Biology subjects

Davalos, D.

Publications and source records attributed to Davalos, D..

9 recordsLinked to original sources

bioRxiv2026

Early Increases in Hippocampal Synchrony Predict Chronic Epileptiform Burden in a Temporal Lobe Epilepsy Model

Temporal lobe epilepsy (TLE), the most common focal epilepsy, is often drug-resistant and arises predominantly in the hippocampus. Disease severity is conventionally assessed by seizure frequency and duration, yet epileptiform activity outside discrete seizures may also track disease progression. Whether this activity reflects hippocampal network reorganization as part of epileptogenesis, and whether such reorganization predicts chronic severity, is unknown. Here, we combined longitudinal two-photon calcium imaging of hippocampal CA1 neurons with repeated 24-hour EEG recordings that quantified epileptiform burden in the same pilocarpine treated mice over 16 weeks. CA1 firing and synchrony rose acutely, subsided during a latent period, and increased again chronically, with synchronized firing organized into brief waves that propagated in a consistent direction. Epileptiform burden followed a similar temporal trajectory and increasingly contained electrographic seizures. CA1 synchrony correlated with epileptiform burden and stratified mice into groups with distinct neuronal and electrographic outcomes. CA1 synchrony measured within three weeks of pilocarpine induction predicted chronic epileptiform burden, identifying early hippocampal synchrony as a candidate imaging biomarker and pointing to an early window for intervention in TLE.

neuroscience↗

bioRxiv2026

A Single-Cell Atlas of the Mouse Dural Meninges Reveals Pervasive Sex Differences Across Cellular Compartments

The dural compartment of the meninges forms a dynamic interface between the brain and the periphery, hosting diverse immune, vascular, mural and fibroblast populations. Single-cell studies have begun charting meningeal cellular diversity, yet a comprehensive view encompassing all major cellular compartments, intercellular communication, and the influence of sex remains lacking. Here, we present a single-cell transcriptomic atlas of the adult mouse dural meninges, profiling all major cell types in male and female mice at steady state. We uncover broad sex differences in cell-type-specific proportion, transcriptional programs, intercellular communication, and disease relevant signatures. Histological and cytometry analyses validate the biological relevance of these findings, establishing this atlas as a foundation for studying meningeal contributions to neurological disease in a sex-aware manner.

neuroscience↗

bioRxiv2026

Chemogenetic Pericyte Activation Reveals Broad Contractile Ability and Limbic Vulnerability to Capillary Flow Deficits

Capillary pericytes contact most of the brains microvasculature. Yet, their influence on blood flow remains incompletely understood both locally in capillary networks and across brain regions. Here, we sparsely expressed the chemogenetic actuator Gq-DREADD in mouse brain pericytes to stochastically probe their contractility and influence on tissue perfusion and oxygenation. Chemogenetic stimulation induced robust contraction of pericytes over minutes, including those with thin processes on capillary segments proximal to venules, indicating control of vascular tone across the entire capillary bed. Pericyte contraction combined circumferential compression with longitudinal tension applied through thin processes, resulting in vasoconstriction and hypoperfusion. Histology revealed hypoxic microdomains induced by sparse pericyte contraction across the brain, and enriched hypoxia in limbic structures including the amygdala and hippocampus. These microscale perfusion deficits were undetectable by arterial spin labeling MRI. Our findings reveal the in vivo mechanics of pericyte contraction and identify limbic system vulnerability to capillary flow impairment.

neuroscience↗

bioRxiv2025

RIP3 and MLKL regulate Hepatic ER stress in alcohol-associated liver disease and pharmacological ER stress models: insights beyond necroptosis

