Background & Aims

The nervous system allocates disproportional neuronal resources to sensory information that are critical for an organism’s survival and reproduction. Indeed, the most striking feature of the somatosensory homunculus is the enlarged area representing the distal limbs especially the hairless glabrous skin regions such as the palms of the hands and soles of the feet to facilitate environmental exploration. Heighted tactile and pain sensitivity in the glabrous skin has been well established. However, whether regional differences exist in itch signal processing is not clear. Our recent study demonstrated that MrgprC11+ DRG sensory neurons mediate both hairy and glabrous skin itch, providing a cellular target to investigate regional differences in itch. This study revealed heightened itch sensitivity in the glabrous skin, supported by the unique axonal branching pattern of itch-sensing neurons.

Methods

We have generated a BAC transgenic MrgprC11-CreER line which allows genetic tracing and manipulation of MrgprC11+ itch-sensing neurons. We employed an optogenetic approach with MrgprC11-ChR2 mice to test itch sensitivity in different skin locations inlcuding the trunk hairy skin and plantar glabrous skin. Using CreER-mediated sparse genetic labeling and whole mount PLAP histochemistry, we were able to visualize the individual itch-sensing axonal arborizations in the skin and spinal cord and analyzed their morphologies in different skin locations. We also examined the peripheral intraepidermal nerve density of nociceptors using MrgprC11-tdTomato mice.

Results

Light stimulation of MrgprC11+ nerves in both trunk hairy skin and plantar glabrous skin evoked itch behavior. Interestingly, a much lower laser power is required to evoke glabrous skin biting, suggesting heightened itch processing for the glabrous skin. Consistently, we found that plantar glabrous skin is much more sensitive to Bam8-22, a MrgprC11 agonist, than other skin locations. The heightened itch sensitivity is not attributable to an increased density of peripheral nerves because MrgprC11+ IENDs in the paw skin are significantly lower. MrgprC11+ skin arbors in different locations are all typical “free endings” featuring extensive axonal branching inside of the arbor. However, the arbors are larger in the paws and the largest ones are observed in the hindpaw glabrous skin. Furthermore, glabrous skin-innervating MrgprC11+ neurons exhibit distinct central arbor morphology in the spinal cord. Spinal cord arbors representing the trunk skin and proximal limb show long morphology, while arbors representing the plantar glabrous skin exhibit round morphology.

Conclusions

In summary, our results demonstrate regional differences in itch processing, with higher itch sensitivity in the glabrous skin, which aligns with the regionally distinct morphological organization of itch-sensing neurons. MrgprC11+ neurons exhibit low IEND and larger axonal arborization in the glabrous skin, and regionally distinct central arbors in the spinal cord. Previous studies have linked regional-specific central arbor morphology to the enhanced signal transmission of touch and pain in glabrous skin. Conversely, the peripheral nerve organization is in contrast to the low innervation density and smaller receptive field observed in touch sensors of the distal limbs. Taken together, our findings suggest that region-specific morphological organization serves as a fundamental somatotopic mechanism to facilitate regional differences in sensory processing, although distinct organizations were employed by different sensory modalities.

References

Beuers, U., A.E. Kremer, R. Bolier, and R.P. Elferink. 2014. “Pruritus in cholestasis: facts and fiction.” Hepatology 60(1):399-407.
Brown, P.B.and H.R. Koerber. 1978. “Cat hindlimb tactile dermatomes determined with single-unit recordings.” J Neurophysiol 41(2):260-267.
Han, L., N. Limjunyawong, F. Ru, Z. Li, O.J. Hall, H. Steele, Y. Zhu, J. Wilson, W. Mitzner, M. Kollarik, B.J. Undem, B.J. Canning, and X. Dong. 2018. “Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness.” Nat Neurosci 21(3):324-328.
Lehnert, B.P., C. Santiago, E.L. Huey, A.J. Emanuel, S. Renauld, N. Africawala, I. Alkislar, Y. Zheng, L. Bai, C. Koutsioumpa, J.T. Hong, A.R. Magee, C.D. Harvey, and D.D. Ginty. 2021. “Mechanoreceptor synapses in the brainstem shape the central representation of touch.” Cell 184(22):5608-5621 e5618.
Liu, Q., S. Vrontou, F.L. Rice, M.J. Zylka, X. Dong, and D.J. Anderson. 2007. “Molecular genetic visualization of a rare subset of unmyelinated sensory neurons that may detect gentle touch.” Nat Neurosci 10(8):946-948.
Mancini, F., A. Bauleo, J. Cole, F. Lui, C.A. Porro, P. Haggard, and G.D. Iannetti. 2014. “Whole-body mapping of spatial acuity for pain and touch.” Ann Neurol 75(6):917-924.
Olson, W., I. Abdus-Saboor, L. Cui, J. Burdge, T. Raabe, M. Ma, and W. Luo. 2017. “Sparse genetic tracing reveals regionally specific functional organization of mammalian nociceptors.” Elife 6.
Steele, H.R., Y. Xing, Y. Zhu, H.B. Hilley, K. Lawson, Y. Nho, T. Niehoff, and L. Han. 2021. “MrgprC11(+) sensory neurons mediate glabrous skin itch.” Proc Natl Acad Sci U S A 118(15).
Vrontou, S., A.M. Wong, K.K. Rau, H.R. Koerber, and D.J. Anderson. 2013. “Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo.” Nature 493(7434):669-673.
Xing, Y., H.R. Steele, H.B. Hilley, Y. Zhu, K. Lawson, T. Niehoff, and L. Han. 2021. “Visualizing the Itch-Sensing Skin Arbors.” J Invest Dermatol 141(5):1308-1316.

Presenting Author

Liang Han

Poster Authors

Liang Han

PhD

Georgia Institute of Technology

Lead Author

Yanyan Xing

PhD

Georgia Institute of Technology

Lead Author

Yeseul Nho

Georgia Institute of Technology

Lead Author

Katy Lawson

Georgia Institute of Technology

Lead Author

Haley Steele

Georgia Institute of Technology

Lead Author

Topics

  • Mechanisms: Biological-Molecular and Cell Biology