Biology subjects

Barr, H. J.

Publications and source records attributed to Barr, H. J..

7 recordsLinked to original sources

bioRxiv2026

Microglia drive demyelination via multiple sclerosis antibodies and BTK signaling

Microglia are the predominant immune cells in multiple sclerosis (MS) demyelinating lesions, where they phagocytose myelin, but whether they destroy myelin or merely scavenge its debris is unknown. Here, we explore whether pathogenic autoantibodies found in MS may induce the phagocytic destruction of myelin by microglia. Applying patient-derived, myelin-targeting antibodies to the mouse cortex, we developed an in vivo model of MS with focal demyelination that depended on epitope specificity and Fc gamma receptor and complement binding. Longitudinal monitoring of microglia-myelin interactions using in vivo two-photon microscopy revealed rapid microglial envelopment of intact myelin driving myelin loss, while single-cell RNA sequencing identified a demyelination-associated microglial signature. Parallel changes were observed in human MS lesions, where microglia enveloped intact myelin and similar genes were upregulated. Inhibition of Brutons tyrosine kinase (BTK) limited microglial transcriptional changes and prevented myelin loss following microglial envelopment. These findings directly implicate microglia in pathological myelin loss and support BTK inhibition as a therapeutic strategy to prevent demyelination by modulating microglia behavior.

neuroscience↗

bioRxiv2026

Engulfment by brain macrophages in a short-lived vertebrate

Engulfment by macrophages is critical for waste clearance in the vertebrate brain. Understanding clearance mechanisms may open new therapeutic possibilities to counter brain aging and neurodegenerative diseases. However, few in vivo models exist to study engulfment in the brain and characterize this process during aging and across species. Here we present a genetic model for secretion of a fluorescent protein by neurons in the brain of the African turquoise killifish, the shortest-lived vertebrate that can be bred in captivity. We use this model to identify a population of brain macrophages in the killifish responsible for engulfment of material from the brain extracellular space. Intriguingly, many of these cells bear similarities to mammalian border-associated and monocyte-derived macrophages, rare subsets of macrophages in mouse and human brains noted for their engulfment capabilities. We also find that in our model, killifish brain macrophages decline in engulfment capacity with age. This work highlights how vertebrate brain macrophages, particularly those at brain border regions, can play a critical role in clearance and provides an opportunity to test interventions that can boost engulfment by these macrophages to promote brain resilience in old age and disease.

cell biology↗

bioRxiv2025

Conserved phenotype and function of human brain border-associated macrophages in iPSC-derived models

Border-associated macrophages (BAMs) are increasingly implicated in protective brain functions including the removal of pathogenic material such as amyloid-beta (A{beta}). However, there is a lack of available and deeply characterized human BAM models. Here, we report that postnatal transplantation of induced pluripotent stem (iPS) cell-derived hematopoietic progenitors to the murine brain sufficiently chimerizes the brain border immune compartment to allow functional interrogations. Human xenotransplanted BAMs (xBAMs) line the leptomeninges and brain vasculature beyond the glia limitans. Via single-cell RNA sequencing, we show that a conserved transcriptional signature distinguishes BAMs from microglia across species origin, age, and genetic background. Both xBAMs and murine BAMs are defined by a hyper-endocytic phenotype and function, surpass other brain macrophages in acute A{beta} scavenging, and exhibit compartment-restricted sampling of parenchymal material. Using a modified differentiation protocol, we find that we can generate iPS-derived BAM-like cells (iBAMs) in vitro, which are also characterized by a hyper-endocytic phenotype and enhanced engulfment capacity relative to iPS-derived microglia-like cells (iMGLs). Together, these data define a conserved hyper-endocytic BAM phenotype and provide a toolbox for studying human BAMs both in vivo and in vitro.

neuroscience↗

bioRxiv2025

The circadian clock regulates scavenging of fluid-borne substrates by brain border-associated macrophages

