Biology subjects

Dziabis, J. E.

Publications and source records attributed to Dziabis, J. E..

5 recordsLinked to original sources

bioRxiv2026

Context-dependent effects of microglial MyD88 removal on voluntary ethanol consumption in mice

Neuroimmune signaling is increasingly implicated in alcohol use disorder (AUD). Microglia, the brains resident immune cells, signal in part through the adaptor protein myeloid differentiation primary response 88 (MyD88), a key mediator of innate immune responses. Here, we investigated whether microglial-specific MyD88 signaling regulates voluntary alcohol consumption in adulthood, as whole-body loss of MyD88 was previously shown to increase drinking. We further determined if alcohol altered parvalbumin-expressing interneurons (PVIs) and microglia within the pre-frontal cortex, based on our previously described role for MyD88 signaling on perineuronal net (PNN) deposition on PVIs in several brain regions, and the well characterized role of inhibitory signaling in alcohol use disorders. Loss of microglial-MyD88 had minimal effects on voluntary alcohol intake and anxiety-like behaviors. Alcohol exposure did not modify observed MyD88-dependent changes in PVIs/PNNs, despite altering microglial morphology in the male prefrontal cortex independent of genotype. The addition of an early life endotoxin challenge was sufficient to induce an increase in adult alcohol consumption in both MyD88-deficient and control males. However, injection of saline alone also induced an increase in adult drinking in MyD88-deficient males. These findings suggest that microglial-MyD88 signaling does not strongly regulate alcohol intake under baseline conditions in a one-bottle, voluntary binge-drinking paradigm, however there may be a role for microglial-MyD88 signaling in modulating the impact of developmental environmental contexts, such as stress, in later-life male drinking behavior. This work highlights the importance of developmental context, such as stress or inflammatory history, in understanding underlying microglia signaling mechanisms in conferring AUD risk.

neuroscience↗

bioRxiv2026

CGRP reception potentiates anxiety in an influenza A derived immune engram

An immune engram is a recently described phenomenon in which neuronal populations encode functional aspects of an immune challenge. Here we investigate an immune engram arising from respiratory infection with influenza A virus, demonstrating a molecular mechanism with differential influence over behavioral and immunological aspects of the engram. We first define a cellular response to acute non-neurotropic influenza A/Puerto Rico/8/1934 (PR8) infection by mapping cFos+ cells and microglia morphology across brain regions. In the posterior insula, this response has an early peak at 3 days post infection. Using a cre-dependent excitatory chemogenetic system in TRAP2 mice, we capture an engram at this same region and infection timepoint. Activation of this PR8 engram results in anxiety behavior and increased transcriptional expression of cytokines in lung tissue but not spleen tissue. We further explore how pulmonary signals contribute to this PR8 engram. Using tissue-specific, cre-dependent expression of diphtheria toxin fragment in Calcacre mice, we ablate Calca-expressing cells including pulmonary neuroendocrine cells in respiratory tissue. Loss of Calca-expressing cells prevents changes in synaptic engulfment by microglia in the insula during PR8 infection without altering the cellular response to infection in pulmonary tissue. Signaling of calcitonin gene related peptide (CGRP), a peptide encoded by Calca, can be blocked with the small molecule CGRP receptor antagonist rimegepant. Using rimegepant during acute PR8 infection we again demonstrate that loss of Calca signaling prevents the cellular response to PR8 infection in the insula. Finally, applying rimegepant alongside the chemogenetic system in TRAP2 mice we show that CGRP receptor antagonism during engram formation prevents anxiety behavior but not peripheral gene expression changes resulting from PR8 engram activation.

neuroscience↗

bioRxiv2026

Maternal high-fat diet drives sex-specific microglia remodeling of serotonergic reward circuits

Maternal nutrition shapes offspring brain development and influences neurodevelopmental disorder risk, but the underlying mechanisms remain unclear. In mice, maternal high-fat diet exposure disrupted microglia-serotonin interactions during a critical postnatal period, producing persistent, sex-specific mesolimbic alterations. Male but not female offspring showed increased serotonergic fiber density in the nucleus accumbens (NAc), coincident with reduced microglial phagocytosis of serotonergic projections. Microglial 5-HT2C receptor signaling is a key regulator of this process. Viral over expression in microglia, mimicking diet-induced upregulation, was sufficient to cause serotonergic hyperinnervation. By adulthood, male offspring displayed increased NAc serotonin release and projection-specific changes in dorsal raphe physiology. These circuit alterations accelerated reward-motivated learning, a phenotype reproduced by chemogenetic activation of NAc-projecting serotonergic neurons. Together, these findings reveal a novel mechanism by which maternal diet programs serotonergic circuit assembly and behavior in a sex-specific manner, providing a potential link between early-life metabolic inflammation and lifelong serotonergic dysfunction.

neuroscience↗

bioRxiv2025

Microglial MyD88-dependent signaling influences extracellular matrix development and interneuron maturation in the hippocampus

Parvalbumin interneurons (PVIs) are disrupted across diverse neurodevelopmental disorders, highlighting their vulnerability to developmental perturbations. Inflammation can perturb PVI development and function, and inflammatory mechanisms are often propagated within the brain by microglia. Yet the microglial mechanisms linking inflammatory signals to interneuron development are unclear. To test the role of microglial innate immune signaling in PVI development, we used mice lacking toll-like receptor adaptor MyD88 specifically in microglia. MyD88-deficient microglia showed reduced inflammatory responses but increased early-life phagocytosis of inhibitory synaptic material. In adulthood, males without microglial MyD88 exhibited increased hippocampal PVI density, increased extracellular matrix (ECM) deposition, increased inhibitory signaling, and impaired discrimination behaviors. We determined the cytokine interleukin (IL)-33, which normally drives adult microglial remodeling of the ECM, is developmentally regulated in the hippocampus. MyD88-deficient microglia fail to respond to IL-33, leading to reduced remodeling of the ECM component aggrecan. These results reveal microglial immune signaling via MyD88 regulates hippocampal inhibitory circuit development in a sex-specific manner.

neuroscience↗

bioRxiv2020

Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number, independent of microglial inflammatory signaling

Decreases in social behavior are a hallmark aspect of acute "sickness behavior" in response to infection. However, immune insults that occur during the perinatal period may have long-lasting consequences for adult social behavior by impacting the developmental organization of underlying neural circuits. Microglia, the resident immune cells of the central nervous system, are sensitive to immune stimulation and play a critical role in the developmental sculpting of neural circuits, making them likely mediators of this process. Here, we investigated the impact of a postnatal day (PND) 4 lipopolysaccharide (LPS) challenge on social behavior in adult mice. Somewhat surprisingly, neonatal LPS treatment decreased sociability in adult female, but not male mice. LPS-treated females also displayed reduced social interaction and social memory in a social discrimination task as compared to saline-treated females. Somatostatin (SST) interneurons within the anterior cingulate cortex (ACC) have recently been suggested to modulate a variety of social behaviors. Interestingly, the female-specific changes in social behavior observed here were accompanied by an increase in SST interneuron number in the ACC. Finally, these changes in social behavior and SST cell number do not appear to depend on microglial inflammatory signaling, because microglia-specific genetic knock-down of myeloid differentiation response protein 88 (MyD88; the removal of which prevents LPS from increasing proinflammatory cytokines such as TNF and IL-1{beta}) did not prevent these LPS-induced changes. This study provides novel evidence for enduring effects of neonatal immune activation on social behavior and SST interneurons in females, independent of microglial inflammatory signaling.

neuroscience↗