DRG afferents that mediate physiologic and pathologic mechanosensation from the distal colon

Wolfson, Rachel L.; Abdelaziz, Amira; Rankin, Genelle; Kushner, Sarah; Qi, Lixin; Mazor, Ofer; Choi, Su-Jeong; Sharma, Nikhil; Ginty, David D.

doi:10.1016/j.cell.2023.07.007

Cited by 34 publications

(18 citation statements)

References 71 publications

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“…This molecular profile of non-peptidergic, myelinated is consistent with features previously described for the low class. [35][36][37] The of AAV-terminals we identified in the dorsal horn of the spinal cord is also consistent with a higher tropism in myelinated, nonpeptidergic afferents. 53,54 Our conclusion is further supported by our observation that AAV-positive sensory terminals in the bladder were rarely identified as CGRP-positive.…”

Section: Discussionsupporting

confidence: 79%

“…Although this quantitative classification was performed only in L6, in DRG of adjacent spinal levels the AAV-positive neurons showed similar overall patterns of co-expression, that is, many were immunoreactive for NF200 or GFRα1 and it was difficult to find many AAV-positive neurons that expressed CGRP or TRPV1. Based on current molecular classification of rodent sensory neurons, [35][36][37] our results show the majority of AAV-positive neurons express NF200 and GFRα1 (but not CGRP or TRPV1) belong to the Aδ-low threshold mechanoreceptor (LTMR) class of visceral sensory neurons.…”

Section: Aav Gfrα1mentioning

confidence: 86%

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An adeno‐associated viral labeling approach to visualize the meso‐ and microanatomy of mechanosensory afferents and autonomic innervation of the rat urinary bladder

Wiedmann,

Fuller‐Jackson,

Osborne

et al. 2023

The FASEB Journal

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The urinary bladder is supplied by a rich network of sensory and autonomic axons, commonly visualized by immunolabeling for neural markers. This approach demonstrates overall network patterning but is less suited to understanding the structure of individual motor and sensory terminals within these complex plexuses. There is a further limitation visualizing the lightly myelinated (A‐delta) class of sensory axons that provides the primary mechanosensory drive for initiation of voiding. Whereas most unmyelinated sensory axons can be revealed by immunolabeling for specific neuropeptides, to date no unique neural marker has been identified to immunohistochemically label myelinated visceral afferents. We aimed to establish a non‐surgical method to visualize and map myelinated afferents in the bladder in rats. We found that in rats, the adeno‐associated virus (AAV), AAV‐PHP.S, which shows a high tropism for the peripheral nervous system, primarily transduced myelinated dorsal root ganglion neurons, enabling us to identify the structure and regional distribution of myelinated (mechanosensory) axon endings within the muscle and lamina propria of the bladder. We further identified the projection of myelinated afferents within the pelvic nerve and lumbosacral spinal cord. A minority of noradrenergic and cholinergic neurons in pelvic ganglia were transduced, enabling visualization and regional mapping of both autonomic and sensory axon endings within the bladder. Our study identified a sparse labeling approach for investigating myelinated sensory and autonomic axon endings within the bladder and provides new insights into the nerve‐bladder interface.

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Section: Discussionsupporting

confidence: 79%

Section: Aav Gfrα1mentioning

confidence: 86%

An adeno‐associated viral labeling approach to visualize the meso‐ and microanatomy of mechanosensory afferents and autonomic innervation of the rat urinary bladder

Wiedmann,

Fuller‐Jackson,

Osborne

et al. 2023

The FASEB Journal

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“…Our demonstration that PIEZO2 is critical for HFNs' response to the hair-pull stimuli is in line with recent data demonstrating that PIEZO2 knockout leads to 50% decrease in the fraction of Aδ-HTMRs responding to high-threshold mechanical stimuli 19 . While there is growing evidence that PIEZO2 is involved in transducing pathological pain following sensitization [14][15][16]41,42 , it is worth noting that, even though PIEZO2 contributes to some acute pain responses in mice 14 , we demonstrated for the first time that PIEZO2dependent nociceptors were necessary for perceiving a submodality of acute pain. Recent insights into human sensory neuron transcriptomics provide a unique opportunity to explore cell classes associated with pain and elucidate the cellular mechanisms underlying painful sensations.…”

Section: Discussionmentioning

confidence: 64%

PIEZO2‐dependent rapid pain system in humans and mice

Bouchatta,

Brodzki,

Manouze

et al. 2023

Preprint

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SummaryThe PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception – a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare Aβ deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on Aβ input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

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“…Recent studies have transcriptionally profiled each peripheral neuron lineage (enteric 2,4,8-16 , sensory 10,16-36 , autonomic 7,10,37-42 ), defining dozens of transcriptionally distinct populations of neurons in each lineage. Although these studies used different genomic methodologies, it is evident that there is significant cellular heterogeneity in each of these systems and an emergent need to develop approaches to study uncovered subpopulations.…”

Section: Introductionmentioning

confidence: 99%

Differential control of intestine function by genetically defined enteric neurons

Shi,

Reddy,

Walker

et al. 2024

Preprint

Self Cite

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The function of the intestine is regulated by direct innervation from a combination of enteric, sensory, and autonomic neurons. A central question in neurobiology is how these distinct peripheral neuron populations collectively control intestinal function. However, disambiguating the functions of intestine-innervating neuronal populations has been a challenge. Using intersectional genetic approaches in mice, we enable precise manipulations of defined neuronal populations within the intestinal tract. We examined enteric neurons, which represent the majority of intestine-innervating neurons, by genetically isolating neuronal subclasses, identifying their morphological specializations, and defining subclass-specific influences on intestinal functions. We further found that food consumption can be modulated by select enteric neuron populations via the spinal sensory afferent pathway. Taken together, the presented molecular genetic characterization of intestine-innervating neurons establishes a foundation for detailed studies of the enteric nervous system and its interactions with the broader neural networks of the body.

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DRG afferents that mediate physiologic and pathologic mechanosensation from the distal colon

Cited by 34 publications

References 71 publications

An adeno‐associated viral labeling approach to visualize the meso‐ and microanatomy of mechanosensory afferents and autonomic innervation of the rat urinary bladder

An adeno‐associated viral labeling approach to visualize the meso‐ and microanatomy of mechanosensory afferents and autonomic innervation of the rat urinary bladder

PIEZO2‐dependent rapid pain system in humans and mice

Differential control of intestine function by genetically defined enteric neurons

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