Projection-specific mechanisms mediating postpartum stress effects on the maternal brain

Perinatal or Postpartum Mood and Anxiety Disorders (PMADs) are leading causes of maternal morbidity and mortality, prompting great need to understand factors that influence risk. Parity, the state of having carried pregnancies to a viable gestational age, can promote positive parenting adaptations and/or increase the risk of developing PMADs, especially when compounded by chronic stress over the peripartum period. Yet, how stress and parity interact to result in long-lasting vulnerability is unknown. Therefore, the objective of this K01 proposal is to investigate the molecular and epigenetic mechanisms by which stress negatively interacts with parity programming during the critical postpartum period to influence future risk. Using a novel parity x postpartum stress mouse model, we show that parity alone leads to lasting positive adaptations in maternal and cognitive behaviors. However, the interaction of parity x postpartum stress results in increased anxiety-like phenotypes paired with loss of cognitive adaptations. Thus, we propose a framework in which parity promotes maternal brain plasticity to support behavioral adaptations, but that postpartum stress exploits this period of plasticity to induce lasting susceptibility. Using this model, we identify the dorsal hippocampus (dHpc) as a brain region exhibiting robust transcriptomic sensitivity to parity that may underlie maternal behavioral adaptations, both of which are disrupted by postpartum stress. Further, our data suggests that chronic postpartum stress dysregulates dopamine responsiveness to maternal stimuli via projections from the ventral tegmental area (VTA), underlying long-term perturbations of dHpc plasticity. Thus, under the mentorship of Dr. Ian Maze and the guidance of my Advisory Committee, I have designed three Specific Aims to address the hypothesis that epigenetic regulation of the VTA-dHpc projection alters dopamine signaling during postpartum, which in turn mediates the persistent impacts of parity and postpartum stress on maternal (mal)adaptations. In Aim 1, I will test the involvement of a putative parity-dependent transcription factor in regulating the VTA-dHpc response to postpartum stress by employing a combination of AAV viral vector strategies with transgenic mice, followed by functional and single cell epigenomic assessments. In Aim 2, I will determine the role of dHpc dopamine signaling in postpartum stress-induced acute and persistent behavioral alterations, and whether an additional pregnancy and postpartum exposure will induce maternal deficits and anxiety-like behavior during a subsequent postpartum window. In Aim 3, I will examine the involvement of the novel protein modification “dopaminylation” by using a novel chemical approach coupled with mass spectrometry to identify dopaminylated proteins that may mediate the long-term effects of parity and postpartum stress on dHpc plasticity. This research is critical for understanding how parity and stress interact to shape maternal brain health and PMAD risk, with implications for intervention strategies. Moreover, the training and career development activities in this K01 will provide the expertise and protected time I need to transition to an independent research career. Project Number: 1K01MH139990-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Jennifer Chan | Institution: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, NY | Award Amount: $717,688 | Activity Code: K01 | Study Section: Special Emphasis Panel[ZRG1 ICN-N (92)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11302028