Prenatal stress alters offspring neurovascular, autonomic, and immune development in animal models of neuropsychiatric and cardiometabolic disorders.

Developmental programming, a permanent adaptation of the fetus/neonate to maternal environmental signals, underlies many adult physiological and psychiatric disorders. Prenatal stress induced by the synthetic glucocorticoid dexamethasone has been shown to increase anxiety- and depressive-like behaviors and lead to hyperreactive neuroendocrine and autonomic nervous system (ANS) responses to stress in adult female offspring. Prenatal stressors can also cause maternal immune activation (MIA), impact mood/stress circuitry, and program neural development. One way to engage molecular immune signals is to activate toll-like receptors (TLRs). Developmental changes have been seen following gestational exposure to lipopolysaccharide (LPS; TLR4), poly I:C (TLR3), and, most recently, TLR7 agonists resiquimod (RQ) or imiquimod (IMQ). Studies have identified changes in ANS function that may be tied to blood-brain barrier (BBB) changes in the paraventricular nucleus of the hypothalamus (PVN) that coincide with anxiety- /depressive-like behaviors that manifest after fetal programming. These adult dysfunctions are a consequence of prenatal stressors and may have a common underlying mechanism related to the dysregulation of communication between the PVN and critical ANS centers in the brainstem. Studies in humans indicate that brainstem loci may be important centers of ANS regulation that can be targeted to attenuate major depressive disorder (MDD) symptoms in adults. Furthermore, data suggest that select immune and BBB characteristics in PVN and autonomic nuclei in the brainstem are critical targets for future studies, aligning with the hypothesis that immune signaling plays a major role in the development and expression of psychiatric disorders. The overarching goal of this review is to outline the cellular and physiological pathways by which prenatal stressors, mainly synthetic glucocorticoid exposure and MIA, produce long-term, sex-biased programming of adult behavior and ANS function relevant to physiological and psychiatric disorders.