Sex differences in brain in response to midlife stress linked to fetal stress exposures

Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later. Jill M. Goldstein et al. Proceedings of the National Academy of Sciences, April 13, 2021 118 (15) e2014464118. https://doi.org/10.1073/pnas.2014464118

Significance: Clinical research and animal models have demonstrated a significant connection between maternal stress during pregnancy and sensitivity to stress in offspring, leading to increased susceptibility to neuropsychiatric disorders later in life. In a unique prenatal cohort that was followed for over four decades, we tested associations between pro- and anti-inflammatory markers in maternal prenatal sera and sex differences in neural responses to negative stress in the offspring in early midlife using functional MRI. Men and women exposed in utero to abnormal levels of pro-inflammatory cytokines and to an imbalance of pro- to anti-inflammatory influences showed dysregulation of stress response circuitry 45 y later, with sex-dependent effects.

Abstract: Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring’s risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-α levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-α:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.

Keywords: prenatal immune programmingprenatal stressstress circuitrysexfunctional brain imaging

Press release: Sex differences in brain in response to midlife stress linked to fetal stress exposures --- Exposure to inflammatory substances in the womb due to prenatal stress differentially affects stress circuitry function in male and female offspring, which is retained into midlife. https://www.eurekalert.org/pub_releases/2021-04/mgh-sdi040121.php