Prototypical pacemaker neurons interact with the resident microbiota

Abstract

<jats:p>Pacemaker neurons exert control over neuronal circuit function by their intrinsic ability to generate rhythmic bursts of action potential. Recent work has identified rhythmic gut contractions in human, mice, and hydra to be dependent on both neurons and the resident microbiota. However, little is known about the evolutionary origin of these neurons and their interaction with microbes. In this study, we identified and functionally characterized prototypical ANO/SCN/TRPM ion channel-expressing pacemaker cells in the basal metazoan <jats:italic>Hydra</jats:italic> by using a combination of single-cell transcriptomics, immunochemistry, and functional experiments. Unexpectedly, these prototypical pacemaker neurons express a rich set of immune-related genes mediating their interaction with the microbial environment. Furthermore, functional experiments gave a strong support to a model of the evolutionary emergence of pacemaker cells as neurons using components of innate immunity to interact with the microbial environment and ion channels to generate rhythmic contractions.</jats:p>

Epithelial Infection With Candida albicans Elicits a Multi-System Response in Planarians

“…Likewise, the dramatic increase in the expression of the marker of cholinergic neurons ( chat ) in the initial 24 hpi, suggests that this neuronal type may be important in the innate immune response to C. albicans infection. This is consistent with the idea that certain neuronal groups can act as immunocompetent cells, which is an ancient function conserved between pre-bilaterians and mammals ( Godinho-Silva et al, 2019 ; Klimovich et al, 2020 ). Indeed, murine nociceptive neurons are critical for the innate immune response to cutaneous infection with C. albicans ( Kashem et al, 2015 ).…”

Linking neurons to immunity: Lessons from Hydra

“…An earlier study by the same group, indicated that neurons themselves play direct immune roles by producing antimicrobial factors, such as antimicrobial peptides ( 18 ), that can alter the composition of the microbial communities on the body ( 19 ). Here, Klimovich et al ( 2 ) extend their earlier findings and demonstrate that all neurons in the Hydra body, including the N2 pacemaker cluster, produce a rich repertoire of antimicrobial peptides and proteins, as well as many components of pathogen recognition receptors, such as Toll-like receptors, NOD-like receptors, C-type lectin, etc., indicating that they are immunocompetent cells with critical roles in immune signaling. Stressing further the role of Hydra neurons to immunity, the authors used bioinformatics and machine learning algorithms to demonstrate that a large fraction of neuronal genes unique to this genus, are capable of encoding antimicrobial peptides.…”

“…By analyzing larvae carrying a mutation at the ret locus, the activity of which is required for the development of enteric neurons, Wiles et al ( 20 ) demonstrated that changes in peristalsis alter the relative abundance and distribution of specific bacterial species along the intestine of zebrafish. Based on the findings of Klimovich et al ( 2 ), it is possible that some of the effects observed in the zebrafish study could be due to direct and selective antimicrobial activities of enteric neurons. Characterization of the transcriptomes of enteric neurons in zebrafish, mouse, and human gut will generate valuable resources for establishing the range of antimicrobial factors produced by the intestinal neural networks of vertebrates.…”

“…In their current study, Klimovich et al ( 2 ) take advantage of single-cell RNA sequencing to characterize the molecular features and functional properties of the neuronal populations of Hydra . Based on the differential expression of transcripts encoding neurotransmitter receptors, ion channels, neuropeptides, and transcription factors, the authors demonstrate that the neuronal population of Hydra is subdivided into seven distinct clusters that are likely to include neurons with unique functions.…”

“…Of course, we now understand why Iolaus' contribution was so critical: His flame consumed the local stem cells and stopped them from generating a new head! In PNAS, Klimovich et al (2) go one step further and provide a reasonable explanation as to why the Lernaean Hydra could remain healthy despite inhabiting the dirty waters of an unfathomable Peloponnesian swamp. Using Hydra as the experimental model organism, the authors define the molecular identity of a unique group of neurons that are responsible for the rhythmic contractions of the body and provide insight into the immune mechanisms they (and other neurons) employ to regulate the animal's microbial environment.…”