Biology subjects

Sciortino, R.

Publications and source records attributed to Sciortino, R..

4 recordsLinked to original sources

bioRxiv2025

Neutrophil stalling does not mediate the increase in tau phosphorylation and the cognitive impairment associated with high salt diet

High dietary salt intake has powerful effects on cerebral blood vessels and has emerged as a risk factor for stroke and cognitive impairment. In mice, high salt diet (HSD) leads to reduced cerebral blood flow (CBF), tau hyperphosphorylation and cognitive dysfunction. However, it is still unclear whether the reduced CBF is responsible for the effects of HSD on tau and cognition. Capillary stalling has emerged as a cause of CBF reduction and cognitive impairment in models of Alzheimers disease and diabetes. Therefore, we tested the hypothesis that capillary stalling also contributes to the CBF reduction and cognitive impairment in HSD. Using two-photon imaging, we found that HSD increased stalling of neutrophils in brain capillaries and decreased CBF. Neutrophil depletion reduced the number of stalled capillaries and restored resting CBF but did not prevent tau phosphorylation or cognitive impairment. These novel findings show that, capillary stalling contribute to CBF reduction in HSD, but not to tau phosphorylation and cognitive deficits. Therefore, the hypoperfusion caused by capillary stalling is not the main driver of the tau phosphorylation and cognitive impairment.

neuroscience↗

bioRxiv2025

Prenatal adversity configures a subpopulation of ventral dentate granule cells for recruitment to drive innate anxiety

Adverse prenatal environment is a risk factor for the development of psychiatric disorders. Although studies have implicated epigenetic mechanisms, little is known about how epigenomic changes come about and lead to abnormal behaviors in affected individuals. We sought to identify epigenomic and transcriptomic signatures induced by a proinflammatory gestational environment in the ventral dentate gyrus (vDG), a hippocampal region linked to avoidance of threatening contexts, that persist and promote anxiety-like behavior in mice. Here we show that adversity shifted the methylation of enhancers and promoters with intermediate methylation and altered synapse-related gene expression, resulting in epigenetic and transcriptional heterogeneity in the vDG. Exposure to an anxiogenic environment recruited vDG neurons with the most transcriptional alterations. Differentially expressed synapse-relevant genes in ensemble neurons tended to be differentially methylated. Finally, this ensemble exhibited higher activity in threatening than safe environment suggesting a prenatal adversity-induced epigenetic and neurobiological sequence that leads to anxiety.

neuroscience↗

bioRxiv2023

Brain and blood single-cell transcriptomics in acute and subacute phases after experimental stroke

Cerebral ischemia triggers a powerful inflammatory reaction involving both peripheral leukocytes and brain resident cells. Recent evidence indicates that their differentiation into a variety of functional phenotypes contributes to both tissue injury and repair. However, the temporal dynamics and diversity of post-stroke immune cell subsets remain poorly understood. To address these limitations, we performed a longitudinal single-cell transcriptomic study of both brain and mouse blood to obtain a composite picture of brain-infiltrating leukocytes, circulating leukocytes, microglia and endothelium diversity over the ischemic/reperfusion time. Brain cells and blood leukocytes isolated from mice 2 or 14 days after transient middle cerebral artery occlusion or sham surgery were purified by FACS sorting and processed for droplet-based single-cell transcriptomics. The analysis revealed a strong divergence of post-ischemic microglia, macrophages, and neutrophils over time, while such diversity was less evident in dendritic cells, B, T and NK cells. Conversely, brain endothelial cells and brain associated-macrophages showed altered transcriptomic signatures at 2 days post-stroke, but low divergence from sham at day 14. Pseudotime trajectory inference predicted the in-situ longitudinal progression of monocyte-derived macrophages from their blood precursors into day 2 and day 14 phenotypes, while microglia phenotypes at these two time points were not connected. In contrast to monocyte-derived macrophages, neutrophils were predicted to be continuously de-novo recruited from the blood. Brain single-cell transcriptomics from both female and male aged mice did not show major changes in respect to young mice, but aged and young brains differed in their immune cell composition. Furthermore, blood leukocyte analysis also revealed altered transcriptomes after stroke. However, brain-infiltrating leukocytes displayed higher transcriptomic divergence than their circulating counterparts, indicating that phenotypic diversification into cellular subsets occurs within the brain in the early and the recovery phase of ischemic stroke. In addition, this resource report contains a searchable database https://anratherlab.shinyapps.io/strokevis/ to allow user-friendly access to our data. The StrokeVis tool constitutes a comprehensive gene expression atlas that can be interrogated at the gene and cell type level to explore the transcriptional changes of endothelial and immune cell subsets from mouse brain and blood after stroke.

immunology↗

bioRxiv2022

Meningeal IL-17 producing T cells mediate cognitive impairment in salt-sensitive hypertension

Hypertension, a disease afflicting over one billion individuals worldwide, is a leading cause of cognitive impairment, the mechanisms of which remain poorly understood. In a mouse model of hypertension, we found that the neurovascular and cognitive dysfunction depends on IL-17, a cytokine elevated in hypertensive individuals. However, neither circulating IL-17 or brain angiotensin signaling could account in full for the dysfunction. Rather, IL-17 produced by T-cells in the dura mater was the major culprit by reaching the cerebrospinal fluid and activating IL-17 receptors on brain associated macrophages. Accordingly, depleting brain macrophages, deleting IL17-RA in brain macrophages, or suppressing meningeal T cells completely rescued cognitive function without attenuating blood pressure elevation, circulating IL-17 or brain angiotensin signaling. The data unveil a critical role of meningeal T-cells and macrophage IL-17 signaling in the neurovascular and cognitive dysfunction of hypertension and suggest novel therapies to counteract the devastating effects of hypertension on cognitive health.

neuroscience↗