Biology subjects

Xavier, A. M.

Publications and source records attributed to Xavier, A. M..

5 recordsLinked to original sources

bioRxiv2026

Deciphering epileptogenic and activity-dependent gene programs in the human brain

Neuronal activity is fundamental to brain function, yet chronically elevated activity underlies neurological disorders such as drug-resistant epilepsy (DRE). In animal models, activity induces defined transcriptional programs within activated neurons; however, the nature, cellular specificity, and pathological relevance of such programs in the human brain remain poorly understood. Here, we apply single-nucleus and spatial transcriptomics to epileptogenic, non-epileptogenic, and intraoperatively stimulated non-epileptogenic cortical tissue obtained from individuals with DRE. Across 26 cell types profiled, glutamatergic neurons projecting from cortical layers 2/3, 5, and 6 to intratelencephalic targets exhibit pronounced sensitivity to the epileptogenic microenvironment, inducing shared immediate-early genes alongside cell-type-specific programs linked to synaptic remodeling and cellular stress. Approximately one-third of transcripts enriched in the epileptogenic microenvironment were also induced by acute stimulation, suggesting that a fraction of epilepsy-associated gene expression reflects conserved responses to heightened activity rather than disease-specific programs. While transcripts induced by both epileptogenic and acute activity converged upon immediate-early genes and heat-shock proteins, only acute stimulation triggered a rapid, multicellular induction of transcripts involved in mitochondrial ATP synthesis. This divergence suggests that neurons within epileptogenic cortex may be unable to mount appropriate metabolic adaptations to sustained energetic demands. In parallel, both microglia and circulating CD14+ monocytes exhibit signs of immune activation in epilepsy, suggesting myeloid-driven inflammatory rewiring that extends beyond the brain. Together, these findings illuminate human activity-dependent gene programs and reveal signatures of neuronal vulnerability and inflammation in DRE.

neuroscience↗

bioRxiv2024

A single-cell transcriptomic atlas of sensory-dependent gene expression in developing mouse visual cortex

Sensory experience drives the refinement and maturation of neural circuits during postnatal brain development through molecular mechanisms that remain to be fully elucidated. One likely mechanism involves the sensory-dependent expression of genes that encode direct mediators of circuit remodeling within developing cells. However, while studies in adult systems have begun to uncover crucial roles for sensory-induced genes in modifying circuit connectivity, the gene programs induced by brain cells in response to sensory experience during development remain to be fully characterized. Here, we present a single-nucleus RNA-sequencing dataset describing the transcriptional responses of cells in mouse visual cortex to sensory deprivation or sensory stimulation during a developmental window when visual input is necessary for circuit refinement. We sequenced 118,529 individual nuclei across sixteen neuronal and non-neuronal cortical cell types isolated from control, sensory deprived, and sensory stimulated mice, identifying 1,268 unique sensory-induced genes within the developing brain. To demonstrate the utility of this resource, we compared the architecture and ontology of sensory-induced gene programs between cell types, annotated transcriptional induction and repression events based upon RNA velocity, and discovered Neurexin and Neuregulin signaling networks that underlie cell-cell interactions via CellChat. We find that excitatory neurons, especially layer 2/3 pyramidal neurons, are highly sensitive to sensory stimulation, and that the sensory-induced genes in these cells are poised to strengthen synapse-to-nucleus crosstalk by heightening protein serine/threonine kinase activity. Altogether, we expect this dataset to significantly broaden our understanding of the molecular mechanisms through which sensory experience shapes neural circuit wiring in the developing brain.

neuroscience↗

bioRxiv2023

Integrated high-confidence and high-throughput approaches for quantifying synapse engulfment by oligodendrocyte precursor cells

Oligodendrocyte precursor cells (OPCs) sculpt neural circuits through the phagocytic engulfment of synapses during development and in adulthood. However, precise techniques for analyzing synapse engulfment by OPCs are limited. Here, we describe a two-pronged cell biological approach for quantifying synapse engulfment by OPCs which merges low-and high-throughput methodologies. In the first method, an adeno-associated virus encoding a pH-sensitive, fluorescently-tagged synaptic marker is expressed in neurons in vivo. This construct allows for the differential labeling of presynaptic inputs that are contained outside of and within acidic phagolysosomal compartments. When followed by immunostaining for markers of OPCs and synapses in lightly fixed tissue, this approach enables the quantification of synapses engulfed by around 30-50 OPCs within a given experiment. In the second method, OPCs isolated from dissociated brain tissue are fixed, incubated with fluorescent antibodies against presynaptic proteins, and then analyzed by flow cytometry. This approach enables the quantification of presynaptic material within tens of thousands of OPCs in less than one week. These methods extend beyond the current imaging-based engulfment assays designed to quantify synaptic phagocytosis by brain-resident immune cells, microglia. Through the integration of these methods, the engulfment of synapses by OPCs can be rigorously quantified at both the individual and populational levels. With minor modifications, these approaches can be adapted to study synaptic phagocytosis by numerous glial cell types in the brain.

neuroscience↗

bioRxiv2021

Context-dependent transcriptional regulation of microglial proliferation

Microglia proliferation occurs during brain development and brain lesions, but how this is coordinated at the transcriptional level is not well understood. Here, we investigated transcriptional mechanisms underlying proliferation of mouse microglia during postnatal development and in adults in models of induced microglial depletion-repopulation and brain demyelination. While each proliferative subset displayed globally a distinct signature of gene expression, they also co-expressed a subgroup of 1,370 genes at higher levels than quiescent microglia. Furthermore, expression of these may be coordinated by one of two modes of regulation. A first mode augments expression of genes already expressed in quiescent microglia and is subject to regulation by Klf/Sp, Nfy, and Ets transcription factors. Alternatively, a second mode enables de novo transcription of cell cycle genes and requires additional regulatory input from Lin54 and E2f factors. Overall, proliferating microglia integrate regulation of cell cycle gene expression with their broader, context-dependent, transcriptional landscape.

genomics↗

bioRxiv2018

A new function for Prokineticin 2: recruitment of SVZ-derived neuroblasts to the injured cortex in a mouse model of traumatic brain injury

Traumatic brain injury is an important cause of mortality and morbidity all over the world. After the initial injury there is a cascade of cellular and molecular events that ultimately lead to cell death. Therapies aim not only to counteract these mechanisms but also to replenish the lost cell population in order to achieve a better recovery. The adult mammal brain in not as plastic as the postnatal, but it has at least two neurogenic regions that maintains physiological functions in the brain; the subgranular zone of the dentate gyrus of the hippocampus, which produces neurons that integrate locally, and the subventricular zone (SVZ) of the lateral ventricles, that produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulbs. Brain injuries, as well as neurodegenerative diseases, induce the SVZ to respond by increasing cell proliferation and migration to the injured areas. Here we report that SVZ cells migrate to the injured cortex after traumatic brain injury in mice, and that the physiological RMS migration is not impaired. We also show that Prokineticin 2 (PROK2), a chemokine important for the olfactory bulb neurogenesis by promoting the directional migration of neuroblasts, is induced in the injured cortex. Using PROK2 receptor antagonist and recombinant PROK2 we show for the first time that PROK2 can directionally attract SVZ cells in vitro and in vivo. The data we present here links one more element of the inflammatory process, PROK2 secreted by microglia, to the attempt to regenerate an acutely injured mammalian cortex.\n\nAbbreviations

neuroscience↗