👤 Lucas Javier Sosa

Maternal psychosocial stress during the perinatal period is highly prevalent and a major risk factor for maternal and child health. However, the operationalization of perinatal stress remains fragmented, and its biological embedding is poorly understood. This study aimed to (1) identify latent profiles of maternal perinatal stress and (2) examine their association with maternal NR3C1 expression, a molecular marker of hypothalamic-pituitary-adrenal (HPA) axis regulation reflecting glucocorticoid receptor availability and feedback sensitivity. A total of 241 mothers were recruited during pregnancy and followed up at three months postpartum. Validated measures of state anxiety, depressive symptoms, perceived stress, and pregnancy-related distress were collected in the second and third trimesters and postpartum. Saliva samples were obtained for RNA extraction, and NR3C1 gene expression was quantified using qPCR. Latent profile analysis (LPA) was conducted to classify participants according to psychosocial stress indicators. Results supported a three-profile solution: high (21.2%), moderate (34.4%), and low stress (44.3%). Women in the high-stress profile reported elevated levels across all indicators, while those in the low-stress profile showed consistently lower scores. A one-way ANOVA revealed significant differences in NR3C1 expression across profiles, with the high-stress group displaying the lowest levels and the low-stress group the highest. Given that higher NR3C1 expression is generally interpreted as indicating more efficient HPA axis negative feedback regulation, these findings suggest that cumulative psychosocial stress is associated with reduced glucocorticoid receptor expression and potentially diminished stress-regulatory capacity. This integrative approach advances understanding of biological embedding of perinatal stress and highlights need for targeted support. Show less

The long-term effects of exposure to blast overpressure are an important health concern in military personnel. Increase in amyloid beta (Aβ) has been documented after non-blast traumatic brain injury (TBI) and may contribute to neuropathology and an increased risk for Alzheimer's disease. We have shown that Aβ levels decrease following exposure to a low-intensity blast overpressure event. To further explore this observation, we examined the effects of a single 37 kPa (5.4 psi) blast exposure on brain Aβ levels, production, and clearance mechanisms in the acute (24 h) and delayed (28 days) phases post-blast exposure in an experimental rat model. Aβ and, notably, the highly neurotoxic detergent soluble Aβ42 form, was reduced at 24 h but not 28 days after blast exposure. This reduction was not associated with changes in the levels of Aβ oligomers, expression levels of amyloid precursor protein (APP), or increase in enzymes involved in the amyloidogenic cleavage of APP, the β- and ϒ-secretases BACE1 and presenilin-1, respectively. The levels of ADAM17 α-secretase (also known as tumor necrosis factor α-converting enzyme) decreased, concomitant with the reduction in brain Aβ. Additionally, significant increases in brain levels of the endothelial transporter, low-density related protein 1 (LRP1), and enhancement in co-localization of aquaporin-4 (AQP4) to perivascular astrocytic end-feet were observed 24 h after blast exposure. These findings suggest that exposure to low-intensity blast may enhance endothelial clearance of Aβ by LRP1-mediated transcytosis and alter AQP4-aided glymphatic clearance. Collectively, the data demonstrate that low-intensity blast alters enzymatic, transvascular, and perivascular clearance of Aβ. Show less

Development of the mammalian neocortex requires proper inside-out migration of developing cortical neurons from the germinal ventricular zone toward the cortical plate. The mechanics of this migration requires precise coordination of different cellular phenomena including cytoskeleton dynamics, membrane trafficking, and cell adhesion. The small GTPases play a central role in all these events. The small GTPase Rab21 regulates migration and neurite growth in developing neurons. Moreover, regulators and effectors of Rab21 have been implicated in brain pathologies with cortical malformations, suggesting a key function for the Rab21 signaling pathway in cortical development. Mechanistically, it has been posited that Rab21 influences cell migration by controlling the trafficking of endocytic vesicles containing adhesion molecules. However, direct evidence of the participation of Rab21 or its mechanism of action in the regulation of cortical migration is still incomplete. In this study, we demonstrate that Rab21 plays a critical role in the differentiation and migration of pyramidal neurons by regulating the levels of the amyloid precursor protein on the neuronal cell surface. Rab21 loss of function increased the levels of membrane-exposed APP, resulting in impaired cortical neuronal differentiation and migration. These findings further our understanding of the processes governing the development of the cerebral cortex and shed light onto the molecular mechanisms behind cortical development disorders derived from the malfunctioning of Rab21 signaling effectors. Show less