Biology subjects

Kind, P.

Publications and source records attributed to Kind, P..

7 recordsLinked to original sources

bioRxiv2026

Astrocytes transform the transcriptomic and epigenetic landscape of developing cortical neurons to promote activity via intrinsic excitability control

Astrocytes are implicated in neuronal development and function, particularly of synapses, but their genome-wide impact is unclear. We show that cortical astrocytes trigger epigenetic remodelling in developing cortical neurons and widespread transcriptomic changes distinct from neurons intrinsic developmental trajectory. These changes can cause an emergence of neuronal firing activity independent of functional excitatory synaptogenesis. The mechanism is via through astrocyte-derived signals causing the transcriptional repression of inwardly-rectifying K+-channels (Kirs), causing a pro-excitatory shift in intrinsic properties. This places neurons in a zone of excitability whereupon cell-autonomous homeostatic control was activated, also associated with Kir regulation. Astrocyte-induced neuronal genes were enriched for schizophrenia, epilepsy, ADHD and Alzheimers disease risk, disorders associated with circuit imbalance. Thus, astrocyte-to-neuron signaling can alter firing via intrinsic properties in addition to the classical synaptogenic mechanism. The opposing actions of astrocytes and neuronal activity in regulating neuronal intrinsic properties may prevent hyper- or hypo-activity in neuronal circuits

neuroscience↗

bioRxiv2025

Microglia are not required for normal postnatal brain development and cognitive function in the rat.

The development, maintenance and survival of microglia, the brains resident immune cells, requires signalling via the colony stimulating factor 1 receptor (CSF1R). In mice, the Fms intronic regulatory element (FIRE), a highly conserved super enhancer, is required for CSF1R expression in microglia and germ-line deletion of FIRE leads to microglial deficiency. We have generated Csf1r{Delta}FIRE/{Delta}FIRE (Fireko) rats using CRISPR/Cas9. Fireko rats are born at expected Mendelian frequency, grow normally and survive to adulthood. Like Fireko mice, they lack microglia and subpopulations of resident macrophages in kidney and heart, but retain the other brain associated macrophages and resident populations in the liver, spleen and lungs. In contrast to mutant mice, macrophages in the peritoneum are unaffected and CSF1R expression is not completely abolished in the blood. Aside from the loss of microglia-specific transcripts, the Fireko has no effect on expression of genes associated with neurons, oligodendrocytes or astrocytes in adult rats but is associated with detectable calcification in the thalamus. Despite the absence of microglia, we detected no significant differences in ethologically relevant behaviours compared to littermates. The results suggest that microglia are not essential for normal cognitive development. Fireko rats provide an alternative to mice as a model for human microglial deficiency and the functions of microglia in development and homeostasis in the brain.

immunology↗

bioRxiv2025

RatDISCO, a tissue clearing and immunolabelling protocol for large rat brains.

RatDISCO is a simple, cost-effective, and reproducible tissue-clearing protocol optimised for immunolabeling in adult rat brains. It enables robust detection of diverse neuronal subtypes, glial populations, and vasculature, overcoming key limitations in antibody penetration and optical transparency. It is compatible with virally labelled-and transgenic mice, as well as human-derived brain organoids, highlighting its versatility across species and models. Functionally, it enables the detection of activity-dependent markers after behaviour, verified in a rat model of neurodevelopmental disorders, the Fragile X syndrome. These findings highlight RatDISCO as a broadly applicable tool for investigating neuroanatomical and functional alterations in rat models of disorders. HighlightsO_LIOptimised for immunolabeling in adult rat brains C_LIO_LIEnables detection of neurons, glial cells, and vasculature C_LIO_LIAchieves high tissue transparency without requiring specialised equipment. C_LIO_LICompatible with virally labelled mice and human brain organoids C_LIO_LIFacilitates mapping of activity-dependent markers in rat models of neurodevelopmental disorders C_LI

neuroscience↗

bioRxiv2025

Repopulation of the brain with microglia-like cells following intraperitoneal bone marrow cell transfer in microglia-deficient mice.

