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ID 21427 Poster Board 16Postpartum depression (PPD) affects up to 20% of mothers yet remains understudied. Mitochondria are dynamic organelles that are crucial for cell homeostasis and share a link with many of the proposed mechanisms underlying PPD pathology. The brain relies on mitochondrial energy production to function, and stress, a major risk factor for PPD, amplifies brain energy demands. In turn, brain mitochondrial function is also affected by stress and linked to anxiety-like and social behaviors. We recently found that gestational stress in rats decreased mitochondrial complex I respiration in the prefrontal cortex (PFC) in association with depressive-like behaviors. We hypothesized that enhancing complex I respiration during stress exposure would prevent these stress-induced PPD-relevant behaviors. Nulliparous and time-mated adult female Wistar rats received nicotinamide (NAM, a NAD+ precursor that stimulates complex I respiration, 3mM) or vehicle (VEH) in the drinking water from gestational day 8-21. On gestational day 10, females were exposed to 10 consecutive days of chronic mild unpredictable stress or handling (CON). Sucrose preference, maternal care, anxiety-like and passive coping behaviors were assessed from postpartum day 2 (PD2) -PD10. Rats were euthanized on PD11, and the PFC was extracted and assessed for mitochondrial respiration. Gestational stress significantly decreased postpartum sucrose preference and maternal care, which was prevented by NAM. Notably, these data suggest that targeting complex I respiration may be a viable approach to prevent behavioral features of PPD in the face of stress. Because stress increases the risk of PPD in women, which is associated with cardiovascular risk, we also explored the effects of stressors on cardiometabolic measures during an in-person lab visit in a preliminary study of postpartum women. Perinatal stress load was calculated from demographic, risk factors, and pregnancy experience to serve as a PPD risk score. Women with higher stress loads had lower resistance vessel endothelial function and higher BMI. Taken together, our preclinical data point to an active role for PFC mitochondrial function in gestational stress-induced PPD-relevant behaviors. Further, these animal and human studies highlight stress as a key mediator of postpartum health, and animal studies suggest mitochondria as a potential protective therapeutic target.

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Postpartum depression (PPD) is a major psychiatric complication of childbirth, affecting up to 20% of mothers, yet remains understudied. Mitochondria, dynamic organelles crucial for cell homeostasis and energy production, share links with many of the proposed mechanisms underlying PPD pathology. Brain mitochondrial function is affected by stress, a major risk factor for development of PPD, and is linked to anxiety-like and social behaviors. Considering the importance of mitochondria in regulating brain function and behavior, we hypothesized that mitochondrial dysfunction is associated with behavioral alterations in a chronic stress-induced rat model of PPD. Using a validated and translationally relevant chronic mild unpredictable stress paradigm during late gestation, we induced PPD-relevant behaviors in adult postpartum Wistar rats. In the mid-postpartum, we measured mitochondrial function in the prefrontal cortex (PFC) and nucleus accumbens (NAc) using high-resolution respirometry. We then measured protein expression of mitochondrial complex proteins and 4-hydroxynonenal (a marker of oxidative stress), and Th1/Th2 cytokine levels in PFC and plasma. We report novel findings that gestational stress decreased mitochondrial function in the PFC, but not the NAc of postpartum dams. However, in groups controlling for the effects of either stress or parity alone, no differences in mitochondrial respiration measured in either brain regions were observed compared to nulliparous controls. This decrease in PFC mitochondrial function in stressed dams was accompanied by negative behavioral consequences in the postpartum, complex-I specific deficits in protein expression, and increased Tumor Necrosis Factor alpha cytokine levels in plasma and PFC. Overall, we report an association between PFC mitochondrial respiration, PPD-relevant behaviors, and inflammation following gestational stress, highlighting a potential role for mitochondrial function in postpartum health.