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.

• MeSH
• cytokiny krev   MeSH
• dospělí MeSH
• hypothalamus diagnostické zobrazování   MeSH
• konektom * MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• psychický stres diagnostické zobrazování   MeSH
• sexuální faktory MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice diagnostické zobrazování   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Cardiac autonomic dysregulation has been implicated in the comorbidity of major psychiatric disorders and cardiovascular disease, potentially through dysregulation of physiological responses to negative stressful stimuli (here, shortened to stress response). Further, sex differences in these comorbidities are substantial. Here, we tested the hypothesis that mood- and sex-dependent alterations in brain circuitry implicated in the regulation of the stress response are associated with reduced peripheral parasympathetic activity during negative emotional arousal. Fifty subjects (28 females) including healthy controls and individuals with major depression, bipolar psychosis and schizophrenia were evaluated. Functional magnetic resonance imaging and physiology (cardiac pulse) data were acquired during a mild visual stress reactivity challenge. Associations between changes in activity and functional connectivity of the stress response circuitry and variations in cardiovagal activity [normalized high frequency power of heart rate variability (HFn)] were evaluated using GLM analyses, including interactions with depressed mood and sex across disorders. Our results revealed that in women with high depressed mood, lower cardiovagal activity in response to negative affective stimuli was associated with greater activation of hypothalamus and right amygdala and reduced connectivity between hypothalamus and right orbitofrontal cortex, amygdala, and hippocampus. No significant associations were observed in women with low levels of depressed mood or men. Our results revealed mood- and sex-dependent interactions in the central regulation of cardiac autonomic activity in response to negative affective stimuli. These findings provide a potential pathophysiological mechanism for previously observed sex differences in the comorbidity of major depression and cardiovascular disease.

• MeSH
• amygdala MeSH
• depresivní porucha unipolární * MeSH
• hipokampus MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• mozek diagnostické zobrazování   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH