Development of the blood–brain barrier within the paraventricular nucleus of the hypothalamus: influence of fetal glucocorticoid excess

Abstract

The blood–brain barrier (BBB) is a critical contributor to brain function. To understand its development and potential function in different brain regions, the postnatal (P) BBB was investigated in the mouse cortex (CTX), lateral hypothalamus, and paraventricular nucleus of the hypothalamus (PVN). Brains were examined on postnatal days (P)12, P22 and P52 for BBB competency and for pericytes as key cellular components of the BBB demarcated by immunoreactive desmin. Glucocorticoid influences (excess dexamethasone; dex) during prenatal development were also assessed for their impact on the blood vessels within these regions postnatally. At P12, there was significantly more extravascular leakage of a low molecular weight dye (fluorescein isothiocyanate) in the CTX than within hypothalamic regions. For pericytes, there were low levels of desmin immunoreactivity at P12 that increased with age for all regions. There was more desmin immunoreactivity present in the PVN at each age examined. Fetal dex exposure resulted in decreased blood vessel density within the PVN at P20. In the CTX, dex exposure increased BBB competency, in contrast to the PVN where there was a decrease in BBB competency and increased pericyte presence. Overall, unique alterations in the functioning of the BBB within the PVN may provide a novel mechanism for fetal antecedent programming that may influence adult disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-014-0787-8) contains supplementary material, which is available to authorized users.

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

“…However, timing of the exposure impacts whether the effect has greater consequences for male or female offspring. This may explain why in some studies higher inflammation (such as in the MIA models) led to greater anxiety or depressive (and neurodevelopmental) phenotypes in male offspring [152,156], while work by our group and others [57,110,157,158] resulted in increased anxiety and depression in female offspring.…”

“…Another group of cells to consider are those involved in neurovascular units. Maternal treatment with DEX caused BBB disruption in offspring prior to puberty independent of sex [57]. Lack of BBB competence was not apparent after puberty.…”

“…These HPA-immune connections have given rise to so-called prenatal stress-immune models of MDD and cardiometabolic disorders. We demonstrated that if these fetal stress and immune risk factors occur during a critical period of the sexual differentiation of the brain (2nd-3rd trimester), they impact highly sexually dimorphic brain regions [24] and the vasculature [55][56][57] in sex-dependent ways. We also argue here (see Fig.…”

“…These cytokines are present in the maternal uterus, cross the placenta and BBB [166,167], and are found in the fetal circulation and brain. Chronically elevated immune activation in mother and offspring as measured by cytokines predisposes to increased oxidative stress [168][169][170], the neural impact of which differs by sex [57,110,157,158]. Exposure to cytokines and oxidative stress may lead to abnormalities in regions such as ACC, HIPP, and HYPO resulting in increased risk of negative stress response circuitry deficits and ANS dysregulation in the offspring.…”

Prenatal stress-induced increases in hippocampal von Willebrand factor expression are prevented by concurrent prenatal escitalopram

“…Regardless, decreased vessel length is consistent with previous reports of stress-induced vascular hypotrophy in the hippocampus (Neigh et al, 2010) and has implications for perfusion of brain tissue (Faraci, 2011). Similarly, offspring born to dexamethasone treated dams exhibit decreased vasculature in a region specific manner, including in the paraventricular nucleus of the hypothalamus, further supporting the sensitivity of brain vasculature to the prenatal environment (Frahm and Tobet, 2014). …”