Investigating Mechanically Activated Currents from Trigeminal Neurons of Non-Human Primates
Posted on: 4 December 2024 , updated on: 5 December 2024
Preprint posted on 7 October 2024
Marmosets display unique subtypes of trigeminal ganglia neurons: implications for normal somatosensory function and pain
Selected by Vanessa Ehlers
Categories: cell biology, neuroscience, physiology
Introduction
Physical pain is hard to ignore, and rightly so – it is a survival mechanism. We need to be able to sense when we are injured to seek treatment, and our somatosensory system allows us to do this. One way this system becomes activated is by physical force (a.k.a. mechanical stimulation). Specialized somatosensory neurons lying outside our brain and spinal cord help us detect and distinguish non-painful and painful mechanical forces.
Although some of these neurons have already received a lot of research attention regarding their role in somatosensation (e.g., dorsal root ganglia neurons(1)), we still don’t know very much about the mechanical sensitivity of another cell type housed near the base of the skull – the trigeminal ganglia (TG) neuron. These neurons are strongly implicated in head and neck pain. In particular, we know very little about human TG neuron mechanical sensitivity, since most prior research has looked at birds, rodents, or iPSC cell lines (2-7). Lindquist and colleagues, the authors of this preprint, therefore aimed to characterize mechanical responses in TG neurons from common marmosets, non-human primates that share evolutionary similarities with humans. How do these neurons respond to mechanical forces, and what do their response profiles mean for basic somatosensation, as well as pain processing?
Key findings
TG neuron classification system:
Lindquist and colleagues used whole-cell patch clamp electrophysiological recordings to characterize TG neurons isolated from adult male marmosets. Current-clamp was used to measure changes in neuron voltage and action potential (AP) firing characteristics, while voltage-clamp mode assessed neuronal current dynamics. The authors classified TG neuronal function on the basis of several distinct criteria: 1) AP duration; 2) shape of the downward AP slope; 3) whether neurons had the capacity to fire AP trains; 4) the degree to which neurons became hyperpolarized after firing an AP; 5) whether and how neurons responded to blunt mechanical indentation of the soma; and 6) neurons’ A-type potassium currents, which are thought to regulate antinociception (8; see preprint Figure 1).
A- and C-fiber response profiles depend on subtype:
The authors found ten separate classes of neurons: five were consistent with C-fiber activity (C1-5), and five resembled A-fibers (A1-5). This separation into C- versus A-type neurons is important since C-fibers are broadly implicated in painful conditions that involve inflammation and/or neuropathy, while A-fibers, depending on subtype (e.g., Aβ or Aδ), play a more nuanced role in somatosensation and are not always implicated in pain, per se. In this study, several subtypes of C-fibers displayed a prominent “hump” on the downward side of the AP, indicative of peptidergic nociceptors (9). Also, while only one subtype of C-fiber was responsive to mechanical poking, four out of five subtypes of A-fibers responded to mechanical stimuli. The authors also used immunofluorescence to further interrogate the relative proportions of C- and A-type neurons and noticed that more C-type neurons expressed calcitonin gene-related peptide (CGRP), a marker implicated in pain (10).
Marmoset TG neurons respond uniquely to mechanical stimulation:
One notable finding was that TG neuron currents from marmosets inactivated more slowly to mechanical force relative to other animal models, and other sensory neurons (e.g., DRG neurons in rodents). The authors noted this and pointed to a lack of proprioceptors and/or altered expression of specific ion channels that facilitate more rapid adaptation, such as Piezo2.
Why I liked this study
As someone who also studies sensory neuron mechanical sensitivity, I chose this preprint because I found it extremely interesting and relevant to my research. Thoroughly classifying neuronal electrophysiological responses is challenging, but necessary for understanding how neuronal heterogeneity facilitates normal somatosensation as well as how it might contribute to painful disorders like migraine. Having characterized these baseline physiological responses to electrical and mechanical stimulation in TG neurons from non-human primates, Lindquist and colleagues are expediting translatability of pain research. TG neurons are clearly complex and can respond heterogeneously to incoming sensory stimulation. This study propels the pain field one step closer to understanding just how the trigeminal system functions under normal physiological conditions and paves the way for future work exploring what happens when chronic pain takes over.
