The role of the placenta-brain axis in psychoneuroimmune programming

Gestational exposures have enduring impacts on brain and neuroimmune development and function. Perturbations of pregnancy leading to placental structure/function deficits, cell stress, immune activation, and endocrine changes (metabolic, growth factors, etc.) all increase neuropsychiatric risk in offspring. The existing literature links obstetric diseases with placental involvement to offspring neuroimmune outcomes and neurodevelopmental risk. Psychoneuroimmune outcomes in offspring brain include changes to microglia, cytokine/chemokine production, cell stress, and long-term immunoreactivity. These outcomes are altered by structural, anti-angiogenic/hypoxic, inflammatory, and metabolic diseases of the placenta. This fetal programming occurs via direct placental passage or production of factors which can act directly on fetal brain substrates, or indirectly via action of circulating factors on intermediates in the placenta. Placental neuroendocrine, vascular/angiogenic, immune, and extracellular vesicular mechanisms are detailed. These mechanisms interact within various placental and pregnancy conditions. An increased understanding of the placental origins of psychoneuroimmunology will yield dividends for human health. Identifying maternal and placental biomarkers for fetal neuroimmune health may also revolutionize early diagnosis and precision psychiatry, empowering patients to make the best healthcare decisions for their families. Targeting placental mechanisms may be a valuable approach for the prevention and mitigation of intergenerational, lifelong neuropathology.