Background and AimEndoplasmic reticulum (ER) stress is an important contributor to liver disease progression, including alcohol-associated liver disease (ALD). While receptor-interacting protein kinase-3 (RIP3) and mixed lineage kinase domain-like pseudokinase (MLKL) are known for their roles in necroptosis, emerging evidence highlights their non-canonical functions in metabolic regulation and cellular stress responses. However, their specific role in regulating hepatic ER stress remains unclear. This study investigates how RIP3, its kinase activity, and MLKL regulate ER stress pathways during chronic ethanol exposure and pharmacological ER stress induction. MethodsRip3-/-, Rip3K51A/K51A and Mlkl-/- mice alongside WT controls and pharmacological necroptosis inhibitors were used to study the role of RIP3 and MLKL in modulating ER stress. Chronic ethanol feeding and pharmacological agents (tunicamycin, thapsigargin) were utilized to induce ER stress in vivo and in isolated primary hepatocytes. ER stress markers were assessed by qPCR and western blot, ER expansion was evaluated by confocal microscopy, and hepatocyte viability was measured using MTS assay. ResultsChronic ethanol increased expression of ER stress markers in WT mice; this response was attenuated in Rip3-/- mice. Tunicamycin exposure increased hepatic ER stress markers in WT mice; this response was diminished in Rip3-/-, Rip3K51A/K51A and Mlkl-/-mice. In primary hepatocytes, genetic and pharmacological inhibition of RIP3 and MLKL also reduced thapsigargin-induced ER stress responses. Hepatocytes isolated from Rip3-/-, Rip3K51A/K51Aand Mlkl-/- mice exhibited enhanced cell viability under ER stress conditions compared to hepatocytes from WT mice, which was associated with ER expansion as a potential mechanism for mitigating ER stress. ConclusionThis study highlights a novel function of RIP3 and MLKL in regulating hepatic ER stress responses, expanding their known roles beyond programmed necrosis. Impact and ImplicationsThis study provides new mechanistic insight into how RIP3 and MLKL regulate hepatic ER stress responses, extending their roles beyond necroptosis. By demonstrating that genetic or pharmacological inhibition of Rip3, RIP3 kinase activity and Mlkl attenuates ER stress signaling, reduces cell death, and promotes adaptive ER remodeling, our findings identify these proteins as key modulators of hepatocyte survival under stress. These results are important for researchers and clinicians focused on alcohol-associated liver disease and other ER stress-driven liver disorders, as they highlight novel therapeutic targets. In practical terms, modulation of the RIP3- MLKL axis could inform the development of interventions aimed at enhancing ER stress resilience, with potential applications in drug development for ER stress-associated liver injury.

cell biology↗

bioRxiv2025

Preventing Microglial Reactivity Protects from Acute and Progressive Neuronal Dysfunction, Motor Impairments and Sedation following Alcohol Abuse

Alcohol abuse is the primary risk factor for alcohol use disorder (AUD), a leading cause of preventable morbidity and mortality, characterized by systemic inflammation, multi-organ damage, and neurological impairments. While direct effects of alcohol on brain function are well-established, the role of microglia in acute and chronic neurological dysfunction in AUD remains unclear. Using longitudinal in vivo imaging in mice during acute and repeated alcohol abuse, we found that microglia exhibit dynamic morphological responses that precede but parallel ethanol-induced sedation. Ethanol also induced microglia-dependent synapse elimination and reduced neuronal activity and density. Genetic disruption of microglial MyD88 reversed these ethanol-associated changes in microglial reactivity, neuronal structure, and function, while protecting against alcohol-induced intoxication and motor impairments. These findings identify microglia as cellular drivers of acute and chronic brain dysfunction following alcohol abuse, and highlight MyD88 as a critical therapeutic target for the detrimental neurological consequences of AUD.

neuroscience↗

bioRxiv2025

Mitochondria-derived dsRNA-induced stress granules promote IRF3-mediated fibrotic responses

