Research Paper PAIN 165 (2024) 2863–2876
Peripheral nerve injury results in a biased loss of
sensory neuron subpopulations
Andrew H. Cooper a, Allison M. Barry b, Paschalina Chrysostomidou a, Romane Lolignier a, Jinyi Wang a,
Magdalena Redondo Canales a, Heather F. Titterton a, David L. Bennett b, Greg A. Weir a,*
Abstract
There is a rich literature describing the loss of dorsal root ganglion (DRG) neurons following peripheral axotomy, but the vulnerability
of discrete subpopulations has not yet been characterised. Furthermore, the extent or even presence of neuron loss following injury
has recently been challenged. In this study, we have used a range of transgenic recombinase driver mouse lines to genetically label
molecularly defined subpopulations of DRG neurons and track their survival following traumatic nerve injury. We find that spared
nerve injury leads to a marked loss of cells containing DRG volume and a concomitant loss of small-diameter DRG neurons. Neuron
loss occurs unequally across subpopulations and is particularly prevalent in nonpeptidergic nociceptors, marked by expression of
Mrgprd. We show that this subpopulation is almost entirely lost following spared nerve injury and severely depleted (by roughly 50%)
following sciatic nerve crush. Finally, we used an in vitro model of DRG neuron survival to demonstrate that nonpeptidergic
nociceptor loss is likely dependent on the absence of neurotrophic support. Together, these results profile the extent to which DRG
neuron subpopulations can survive axotomy, with implications for our understanding of nerve injury–induced plasticity and pain.
Keywords: Sensory neuron, Neuron death, Transgenic reporter line, Neuropathic pain, Nerve injury
1. Introduction
Dorsal root ganglion (DRG) neurons represent a molecularly
and functionally heterogeneous population. Under normal
conditions, this diversity contributes to the ability of the
somatosensory nervous system to detect a myriad of sensory
stimuli that result in the perceptions of touch, temperature,
itch, and pain. Following nerve injury, physiological changes in
DRG neurons lead to hyperexcitability, 57 which is a key
pathological driver of neuropathic pain. 20,63 Concomitant
molecular changes in discrete subpopulations also occur,
and these have recently been comprehensively described in
single-cell 37,44 and subpopulation-specific sequencing stud-
ies.3 These studies describe a transient and generalized
reduction in the expression of subpopulation-specific genes
following nerve injury. 3,37,44
In addition to molecular changes, there is a rich literature
describing the frank loss of DRG neurons following traumatic
nerve injury in experimental rodent models. 24,50,53,56 Some
studies have suggested that neuron loss occurs in certain patient
cohorts,48,66 but this is yet to be definitively demonstrated in
humans. In rodents, most studies support a preferential loss of
small cells that give rise to unmyelinated fibers 53 but some
contrasting studies describe the preferential loss of large cells 6 or
loss of cells of all sizes. 46 Variation is evident across studies in
terms of experimental species, age, type of injury, and
quantification methods.56 Shi et al. 50 used stereological counting
methods to identify a 54% loss of DRG neuron number 4 weeks
after “mid-thigh” sciatic nerve transection in C57BL/6 mice.
Estimates for the degree of loss following commonly used nerve
injury paradigms (eg, spared nerve injury [SNI] and sciatic nerve
crush) are not available and because of the neurochemical
changes following injury and the loss of subpopulation marker
gene expression,5,44,50 the vulnerability of molecularly defined
subpopulations has not been characterized. Moreover, more
recent studies have cast doubt on the extent or even presence of
DRG neuron death following nerve injury. One study which
developed a deep learning approach to assess rat DRG cellular
plasticity found no loss of neurons up to 2 weeks post-SNI,49