groups were exposed to 5 consecutive days of witness stress, a modified social defeat paradigm where a female observes social defeat from a protected compartment of the aggressive resident’s cage, on gestational days 8-12. Following parturition, postpartum maternal care, avoidance behavior, and sucrose preference were assessed. Cardiac function and geometry were assessed using echocardiography on postpartum days 14 and 22. Females were euthanized on postpartum days 23-25 and mitochondrial respiration was assessed in prefrontal cortex, hypothalamus, and heart homogenates using high-resolution respirometry. Results: Gestational witness stress significantly decreased maternal care (t=3.1, df=15, p=0.008) and sucrose preference (F(1,32) = 4.9, p=0.03), and increased avoidance behavior (F (1,33) = 3.7, p=0.06) relative to non-pregnant control females. There was a main effect of parity to reduce heart rate (F (1,12) = 15.6, p=0.001) and increase stroke volume (F (1,12) = 9.5, p=0.009) in the mid-postpartum. Gestational witness stress blunted stroke volume (F (1, 18) = 5.1, p=0.03) in the late postpartum and increased left atrial area (F(1,17)=5.0, p=0.01). There was a main effect of witness stress to decrease mitochondrial respiration in the prefrontal cortex, but not the heart (F (1, 11) = 0.02, p=0.88) or hypothalamus (F (1, 24) = 0.1, p=0.75). Conclusions: These data highlight dynamic long-term effects of gestational witness stress on the postpartum brain, heart, and behavior possibly linked to mitochondrial function. This work was supported by P20GM109091, 1U54HL169191-01, and BX006218-02 (F.H.), R01HL130972-01A1, R01HL5949, BX005320-01A1, BX000168-10A1 (F.G.S.), BX005661 (SKW). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.