Biology subjects

Fall, S.

Publications and source records attributed to Fall, S..

3 recordsLinked to original sources

bioRxiv2026

Schizophrenia-like neurodevelopmental pathology reshapes experience-dependent brain network remodeling following adolescent alcohol exposure

Background Alcohol use disorder (AUD) is highly prevalent in schizophrenia, yet the neurobiological basis of this vulnerability remains poorly understood. Neurodevelopmental models suggest that pre-existing brain dysconnectivity may increase vulnerability to AUD. We therefore tested whether schizophrenia-like neurodevelopmental pathology alters how alcohol-related experience is incorporated into large-scale brain networks. Methods Resting-state functional connectivity was assessed in male Sprague-Dawley rats (n = 18-21/group) with neonatal ventral hippocampal lesions (NVHL), a neurodevelopmental model of schizophrenia, and sham-operated controls, with or without voluntary adolescent alcohol exposure. Functional connectivity was assessed using seed-to-voxel and seed-to-seed analyses within a cortico-striato-limbic network. We additionally examined whether individual alcohol intake during adolescence predicted adult functional connectivity according to neurodevelopmental status. Results NVHL and adolescent alcohol exposure independently produced predominantly hypoconnected cortico-striato-limbic networks. However, alcohol exposure did not exacerbate NVHL-associated dysconnectivity but instead induced a distinct network reorganization characterized by functional hyperconnectivity. Although alcohol intake was comparable between groups, dose-dependent relationships between adolescent alcohol consumption and adult functional connectivity were observed in sham animals but were absent or markedly attenuated in NVHL rats. These effects were primarily centered on prelimbic cortex connectivity with the amygdala, hippocampus, and dorsal striatum, highlighting this circuitry as a major locus of altered experience-dependent remodeling. Conclusions These findings suggest that vulnerability to AUD associated with schizophrenia-like neurodevelopment may arise less from additive network dysfunction than from an altered capacity of large-scale brain networks for experience-dependent functional remodeling. Schizophrenia-like neurodevelopmental pathology may therefore change how alcohol-related experience is translated into persistent brain network organization.

neuroscience↗

bioRxiv2026

Postnatal Pax7-expressing limb cells are multipotent and generate non-myogenic lineages that persist into adulthood.

Organs are composed of a complex arrangement of diverse cell types that can originate from independent cell lineages or shared progenitors. Skeletal muscle is derived from mesodermal Pax7+ stem/progenitor cells that can differentiate into myoblasts to form muscle fibers. During embryogenesis, however, somitic Pax7+ cells can also give rise to non-muscle cell types, including dermis and adipocytes. Here, we asked whether Pax7+ cells retain such multipotency during early postnatal growth of limb muscles. Using lineage tracing, we uncovered unexpected plasticity at early postnatal days, leading to the generation of multiple non-myogenic lineages, including a previously unrecognized Pax7-derived subpopulation of fibro-adipogenic progenitors that we termed Pax7FAPs and further investigated. Using mouse models, we further show that Notch signaling primes neonatal Pax7+ cells toward a fibrogenic molecular identity at the expense of myogenic differentiation, thereby biasing their trajectory toward a fibrogenic fate. In the adult muscle, long-term tracing revealed that neonatally produced Pax7FAPs persist into adulthood. In addition, injury in adult muscle triggered de novo generation of Pax7FAPs, which displayed higher proliferative capacity than resident stromal cells. This newfound multipotency of postnatal Pax7+ cells adds a new dimension to our understanding of cellular contributions during postnatal muscle development and regeneration.

developmental biology↗

bioRxiv2024

Integrating in silico predictions with an engineered tissue assay identifies Perlecan as an age-perturbed re-quiescence cue for muscle stem cells

Skeletal muscle regeneration is mediated by resident muscle stem cells that produce progeny to repair or recreate muscle. Critical to this function is the ability to transition between states of proliferation and quiescence. This balancing act is disrupted with age, leading to eroded regenerative capacity. Notwistanding, mechanisms by which the regenerating niche directs MuSCs return to the dormant state are largely unknown. Since single-cell RNAseq methods exclude the analysis of multinucleated cells, we generated single-nuclei RNAseq datasets of regenerating muscle to capture the full breadth of myogenic progression. With this, we uncovered new transition states between differentiating myocytes and syncytial multinucleated cells. Using cell communication inference tools, we highlighted receptor-ligand interactions between MuSCs and fusing nuclei. We leveraged a bespoke biomimetic 3D niche that induces MuSC quiescence, to filter the predicted interactions using a Cas9-based functional genomics approach. We found the proteoglycan Perlecan (Hspg2) promotes MuSC re-quiescence. Hspg2 silencing in vivo, during muscle regeneration, induced an aging-like phenotype and perturbed MuSC re-quiescence. Notably, the temporal profile and overall levels of Perlecan were altered with age. Exogenous supplementation with Endorepellin (truncated Perlecan) rescued MuSC decline following aged muscle regeneration, offering a new therapeutic target. Thus, coupling in silico predictions with a 3D in vitro assay followed by in vivo investigations revealed a previously inaccessible window of biology; that spatiotemporal coordination of MuSC re-quiescence is directed by fusing myonuclei.

cell biology↗