Behavioral Thermoceptive Responses and Morphologic Correlates in Mouse Models of CMT1A, HNPP and Aging

Background

Thermoceptive dysfunction is a frequent but understudied feature of peripheral neuropathies and aging. Patients often report abnormal heat perception, yet the underlying sensory mechanisms remain unclear. This study evaluated thermoceptive behavior and corresponding structural changes in mouse models of inherited dysmyelinating neuropathy and natural aging to identify shared and divergent mechanisms.

Methods

Thermal preference was assessed using a user-independent gradient apparatus spanning physiological to noxious temperatures, with automated quantification of time in zone, distance traveled, and velocity. Nocifensive responses were evaluated by hot plate latency. Intraepidermal nerve fiber density (IENFD) was measured in paw pads, and TRPV1-positive dorsal root ganglion (DRG) neurons were analyzed by immunofluorescence and confocal imaging.

Results

Thermal gradient testing revealed preserved temperature preference in CMT1A and HNPP mice but significantly altered behavior in aged animals, which spent less time in warmer zones. Hot plate testing showed prolonged times to nocifensive behavior in aged and CMT1A mice, whereas HNPP mice exhibited variable responses. IENFD was markedly reduced in aged mice but preserved in CMT1A and HNPP. DRG analysis revealed smaller soma diameters and reduced proportions of TRPV1-positive Aδ neurons in aged mice, while CMT1A animals maintained normal morphology.

Interpretation

Aging produces thermoceptive deficits through axonal degeneration and selective Aδ-fiber vulnerability, whereas CMT1A mice display conduction-related impairment due to dysmyelination. Both models reproduce key human sensory phenotypes and provide translational platforms for studying small-fiber dysfunction and therapeutic interventions in peripheral neuropathies.

Key Points

• Thermoceptive dysfunction is a common but understudied feature of peripheral neuropathy and aging.

• In aged mice, altered thermal preference, reduced intraepidermal nerve fiber density, and smaller TRPV1-positive Aδ neurons indicate a degenerative mechanism of sensory loss.

• In CMT1A mice, delayed noxious heat responses occur despite preserved epidermal and DRG morphology, consistent with dysmyelination rather than axonal degeneration.

• HNPP mice showed inconsistent nocifensive responses without structural fiber loss, suggesting strain- or injury-dependent effects.

• Thermal gradient and hot plate assays demonstrate strong reproducibility and provide relevant outcome measures for preclinical modeling of thermoceptive dysfunction.