Embryonic Exposure to Dexamethasone Affects Nonneuronal Cells in the Adult Paraventricular Nucleus of the Hypothalamus

Abstract

Neurons in the paraventricular nucleus of the hypothalamus (PVN) integrate peripheral signals and coordinate responses that maintain numerous homeostatic functions. An excess of glucocorticoids during fetal development results in long-lasting consequences tied to disrupted PVN development. The PVN contains a distinct neuronal population and a threefold greater vascular density than the surrounding brain regions that prepubertally is reduced in offspring exposed to excess glucocorticoids in utero. This study expands the examination of sex-specific nonneuronal PVN composition by examining astrocytes, astrocytic endfeet, and pericytes. Blood-brain barrier (BBB) competency and composition were examined along with depressive-like behavior and hypothalamic-pituitary-adrenal function in male and female mice. For PVN vasculature, female offspring of vehicle (veh)-treated mothers had significantly more astrocytes and pericytes than male offspring from the same litters. Female offspring from dexamethasone (dex)-treated mothers had significantly lower levels of astrocytes than female offspring from veh-treated mothers, whereas male offspring from dex-treated mothers had greater levels of pericytes compared with veh-treated male offspring. Using the tail-suspension test, male and female offspring from dex-treated mothers had significantly shorter latencies to immobility, indicating an increase in depression-like behavior, and showed greater plasma corticosterone after restraint stress, which was significantly greater in female offspring from dex-treated mothers even after recovery. Therefore, in addition to long-term sex differences in cellular components of the BBB in the PVN that were differentially regulated by fetal glucocorticoid exposure, there were behavioral differences observed into early adulthood in a sex-specific manner.

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

“…Further, the strongest GxS interaction was detected for SCZ in the 5' UTR of MOCOS (rs11665282; p=1.48×10 −7 ), which, based on evaluation of brain expression datasets, is highly expressed in endothelial cells lining blood vessels (Supplementary Figure 24). Interestingly, our previous work on sex differences in the positioning of cells containing ERα in the PVN associated with impaired GABA-B signaling (65) also was significantly associated with sex differences in vascular development, being more severe in females and associated with depression-related behaviors (94). These previous studies suggest potentially shared genetic risks across these disorders with vascular dysfunctions and may explain high comorbidity of disorders like MDD and SCZ with CVD (90).…”

“…Further, the strongest GxS interaction was detected for SCZ in a locus in the MOCOS gene most highly expressed in endothelial cells lining blood vessels. Interestingly, our previous work on sex differences in neuronal migration due to impaired GABA-B signaling (62) was also significantly associated with sex differences in hypothalamic neurovascular development, being more severe in females and associated with depression-related behaviors (85). In fact, a recent meta-analysis of 22 available gene expression microarrays across multiple organs and tissues cited areas of the brain (i.e., anterior cingulate cortex, implicated in MDD, SCZ and BIP) with the most substantial sex differences in gene expression, followed by the heart (86).…”

The involvement of astrocytes in early‐life adversity induced programming of the brain

“…Further supporting the sensitivity of astrocytes to ELA, there have been several reports on the effect of other forms of early stress on the astrocytic population, including dexamethasone exposure (Claessens et al, ; Frahm, Handa, & Tobet, ; McArthur, Pienaar, Siddiqi, & Gillies, ), early‐life exposure to noise (Jauregui‐Huerta et al, ; Ruvalcaba‐Delgadillo et al, ), restraint stress (Barros, Duhalde‐Vega, Caltana, Brusco, & Antonelli, ; García‐Cáceres et al, ), and limited nesting and bedding material during development (Gunn et al, ). Notably, all these models have been described to have effect on astrocytes.…”

Sex differences in major depression and comorbidity of cardiometabolic disorders: impact of prenatal stress and immune exposures

“…In development, there is debate as to when the BBB "closes" or begins to regulate the flow of macromolecules into and out of the brain parenchyma. Our previous results suggested that perinatal GABAergic [95] or GC [118] treatments influence BBB development. Evidence currently exists for both sex-dependent GC [119] and reproductive hormone [120] influences on some aspects of BBB function, such as permeability and expression of molecular pumps.…”