Biology subjects

Muller, P. A.

Publications and source records attributed to Muller, P. A..

5 recordsLinked to original sources

bioRxiv2026

Mapping Enteric Neural Circuits by Anterograde Transsynaptic Tracing

The diverse functions of the enteric nervous system (ENS) arise from communication between molecularly distinct neuronal populations organized into complete circuits. While recent single-cell transcriptomic studies have resolved the molecular identity of enteric neuron classes, methods for defining their synaptic connectivity remain limited. Here, we describe the implementation of mWmC, an anterograde monosynaptic tracer based on a fusion of wheat germ agglutinin (WGA) and mCherry, as a non-toxic, single-component viral tool for mapping neuronal circuits within and beyond the ENS. Following adeno-associated virus (AAV)-mediated expression in enteric neurons, mWmC was efficiently expressed and transmitted selectively to postsynaptic neurons, with no detectable transfer to enteric glia, interstitial cells of Cajal, blood vessels or other mesenchymal cell types. The method also identified postsynaptic neurons in the celiac-superior mesenteric ganglia following tracing of intestinofugal enteric neurons, demonstrating its utility for mapping inter-organ circuits. As proof of principle, we applied mWmC to two genetically defined myenteric interneuron populations and identified preferential postsynaptic targets, revealing selective connectivity with distinct enteric neuron classes. Time-course experiments showed that transsynaptic labeling occurred between 4 and 10 days and reached a plateau thereafter, consistent with monosynaptic transfer. Finally, we developed a dual-reporter version of the system that simultaneously distinguishes input and target neurons within the same tissue. Together, mWmC provides a robust approach for defining circuit architecture in the ENS, linking molecular cell atlases with neuronal connectivity and paving the way for deeper insights into the circuit mechanisms underlying gut physiology. Graphical AbstractSchematics illustrating the implementation and applications of the anterograde monosynaptic tracer mWmC for mapping enteric neuronal circuits. Parts of schematics are generated with Biorender. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=36 SRC="FIGDIR/small/741165v2_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@19635bborg.highwire.dtl.DTLVardef@a18ffborg.highwire.dtl.DTLVardef@f3d011org.highwire.dtl.DTLVardef@e1359c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Microbiota-modulated enteric neuron translational profiling uncovers a CART+ glucoregulatory subset

Microbial density and diversity increase towards the distal intestine, affecting tissue physiology, metabolism, and function of both immune and nervous systems. Intrinsic enteric-associated neurons (iEAN) continuously monitor and modulate intestinal functions, including nutrient absorption and motility. Through molecular, anatomic and functional approaches, we characterized the influence of the microbiota on iEAN. We found that iEAN are functionally adapted to the intestinal segment they occupy, with a stronger microbiota influence on distal intestine neurons. Chemogenetic characterization of microbiota-influenced iEAN identified a subset of viscerofugal CART+ neurons, enriched in the distal intestine, able to modulate feeding through insulin-glucose levels. Retro- and anterograde tracing revealed that CART+ viscerofugal neurons send axons to the gut sympathetic ganglion and are synaptically connected to the liver and pancreas. Our results demonstrate a region-specific adaptation of enteric neurons and indicate that specific iEAN subsets are capable of regulating host physiology independently from the central nervous system. One Sentence SummaryMicrobes impact regionally defined intrinsic enteric neuron translatomes, including a novel CART+ glucoregulatory viscerofugal population.

neuroscience↗

bioRxiv2019

Adrenergic signaling in muscularis macrophages limits neuronal death following enteric infection

Enteric-associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility. Bidirectional interactions between immune and neuronal cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated how infection-induced inflammation affects intrinsic EANs and the role of intestinal muscularis macrophages (MMs) in this process. Using murine model of bacterial infection, we observed long-term gastrointestinal symptoms including reduced motility and subtype-specific neuronal loss. Neuronal-specific translational-profiling uncovered a caspase 11-dependent EAN cell-death mechanism induced by enteric infections. MMs responded to luminal infection by upregulating a neuroprotective program; gain- and loss-of-function experiments indicated that {beta}2-adrenergic receptor ({beta}2-AR) signaling in MMs mediates neuronal protection during infection via an arginase 1-polyamine axis. Our results identify a mechanism of neuronal cell death post-infection and point to a role for tissue-resident MMs in limiting neuronal damage.

immunology↗

bioRxiv2019

Microbiota imprint gut-intrinsic neuronal programming and sympathetic activity

Microbial density and diversity increases from proximal to distal regions of the intestine, affecting tissue physiology, metabolism, and function of the immune and nervous systems. Both intrinsic and extrinsic enteric-associated neurons (EAN) continuously monitor and modulate homeostatic intestinal functions, including nutrient absorption and motility. However, a systemic and circuit-based link between gut microbes and the nervous system has yet to be established. Through a combination of molecular, anatomic and functional approaches, we characterized the influence of the microbiota on EAN. We found that intrinsic EAN are functionally adapted to the specific intestinal region they occupy in a microbiota-dependent manner. Furthermore, we observed that gut-extrinsic sympathetic neurons are hyperactivated in the absence of microbes, while the production of butyrate is sufficient to suppress sympathetic activity. Finally, retrograde polysynaptic neuronal tracing from the intestinal wall revealed that brainstem GABAergic neurons are a potential central hub for modulation of gut-specific sympathetic neurons. These results reveal that commensal microbiota imprint gut-intrinsic neuronal gene programs and control extrinsic sympathetic activity through a metabolite-mediated gut-brain circuit.

neuroscience↗

bioRxiv2018

Compartmentalized lymph node drainage dictates intestinal adaptive immune responses

The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure in such balance leads to a range of severe intestinal and systemic diseases such as inflammatory bowel diseases, food allergies or invasive gastrointestinal infections1,2. Multiple innate and adaptive immune mechanisms are therefore in place to maintain tissue integrity, including efficient peripheral generation of effector T (TH) cells and FOXP3+ regulatory T (pTreg) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively2-5. The gut-draining mesenteric lymph nodes (mLNs) are critical sites for orchestrating adaptive immunity to luminal perturbations6-8. However, how they manage to simultaneously support tolerogenic and inflammatory reactions is incompletely understood. Here we report that individual mLNs are anatomically and immunologically distinct according to the functional gut segment they drain. Dendritic cell gene signatures and adaptive T cell polarization against the same luminal antigen differed between mLNs along the intestine, the proximal small intestine-draining mLNs preferentially giving rise to tolerogenic and the distal mLNs to pro-inflammatory T cell responses. This compartmentalized dichotomy could be perturbed by duodenal infection, surgical removal of select distal mLNs, dysbiosis, or ectopic antigen delivery, impacting both lymphoid organ and tissue immune responses. Our findings reveal that the conflict between tolerogenic and inflammatory adaptive responses is in part resolved by discrete mLN drainage, and encourage gut segment-specific antigen targeting for therapeutic immune modulation.

immunology↗