Central networks, peripheral factors, and individual vulnerability to postpartum mood disorder

Nearly 70% of women experience some sadness, anhedonia or other mood disturbances in the weeks following the birth of a child [1,2]. Unfortunately, 15-20% of women may continue to develop more severe, persistent symptoms known as postpartum depression (PPD). Postpartum Depression is one of the most common complications of childbearing, and suicide is one of the leading causes of death in new mothers in the United States - indicating that doctors may be unable to identify, diagnose or effectively treat PPD within the relatively short timeframe that it emerges [3,4]. Sadly, PPD is also associated with poor attachment and poor interactions with infants during the first year of their life, an effect that can have significant lifelong consequences for these babies [5]. Despite the significance of this problem, the exact mechanisms that precipitate changes in postpartum mood are still largely unknown. Our lab has taken a novel approach to this problem. We have identified an individual vulnerability to postpartum anhedonia in rats, which we have replicated across multiple cohorts. In our model, a tertile split of postpartum sucrose preference reveals unique subsets of dams with associated differences in postpartum behaviors. Specifically, 30% of the new moms exhibit significant and persistent postpartum anhedonia in a sucrose preference test, which we have identified as susceptible dams. In contrast, approximately 40% of the new moms continue to exhibit a strong preference for the sucrose solution, identified as our resilient dams. There is another 30% of dams that show transient postpartum anhedonia. Interestingly, the susceptible dams also exhibit increased anxiety in the elevated plus maze, deficits in novelty suppressed feeding, and deficits in maternal care and motivation. The susceptible dams exhibit behaviors that are similar to the symptoms of PPD in women, providing face validity to our model. The goal of these experiments is to leverage this unique model to test the hypothesis that allopregnanolone differentially affects the expression of GABAergic receptor subunit expression in the brain across pregnancy and postpartum in susceptible and resilient dams. In turn, this differentially affects the well-known changes in neural connectivity that occur in postpartum women, but are deficient in women with PPD. We can test this hypothesis by examining the effects and underlying mechanisms of allopregnanolone in our model, both during pregnancy and postpartum as a therapeutic. Allopregnanolone drugs (e.g. zuranolone) are extremely efficacious in treating PPD, but their mechanism of action is completely unknown, and their costs are prohibitive. Our goals are to (1) identify translatable peripheral or neural network biomarkers that could predict or help rapidly identify the risk for postpartum depression in new mothers, and (2) identify the molecular mechanisms associated with the risk and the etiology of postpartum mood disorder that might provide novel therapeutic targets intended for many women suffering from postpartum mood disorders during this unique and sensitive period of their lives.