Anatomical differences in nociceptor neurons sensitivity

Abstract

Background Dorsal Root Ganglia (DRG) neurons are derived from the neural crest and mainly innervate the skin, while Jugular Nodose Complex (JNC) neurons originate from the placode and innervate internal organs. These ganglia are composed of highly heterogeneous groups of neurons aimed at assessing and preserving homeostasis. Among other subtypes, nociceptor neurons are specialized in sensing and responding to environmental dangers. As form typically follows function, we hypothesized that JNC and DRG neurons would be phenotypically and transcriptomically different. Methods Mouse JNC and DRG neurons were cultured ex vivo. Using calcium imaging, qPCR and neurite outgrowth assay, we compared the sensitivity of JNC and DRG neurons. Using in-silico analysis of existing RNA sequencing datasets, we confronted our results to transcriptomic differences found between both ganglia. Results We found drastically different expression levels of Transient Receptor Potential (TRP) channels, growth factor receptors and neuropeptides in JNC and DRG neurons. Functionally, naïve JNC neurons’ TRP channels are more sensitive to thermal cues than the ones from DRG neurons. However, DRG neurons showed increased TRP channel responsiveness, neuropeptide release and neurite outgrowth when exposed to Nerve Growth Factor (NGF). In contrast, JNC neurons preferentially responded to Brain-derived neurotrophic factor (BDNF). Conclusion Our data show that JNC and DRG neurons are transcriptomically and functionally unique and that pain sensitivity is different across anatomical sites. Drugs targeting NGF signaling may have limited efficacy to treat visceral pain. Bioelectronics nerve stimulation should also be adjusted to the ganglia being targeted and their different expression profile.

Cytokines reprogram airway sensory neurons in asthma

“…Via vagal projections, the JNC innervates most visceral organs (24). Single-cell RNA sequencing datasets revealed that JNC neurons are highly heterogenous (2, 3, 25) and provide a transcriptome-based neuron subtype classification (2, 3, 6, 26). While genetically guided optogenetic studies identified JNC neuronal subtypes controlling breathing and tracheal reflexes (1, 25), additional molecular characterization of airway nociceptors is lacking.…”

“…Sensory neurons are heterogenous and can be differentiated based on their expression profiles (1–3), degree of myelination (4), the type of cues to which they are sensitive (4, 5), the reflexes that they initiate, their anatomical location (6) or the organ that they innervate (7, 8). For instance, internal organs such as the lungs are innervated by the vagus nerve, whose neurons originate from the jugular nodose complex ganglia (JNC).…”

Calcium imaging and analysis of the jugular-nodose ganglia enables identification of distinct vagal sensory neuron subsets

“…Accessing and stabilizing the jugular-nodose ganglia has been a challenge due to its location in the body and its close proximity to deeply embedded tissues and major blood vessels ( Han and de Araujo 2021 ). Prior efforts to monitor neural activity in peripheral ganglia have focused on dorsal root ganglia (DRG) or have utilized in vitro approaches ( Crosson and Talbot 2022 ). Because there are major differences in the signal-to-noise of the jugular-nodose ganglia fluorescence signal, compared to standard intracranial recordings, we then outline how to implement and modify Calcium Imaging Analysis (CaImAn), a Python-based analysis pipeline ( Giovannucci et al 2019 ), to accurately extract calcium transients from raw fluorescence intensity data.…”