Nucleic acid-induced activation of the anti-viral transcription factor interferon regulatory factor 3 (IRF3) promotes transforming growth factor-beta (TGF{beta})-induced fibrotic responses of hepatic stellate cells in vitro. Herein, we identified molecular mechanisms underlying TGF{beta}-induced IRF3 activation. Gene silencing of IRF3 with short interfering RNA (siRNA) in LX2 human hepatic stellate cells decreased TGF{beta}-induced fibrotic responses. An unbiased proteomic analysis of homeostatic IRF3-interacting proteins revealed striking enrichment in cytoplasmic stress granule components, including G3BP stress granule assembly factor 1 (G3BP1), G3BP2, and cell cycle associated protein 1 (CAPRIN1). TGF{beta} induced cytoplasmic accumulation of mitochondria-derived double-stranded RNA (mt-dsRNA) and assembly of IRF3-containing stress granules. Finally, blockade of G3BP1 activity or depletion of mt-dsRNA decreased TGF{beta}-induced fibrotic responses. Collectively, these findings identify a novel TGF{beta}-mt-dsRNA-stress granule axis in hepatic stellate cells that promotes IRF3-mediated fibrotic responses and potentially implicate cytoplasmic stress granules as a global regulator of fibrosis.

cell biology↗

bioRxiv2024

Microglia are not required for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism

Microglia are resident immune cells of the central nervous system, yet their functions far exceed those related to immunology. From pruning neural synapses during development to preventing excessive neural activity throughout life, microglia are intimately involved in the brains most basic processes. Studies have reported a close interaction between microglia and endothelial cells, as well as both helpful and harmful roles for microglia at the blood-brain barrier (BBB) in the context of disease. However, much less work has been done to understand microglia-endothelial cell interactions in the healthy brain. Here, we aim to determine the role of microglia at the healthy BBB. We used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia and analyzed BBB ultrastructure, permeability, and transcriptome. Interestingly, we found that, despite their direct contact with endothelial cells, microglia are not necessary for maintenance of BBB structure, function, or gene expression in the healthy brain. However, we found that PLX5622 treatment alters brain endothelial cholesterol metabolism, and this effect was independent from microglial depletion, suggesting PLX5622 has off-target effects on brain vasculature.

neuroscience↗

bioRxiv2023

Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer's Disease

Several microglia-expressed genes have emerged as top risk variants for Alzheimers disease (AD). Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD-risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (A{beta}), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. LD formation is dependent on age and disease progression and is prominent in the hippocampus in mice and humans. Despite differences in microglial LD load between brain regions and sexes in mice, LD-laden microglia exhibited a deficit in A{beta} phagocytosis. Unbiased lipidomic analysis identified a decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. DGAT2, a key enzyme for converting FFAs to TGs, promotes microglial LD formation and is increased in 5xFAD and human AD brains. Inhibition or degradation of DGAT2 improved microglial uptake of A{beta} and drastically reduced plaque load in 5xFAD mice, respectively. These findings identify a new lipid-mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.

neuroscience↗

bioRxiv2019

JAM-A functions as a female microglial tumor suppressor in glioblastoma

Glioblastoma (GBM) remains refractory to treatment. In addition to its cellular and molecular heterogeneity, epidemiological studies indicate the presence of additional complexity associated with biological sex. GBM is more prevalent and aggressive in male compared to female patients, suggesting the existence of sex-specific growth, invasion, and therapeutic resistance mechanisms. While sex-specific molecular mechanisms have been reported at a tumor cell-intrinsic level, sex-specific differences in the tumor microenvironment have not been investigated. Using transgenic mouse models, we demonstrate that deficiency of junctional adhesion molecule-A (JAM-A) in female mice enhances microglia activation, GBM cell proliferation, and tumor growth. Mechanistically, JAM-A suppresses anti-inflammatory/pro-tumorigenic gene activation via interferon-activated gene 202b (Ifi202b) and found in inflammatory zone (Fizz1) in female microglia. Our findings suggest that cell adhesion mechanisms function to suppress pathogenic microglial activation in the female tumor microenvironment, which highlights an emerging role for sex differences in the GBM microenvironment and suggests that sex differences extend beyond previously reported tumor cell intrinsic differences.\n\nSummaryTuraga et al. demonstrate that female microglia drive a more aggressive glioblastoma phenotype in the context of JAM-A deficiency. These findings highlight a sex-specific role for JAM-A and represent the first evidence of sexual dimorphism in the glioblastoma microenvironment.

cancer biology↗