Germ-line deletion of a conserved enhancer (the Fms intrinsic regulatory element, FIRE) in the mouse Csf1r locus causes congenital absence of microglia. Homozygous FIRE deletion on a C57BL/6J background leads to perinatal lethality and hydrocephalus (HC) in surviving pups. We developed a congenic C57BL/6J line with defined regions of non-C57BL/6J genomic DNA, increased postnatal viability and reduced incidence of HC. Both perinatal lethality and HC were eliminated in F2 mice following outcross of the congenic line to CBA/J or BALBc/J backgrounds. To assess the impacts of microglial deficiency in postnatal neurodevelopment we analyzed deep total RNA-seq data from multiple brain regions of wild-type and Csf1r{Delta}FIRE/{Delta}FIRE mice. Aside from the loss of microglial-specific transcripts, we found no significant alterations in relative abundance of any cell-type or region-specific transcriptomic signature. Transcripts associated with endosome/lysosome function, which are enriched in microglia, were not affected, suggesting compensatory expression by other cell types. On the C57BL/6J x CBA/J F2 background, congenital absence of microglia did not affect motor activity, behavior or myelination up to 7 months of age but was associated with astrocytosis and calcification in the thalamus. In the congenic C57BL/6J Csf1r{Delta}FIRE/{Delta}FIRE mouse line, intraperitoneal transfer of wild-type bone marrow cells (BMT) at weaning led to complete repopulation of the brain with microglia-like cells without giving rise to monocytic intermediates. Our results suggest novel strategies for treatment of microglial deficiency.

neuroscience↗

bioRxiv2020

Functional Predictors of Causative Cis-Regulatory Mutations in Mendelian Disease

Undiagnosed neurodevelopmental disease is significantly associated with rare variants in cis-regulatory elements (CRE) but demonstrating causality is challenging as target gene consequences may differ from a causative variant affecting the coding region. Here, we address this challenge by applying a procedure to discriminate likely diagnostic regulatory variants from those of neutral/low-penetrant effect. We identified six rare CRE variants using targeted and whole genome sequencing in 48 unrelated males with apparent X-linked intellectual disability (XLID) but without detectable coding region variants. These variants segregated appropriately in families and altered conserved bases in predicted CRE targeting known XLID genes. Three were unique and three were rare but too common to be plausibly causative for XLID. We compared the cis-regulatory activity of wild-type and mutant alleles in zebrafish embryos using dual-color fluorescent reporters. Two variants showed striking changes: one plausibly causative (FMR1CRE) and the other likely neutral/low-penetrant (TENM1CRE). These variants were "knocked-in" to mice and both altered embryonic neural expression of their target gene. Only Fmr1CRE mice showed disease-relevant behavioral defects. FMR1CRE is plausibly disease-associated resulting in complex misregulation of Fmr1/FMRP rather than loss-of-function. This is consistent both with absence of Fragile X syndrome in the probands and the observed electrophysiological anomalies in the FMR1CRE mouse brain. Although disruption of in vivo patterns of endogenous gene expression in disease-relevant tissues by CRE variants cannot be used as strong evidence for Mendelian disease association, in conjunction with extreme rarity in human populations and with relevant knock-in mouse phenotypes, such variants can become likely pathogenic.

genetics↗

bioRxiv2019

LAB-AID (Laboratory Automated Interrogation of Data): an interactive web application for visualization of multi-level data from biological experiments

A key step in understanding the results of biological experiments is visualization of the data. Many laboratory experiments contain a range of measurements that exist within a hierarchy of interdependence. An automated way to visualise and interrogate experimental data would: 1) lead to improved understanding of the results, 2) help to determine which statistical tests should be performed, and 3) easily identify outliers and sources of batch effects. Unfortunately, existing graphing solutions often demand expertise in programming, require considerable effort to import and examine such multi-level data, or are unnecessarily complex for the task at hand. Here we present LAB-AID (Laboratory Automated Interrogation of Data), an interactive tool specifically designed to automatically visualize and query hierarchical data resulting from biological experiments.

bioinformatics↗

bioRxiv2018

Cellular and Synaptic Phenotype Compensations Limit Circuit Disruption in Fmr1-KO Mouse Layer 4 Barrel Cortex but Fail to Prevent Deficits in Information Processing

Sensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS). However, how developmental changes in neuronal function ultimately culminate in the network dysfunction that underlies sensory hypersensitivities is not known. To address this, we studied the layer 4 barrel cortex circuit in Fmr1 knockout mice, a critical sensory processing circuit in this mouse model of FXS. By systematically studying cellular and synaptic properties of layer 4 neurons and combining with cellular and network simulations, we explored how the array of phenotypes in Fmr1 knockout produce circuit pathology during development that result in sensory processing dysfunction. We show that many of the cellular and synaptic pathologies in Fmr1 knockout mice are antagonistic, mitigating circuit dysfunction, and hence can be regarded as compensatory to the primary pathology. Despite this compensation, the layer 4 network in the Fmr1 knockout exhibits significant alterations in spike output in response to ascending thalamocortical input that we show results in impaired sensory encoding. We suggest that it is this developmental loss of layer 4 sensory encoding precision that drives subsequent developmental alterations in layer 4 - layer 2/3 connectivity and plasticity observed in the Fmr1 knockout, and is a critical process producing sensory hypersensitivity.

neuroscience↗