Human Dorsal Root Ganglia

Haberberger, Rainer Viktor; Barry, Christine; Dominguez, Nicholas; Matusica, Dusan

doi:10.3389/fncel.2019.00271

Cited by 184 publications

(203 citation statements)

References 166 publications

(297 reference statements)

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“…Price & Flores, 2007; Schmelz et al, 2000). Our present findings, combined with our previous work using in situ hybridization techniques (Shiers et al, 2020), as well as many previously published studies (Haberberger, Barry, Dominguez, & Matusica, 2019; T. J. Price & Flores, 2007; Yiangou et al, 2000), clearly demonstrate that peptidergic and non-peptidergic populations are, in the best case, mixed in human DRG.…”

Section: Discussionsupporting

confidence: 89%

Convergence of peptidergic and non-peptidergic protein markers in the human dorsal root ganglion and spinal dorsal horn

Shiers

Sankaranarayanan

Jeevakumar

et al. 2020

Preprint

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Peripheral sensory neurons are characterized by their size, molecular profiles, and physiological responses to specific stimuli. In mouse, the peptidergic and non-peptidergic subsets of nociceptors are distinct and innervate different lamina of the spinal dorsal horn. The unique molecular signature and neuroanatomical organization of these neurons supports a labeled line theory for certain types of nociceptive stimuli. However, long standing evidence supports the polymodal nature of nociceptors in many species. We have recently shown that the peptidergic marker, CGRP, and the non-peptidergic marker, P2X3R, show largely overlapping expression at the mRNA level in human dorsal root ganglion (DRG). Herein, our aim was to assess the protein distribution of nociceptor markers, including their central projections, in the human DRG and spinal cord. Using DRGs obtained from organ donors, we observed that CGRP and P2X3R were co-expressed by approximately 33% of human DRG neurons and TrpV1 was expressed in ~60% of human DRG neurons. In the dorsal spinal cord, CGRP, P2X3R, TrpV1 and Nav1.7 protein stained the entirety of lamina II, with only P2XR3 showing a gradient of expression. This was confirmed by measuring the size of the substantia gelatinosa using Hematoxylin and Eosin staining of adjacent sections. Our findings are consistent with the known polymodal nature of most primate nociceptors and indicate that the central projection patterns of nociceptors are different between mice and humans. Elucidating how human nociceptors connect to subsets of dorsal horn neurons will be important for understanding the physiological consequences of these species differences.

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Section: Discussionsupporting

confidence: 89%

Convergence of peptidergic and non-peptidergic protein markers in the human dorsal root ganglion and spinal dorsal horn

Shiers

Sankaranarayanan

Jeevakumar

et al. 2020

Preprint

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“…We initially sectioned the nodose samples sparsely (~3-5 sections spanning the rostral/caudal nodose, approximately 5 mm between slices, 5 µm slices), and in some animals we identified a very large grouping containing an aggregation of classic pseudo-unipolar cell bodies, which we also refer to as a "fascicle" for simplicity ( Figure 7). Cell bodies of pseudo-unipolar cells were identified by surrounding supporting satellite glia cells and by the nucleus of the soma (Haberberger et al 2019;Ling and Wong 1988;Ohara et al 2009). In other animals we observed a large number of fascicles roughly organized into a grouping, in which the occasional pseudo-unipolar cell body was visible ( Figure 7B).…”

Section: Vagotopy Of the Cervical Vagus Nerve Swinementioning

confidence: 99%

Functional Vagotopy in the Cervical Vagus Nerve of the Domestic Pig: Implications for the Study of Vagus Nerve Stimulation

Settell

Knudsen

Dingle

et al. 2019

Preprint

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Given current clinical interest in vagus nerve stimulation, there are surprisingly few studies characterizing the anatomy of the vagus nerve in large animal models as it pertains to on-and off-target engagement of local fibers. We sought to address this gap by evaluating vagal anatomy in the domestic pig, whose vagus nerve organization and size approximates the human cervical vagus nerve. We provide data on key features across the cervical vagus nerve including diameter, number and diameter of fascicles, and distance of fascicles from the epineural surface where stimulating electrodes are placed. We also characterized the relative locations of the superior and recurrent laryngeal branches of the vagus nerve that have been implicated in therapy limiting side effects with common electrode placement. We identified key variants across the cohort that may be important for vagus nerve stimulation with respect to changing sympathetic/parasympathetic tone, such as cross-connections to the sympathetic trunk. We discovered that cell bodies of pseudo-unipolar cells aggregate together to form a very distinct grouping within the nodose ganglion. This distinct grouping gives rise to a larger number of smaller fascicles as one moves caudally down the cervical vagus nerve. This often leads to a distinct bimodal organization, or ‘vagotopy’ that may be advantageous to exploit in design of electrodes/stimulation paradigms. Finally, we placed our data in context of historic and recent histology spanning mouse, rat, canine, pig, non-human primate and human models, thus providing a comprehensive resource to understand similarities and differences across species.

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“…For instance, studies in rats have shown that there is a large overlap in the expression of CGRP and IB4-positive neurons in DRG [36] and NF200 marks all sensory neurons in human DRG [39]. Relatively few previous studies have quantitatively investigated the expression and population distribution for a broad number of mRNA targets in both mouse and human DRG, although several studies have found important differences using bulk RNA-seq, physiological or histochemical measures [19]. The goal of the present work was to define DRG mRNA expression similarities or differences between mouse and human for (A) genes that are important population markers, (B) genes that are specifically expressed in DRG, (C) genes that are existing or potential drug targets, or (D) genes that have clear links to human pain states.…”

Section: Introductionmentioning

confidence: 99%

Quantitative differences in neuronal subpopulations between mouse and human dorsal root ganglia demonstrated with RNAscopein situhybridization

Shiers

Klein

Price

2020

Preprint

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Next generation transcriptomics in combination with imaging-based approaches have emerged as powerful tools for the characterization of dorsal root ganglion (DRG) neuronal subpopulations. The mouse DRG has been wellcharacterized by many independently conducted studies with convergent findings, but few studies have directly compared expression of population markers between mouse and human. This is important because of our increasing reliance on the mouse as a preclinical model for translational studies. While calcitonin gene-related peptide (CGRP) and P2X purinergic ion channel type 3 receptor (P2X3R) have been used to define peptidergic and non-peptidergic nociceptor subpopulations, respectively, in mouse DRG, these populations may be different in other species. To directly test this, as well as a host of other markers, we used multiplex RNAscope in-situ hybridization to elucidate the distribution of a multitude of unique and classic neuronal mRNAs in peptidergic (CGRP expressing) and non-peptidergic (P2X3R expressing) nociceptor subpopulations in mouse and human DRG. We found a large overlapping CGRP and P2X3R neuronal subpopulation in human, lumbar DRG that was not present in mouse. We also found differential expression in a variety of mRNAs for Trp-channels, cholinergic receptors, potassium channels, sodium channels, other markers/targets. These data offer insights into the spatial and functional organization of neuronal cell subpopulations in the rodent and human DRG and support the idea that sensory system organizational principles are likely different between both species.

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Human Dorsal Root Ganglia

Cited by 184 publications

References 166 publications

Convergence of peptidergic and non-peptidergic protein markers in the human dorsal root ganglion and spinal dorsal horn

Convergence of peptidergic and non-peptidergic protein markers in the human dorsal root ganglion and spinal dorsal horn

Functional Vagotopy in the Cervical Vagus Nerve of the Domestic Pig: Implications for the Study of Vagus Nerve Stimulation

Quantitative differences in neuronal subpopulations between mouse and human dorsal root ganglia demonstrated with RNAscopein situhybridization

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