Neural circuit mechanisms underlying postpartum social cognitive impairment induced by adolescent stress

About This Grant

PROJECT SUMMARY/ABSTRACT Early life stress (ELS) significantly increases the risk of postpartum psychiatric conditions, especially cognitive impairment. Given the time gap between ELS events and the postpartum period, identifying high-risk individuals with ELS and intervening early appears feasible. However, understanding this longitudinal relationship through human studies alone is challenging, necessitating animal models. Most animal studies on postpartum psychiatric disorders focus on behavioral changes after hormone injections, neglecting the pathological trajectory from ELS to postpartum cognitive impairment. To address this, we developed a new mouse model to explore how ELS affects postpartum behaviors. In our model, female mice exposed to mild social isolation during late adolescence (SILA) do not show increased levels of plasma corticosterone (CORT) or significant behavioral changes. Pregnancy/delivery alone do not lead to notable abnormalities. Notably, by postpartum day (PD) 7, mice exposed to SILA exhibit behavioral changes related to mood, social cognition, and parenting only when combined with pregnancy and delivery. SILA dams also exhibit elevated and sustained plasma corticosterone (CORT) levels, mirroring those in postpartum depression patients. While CORT levels in SILA and non-SILA dams are similar in late pregnancy, SILA dams show higher levels from PD 0, persisting for at least three weeks postpartum, aligning with long-lasting behavioral changes. Blocking glucocorticoid receptors (GR) during the first postpartum week improves SILA dams’ behavior, highlighting CORT’s role in ELS-associated postpartum changes. Our proposal will use this new mouse model to functionally and transcriptionally investigate how enhanced and sustained levels of plasma CORT alter neuronal function and lead to behavioral deficits in the first postpartum week, focusing on social novelty recognition. Our preliminary data suggest that removing GR expression or optogenetically activating the glutamatergic neuronal projections from the anterior insula to the prelimbic cortex (AIPrL glutamatergic pathway) can ameliorate deficits in social novelty recognition observed in SILA dams. CORT influences gene transcription via GR, a nuclear receptor acting as a transcriptional activator and suppressor. Thus, we hypothesize that continuous GR activation by CORT during the initial postpartum week disrupts the transcriptional regulation in the AIPrL glutamatergic pathway, reduces their synaptic activities in PrL, and consequently impairs social novelty recognition in stressed dams. This study will determine how CORT affects the AI-PrL glutamatergic pathway via GR in stressed dams, elucidate the molecular mechanisms involved, and evaluate the impact on social novelty recognition and other behaviors. The findings aim to explain how adolescent psychosocial stress leads to social cognition deficits in mothers, guide interventions to mitigate these effects, and provide crucial insights into postpartum social behavior impairments affecting mothers, their children, and families.