Role of gestational hypoxia in maternal brain health

PROJECT SUMMARY
Gestational sleep apnea affects 26% of pregnant women and is associated with an increased risk of
developing perinatal cognitive and psychosocial dysfunction. Recent studies have revealed the long-lasting
effects of healthy pregnancy on the structure and function of the maternal brain. Yet, the mechanisms by which
gestational hypoxia, a characteristic of gestational sleep apnea, affects the structure and function of the
maternal brain during pregnancy and postpartum are poorly understood. My long-term goal is to build an
independent academic career focused on immunological mechanisms contributing to pregnancy-associated
cognitive deficits, psychosocial dysfunction, and increased dementia risk. This proposal aims to determine the
role of proinflammatory responses in gestational hypoxia-induced maternal neurobiological and behavioral
changes throughout pregnancy and postpartum. The proposed studies will test the central hypothesis that
gestational hypoxia contributes to maternal neuroinflammation, which mediates cognitive and
psychosocial dysfunction that persists postpartum. During the mentored phase, we will use a preclinical
rat model of gestational sleep apnea-associated intermittent hypoxia to determine the effects of gestational
hypoxia on 1) maternal cognitive and psychosocial function during pregnancy (Aim 1) and 2) the contribution
of maternal hippocampal proinflammatory responses to neuronal dysfunction using hippocampal-specific
knockdown of receptors for the master regulator of proinflammatory responses, TNF-α (Aim 2). The mentored
phase will consist of critical training in rodent behavior analyses and advanced neuroanatomical techniques, as
well as quarterly meetings with my Advisory Committee and career development experiences that are
necessary for transitioning to an independent academic position. In the independent phase (Aim 3), I will
determine the effects of gestational hypoxia on long-term neuroinflammation contributing to persistent maternal
cognitive and psychosocial dysfunction. Using our rat model of gestational intermittent hypoxia, I will
characterize maternal cognitive and psychosocial function alongside maternal brain immune cell activation,
polarization, and function through two months post-pregnancy. Furthermore, I will continue to meet with my
Advisory Committee throughout the independent phase to ensure success as a junior faculty. Overall,
successful completion of the proposed studies will establish the contribution of gestational hypoxia-induced
proinflammatory responses to pregnancy-associated cognitive and psychosocial function and will launch my
independent academic career focused on maternal brain health throughout the lifespan. I am positioned in the
ideal environment for the proposed research and my career development, as my mentors harbor the technical
expertise, successful mentoring backgrounds, and established collaborations alongside state-of-the-art
resources at UNTHSC. This stimulating academic environment at UNTHSC and commitment of my mentors
empower my successful transition to an independent tenure-track academic research position.

Grant Number: 5K99HD115156-02
NIH Institute/Center: NIH
Principal Investigator: Jessica Bradshaw