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

Award Number: K01MH139990
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $717,688 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	1	3/19/2026	NEW	$717,688
														Subtotal = $717,688

Grand Total All Awards = $717,688

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

Award Number: K01MH139990

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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