Circadian disruptions perturb the brain and immune system and increase the risk of developing Alzheimers Disease (AD), yet whether this involves dysregulation of brain immunity remains less clear. Here, we perform single-cell RNA sequencing of the brain immune compartment around the day-night cycle and identify brain border-associated macrophages (BAMs) as highly rhythmic cells. During the rest phase, we find that BAMs exhibit coordinated upregulation of endocytic genes and enhanced uptake of extracellular fluid-borne material including amyloid-beta (A{beta}). Rhythmicity in BAM scavenging is regulated by the clock gene Bmal1, mediated by the endocytic receptor CD206, and perturbed with age. In a mouse model of AD, we show that deletion of Bmal1 in BAMs worsens perivascular and leptomeningeal A{beta} plaque burden. Our results identify endocytosis as a specialized and rhythmic BAM function and identify perturbed timing of brain border immune functions as a potential mechanism by which circadian disruptions precipitate amyloidosis.

neuroscience↗

bioRxiv2025

Early-life stromal niches orchestrate B lymphopoiesis at the brain's borders

The dura mater serves as a critical immunological niche for the central nervous system, yet the mechanisms governing the emergence of this niche in early life remain understudied. Here, we chart the trajectory of dural immune development, uncovering a distinctive function for the murine dura as a transient niche for B lymphopoiesis in the early-postnatal window. Shared embryonic progenitors initiate dural B cell development in concert with a multi-organ wave of extramedullary lymphopoiesis that contributes distinctively to the peripheral B cell pool. In the dura, B cells develop locally in discrete sinus-proximal foci, occupying an anatomically defined and developmentally restricted fibroblast niche. Sinus-proximal fibroblasts express the pro-hematopoietic chemokine CXCL12, and local deletion of this crucial factor severely impairs dural B lymphopoiesis. These data reveal a critical function for dural fibroblasts in shaping the early-life B cell compartment and provide a model for how extramedullary niches may support early-life leukocyte production.

immunology↗

bioRxiv2020

Motor Learning Promotes Remyelination via New and Surviving Oligodendrocytes

Oligodendrocyte loss in neurological disease leaves axons vulnerable to damage and degeneration, and activity-dependent myelination may represent an endogenous mechanism to improve remyelination following injury. Here, we report that while learning a forelimb reach task transiently suppresses oligodendrogenesis, it subsequently increases OPC differentiation, oligodendrocyte generation, and retraction of pre-existing myelin sheaths in the forelimb region of motor cortex. Immediately following demyelination, motor cortex neurons exhibit hyperexcitability, motor learning is impaired, and behavioral intervention provides no long-term benefit to remyelination. However, partial remyelination restores neuronal and behavioral function. Motor learning following partial remyelination increases oligodendrogenesis and enhances the ability of mature oligodendrocytes to generate new myelin sheaths, resulting in almost double the remyelination of denuded axons relative to untrained controls. Together, our findings demonstrate that the correct timing of behaviorally-induced neuronal circuit activation improves recovery from demyelinating injury via enhanced remyelination from new and surviving oligodendrocytes.

neuroscience↗

bioRxiv2019

Dopamine in the songbird auditory cortex shapes auditory preference

In vocal communication, vocal signals can provide listeners with information and also elicit motivated responses. Auditory cortical and mesolimbic reward circuits are often considered to have distinct roles in these processes, with auditory cortical circuits responsible for detecting and discriminating sounds and mesolimbic circuits ascribing salience and modulating preference for those sounds. Here, we investigated whether dopamine within auditory cortical circuits themselves can shape the incentive salience of a vocal signal. Using female zebra finches, who show natural preferences for vocal signals produced by males ( songs), we found that pairing passive song playback with pharmacological manipulations of dopamine in the secondary auditory cortex drives changes to song preferences. Plasticity of song preferences by dopamine lasted for at least one week and was not influenced by norepinephrine manipulations. These data suggest that dopamine acting directly in sensory processing areas can shape the incentive salience of communication signals.

neuroscience↗