Future directions/questions for the authors
What are your hypotheses about how mechanical stretch or changes in osmolarity might affect the response profiles of these TG neurons? Do you think the relative distribution of the five subtypes of C and A-fibers would change at all?
What are the larger implications of your results? How do your C-fiber and A-fiber classifications correspond to what is known about rodent TG neurons? About human TG neurons? Based on your findings are there any insights you can draw regarding how these neurons might function differently under painful conditions?
References:
- Parpaite, T., Brosse, L., Séjourné, N., Laur, A., Mechioukhi, Y., Delmas, P., & Coste, B. (2021). Patch-seq of mouse DRG neurons reveals candidate genes for specific mechanosensory functions. Cell reports, 37(5), 109914. https://doi.org/10.1016/j.celrep.2021.109914
- Schneider, E. R., Anderson, E. O., Feketa, V. V., Mastrotto, M., Nikolaev, Y. A., Gracheva, E. O., & Bagriantsev, S. N. (2019). A Cross-Species Analysis Reveals a General Role for Piezo2 in Mechanosensory Specialization of Trigeminal Ganglia from Tactile Specialist Birds. Cell reports, 26(8), 1979–1987.e3. https://doi.org/10.1016/j.celrep.2019.01.100
- Schneider, E. R., Anderson, E. O., Mastrotto, M., Matson, J. D., Schulz, V. P., Gallagher, P. G., LaMotte, R. H., Gracheva, E. O., & Bagriantsev, S. N. (2017). Molecular basis of tactile specialization in the duck bill. Proceedings of the National Academy of Sciences of the United States of America, 114(49), 13036–13041. https://doi.org/10.1073/pnas.1708793114
- Ziolkowski, L. H., Gracheva, E. O., & Bagriantsev, S. N. (2023). Mechanotransduction events at the physiological site of touch detection. eLife, 12, e84179. https://doi.org/10.7554/eLife.84179
- Fernández-Trillo, J., Florez-Paz, D., Íñigo-Portugués, A., González-González, O., Del Campo, A. G., González, A., Viana, F., Belmonte, C., & Gomis, A. (2020). Piezo2 Mediates Low-Threshold Mechanically Evoked Pain in the Cornea. The Journal of neuroscience : the official journal of the Society for Neuroscience, 40(47), 8976–8993. https://doi.org/10.1523/JNEUROSCI.0247-20.2020
- Romero, L. O., Caires, R., Nickolls, A. R., Chesler, A. T., Cordero-Morales, J. F., & Vásquez, V. (2020). A dietary fatty acid counteracts neuronal mechanical sensitization. Nature communications, 11(1), 2997. https://doi.org/10.1038/s41467-020-16816-2
- Schrenk-Siemens, K., Wende, H., Prato, V., Song, K., Rostock, C., Loewer, A., Utikal, J., Lewin, G. R., Lechner, S. G., & Siemens, J. (2015). PIEZO2 is required for mechanotransduction in human stem cell-derived touch receptors. Nature neuroscience, 18(1), 10–16. https://doi.org/10.1038/nn.3894
- Biet, M., Dansereau, M. A., Sarret, P., & Dumaine, R. (2021). The neuronal potassium current IAis a potential target for pain during chronic inflammation. Physiological reports, 9(16), e14975. https://doi.org/10.14814/phy2.14975
- Patil, M. J., Hovhannisyan, A. H., & Akopian, A. N. (2018). Characteristics of sensory neuronal groups in CGRP-cre-ER reporter mice: Comparison to Nav1.8-cre, TRPV1-cre and TRPV1-GFP mouse lines. PloS one, 13(6), e0198601. https://doi.org/10.1371/journal.pone.0198601
- Russell, F. A., King, R., Smillie, S. J., Kodji, X., & Brain, S. D. (2014). Calcitonin gene-related peptide: physiology and pathophysiology. Physiological reviews, 94(4), 1099–1142. https://doi.org/10.1152/physrev.00034.2013
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