Biology subjects

Sciortino, R.

Publications and source records attributed to Sciortino, R..

7 recordsLinked to original sources

bioRxiv2026

Expanding Hippocampal Ensembles through LINE-1 RNA Downregulation Enhances Cognition

Episodic memories are encoded through the activation of small overlapping neuronal ensembles, a coding principle that ensures efficient encoding and high memory capacity. While cellular excitability is known to drive the allocation of select hippocampal neurons into these ensembles, the underlying molecular mechanisms remain elusive. Here, an epigenetic-functional analysis of hippocampal dentate granule cells revealed robust nuclear expression of RNA from autonomous LINE-1 retrotransposons, with significantly lower LINE-1 RNA levels in environmentally activated neurons compared to non-activated counterparts. Knockdown of LINE-1 RNA in the dentate gyrus increased action potential firing capacity and expanded the number of environmentally activated cells, indicating that LINE-1 expression is inversely correlated with ensemble eligibility. LINE-1 RNA knockdown enhanced spatial working memory at the expense of pattern separation, a trade-off consistent with expanded dentate gyrus ensembles and diminished sparse coding. Together, these findings demonstrate that nuclear LINE-1 RNA was co-opted during evolution to control ensemble eligibility in dentate granule cells, a novel postmitotic neuronal function for LINE-1 RNA that restricts ensemble size to preserve sparse coding and support pattern separation.

neuroscience↗

bioRxiv2026

Large-scale reorganization of DNA methylation and upregulation of extracellular matrix genes in the dorsal dentate gyrus following cocaine taking

Cocaine self-administration induces neurobiological adaptations in brain circuits involved in encoding reward-associated context. The dorsal hippocampus, particularly the dorsal dentate gyrus, plays a critical role in the precise encoding of spatial and contextual information. We hypothesized that the dentate gyrus is uniquely positioned to undergo epigenomic and transcriptomic changes because of the convergence of the contextual features of reward and cocaine-enhanced dopamine and norepinephrine signals during volitional drug-taking. We report that cocaine self-administration produces significant DNA methylation changes at an unusually large number of [~]30,000 genomic regions (>10%, q<0.01) in dentate granule cells (DGCs) of male mice. Cocaine preferentially hypomethylated regions with heterogenous methylation, switching the methylation state in [~]16% of DGCs on average. The cocaine-sensitive/responsive epigenomic regions were overrepresented in enhancers and were associated with 9,833 genes, many of which were involved in diverse functions relevant to neuronal functioning. However, among the differentially methylated genes only two regulatory genes, c-fos and cartpt (known to be activated by cocaine), and a cluster of genes encoding components of the extracellular matrix (implicated in neuroplasticity) were differentially expressed (mostly upregulated) following cocaine self-administration, suggesting a gene regulatory network that is transcriptionally robust to perturbations but still specific for context-driven and reward associated neuroplasticity in DGCs. Overall, our data demonstrates that cocaine self-administration induces epigenomic and transcriptomic changes in the dorsal dentate gyrus that may contribute to dorsal hippocampal plasticity and contextual memory associated with cocaine self-administration.

neuroscience↗

bioRxiv2026

Acquisition and extinction of drug-context memories are linked to distinct epigenetic and transcriptional mechanisms in the mouse dentate gyrus

Acquisition and extinction of drug-context associations both involve learning, yet whether extinction erases the original drug memory remains unresolved. As learning is associated with epigenetically mediated transcriptional plasticity, we asked whether acquisition-induced DNA methylation and gene expression changes are reversed by extinction, or whether extinction induces its own distinct methylation and transcriptional changes. Here, we show that both acquisition and extinction of cocaine conditioned place preference (CPP) preferentially hypomethylated cis-regulatory elements and upregulated transcription, but at largely non-overlapping genomic regions and genes in the dorsal dentate gyrus, a key region in contextual learning. In both learning paradigms, the number of differentially expressed genes was an order of magnitude smaller than those differentially methylated, highlighting the robustness of the transcriptional network to epigenetic modifications, and implicating a non-linear relationship between regulatory elements and transcription characteristic for gene regulatory networks (GRNs). Notably, animals that failed to extinguish cocaine CPP displayed attenuated DNA methylation changes and minimal transcriptional response, consistent with the stochastic output of GRNs to produce alternative outcomes across individuals. Acquisition-upregulated genes were enriched in neuronal cilium functions, consistent with the known role of primary cilia in hippocampal learning and the persistence of drug-context memories through stable axo-ciliary signaling. In contrast, extinction-upregulated genes were overrepresented in mitochondrial energy homeostasis functions, suggesting their role in meeting rapid energy demands during learning. Overall, acquisition and extinction engage fundamentally distinct molecular mechanisms, providing a potential mechanistic explanation for why drug-context memories are suppressed but not erased by extinction.

animal behavior and cognition↗

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↗