Mitochondrial Function in the Maternal Brain: a New Perspective on Gestational Stress and Pathology of Postpartum Depression

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 avoidance 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. Chronic mild unpredictable (CMUS) stress during late gestation resulted in reduced mitochondrial respiration in the medial prefrontal cortex (mPFC) that was linked to increased inflammation and PPD-relevant behaviors, suggesting that mitochondrial dysfunction may play a vital role in postpartum mental health. Since both pregnancy and stress elicit long-term effects on the brain, we next determined whether mitochondrial dysfunction observed in the mPFC during the mid-postpartum period exists post weaning. Our findings revealed brain mitochondrial signatures in the late postpartum that were distinct from the mid-postpartum, suggesting that mitochondrial adaptations influenced by both stress and pregnancy may underlie long-term behavioral changes associated with PPD. Finally, we tested whether co-treatment of nicotinamide during gestational stress could prevent postpartum behavioral deficits by enhancing mitochondrial complex I respiration. We replicated our previous findings showing that CMUS reduced mPFC mitochondrial respiration and induced stress-specific behaviors. However, nicotinamide treatment prevented stress effects on nursing behavior and mitochondrial function, likely by modulation of complex protein expression and potential influences on peripheral inflammation and corticosterone. Overall, we demonstrated that pregnancy and stress acted both independently and dependently to induce temporal and region-specific effects on brain mitochondria that were linked to behavioral alterations. Supported by our findings, we propose that gestational stress induces brain mitochondrial dysfunction that drives behavioral deficits associated with symptoms of PPD. Future studies that delineate the precise mechanisms of mitochondrial effects on behavior will be crucial for understanding stress-related PPD pathology, and thus developing better therapeutics for treatment.