The functional and anatomical dissection of somatosensory subpopulations using mouse genetics

Claire E Le Pichon, Alexander T Chesler, Claire E Le Pichon, Alexander T Chesler

Abstract

The word somatosensation comes from joining the Greek word for body (soma) with a word for perception (sensation). Somatosensory neurons comprise the largest sensory system in mammals and have nerve endings coursing throughout the skin, viscera, muscle, and bone. Their cell bodies reside in a chain of ganglia adjacent to the dorsal spinal cord (the dorsal root ganglia) and at the base of the skull (the trigeminal ganglia). While the neuronal cell bodies are intermingled within the ganglia, the somatosensory system is in reality composed of numerous sub-systems, each specialized to detect distinct stimuli, such as temperature and touch. Historically, somatosensory neurons have been classified using a diverse host of anatomical and physiological parameters, such as the size of the cell body, degree of myelination, histological labeling with markers, specialization of the nerve endings, projection patterns in the spinal cord and brainstem, receptive tuning, and conduction velocity of their action potentials. While useful, the picture that emerged was one of heterogeneity, with many markers at least partially overlapping. More recently, by capitalizing on advances in molecular techniques, researchers have identified specific ion channels and sensory receptors expressed in subsets of sensory neurons. These studies have proved invaluable as they allow genetic access to small subsets of neurons for further molecular dissection. Data being generated from transgenic mice favor a model whereby an array of dedicated neurons is responsible for selectively encoding different modalities. Here we review the current knowledge of the different sensory neuron subtypes in the mouse, the markers used to study them, and the neurogenetic strategies used to define their anatomical projections and functional roles.

Keywords: TRP channel; itch; nociception; pain; sensory neuron; somatosensation; thermodetection; touch.

Figures

Figure 1
Figure 1
Anatomy of the somatosensory system. (A) Somatosensory neuron cell bodies reside outside the spinal cord in the dorsal root ganglia (DRG). They have a single process that splits, sending an afferent projection to the periphery and an efferent projection to the spinal cord. (B) Somatosensory neurons residing in the trigeminal send processes that innervate peripheral targets through the face, mouth, and dura and central targets in the brainstem. (C) Somatosensory neurons can be divided into three broad categories based on the size of their cell bodies and degree of myelination. Within these broad categories, numerous sub-specializations exist-for example small diameter C fibers are mostly nociceptors while large diameter A neurons respond to low threshold mechanical stimuli. LTMR, low-threshold mechano-receptor.
Figure 2
Figure 2
TRP channels respond to unique types of stimuli. (A) Natural products from chili peppers, onions/garlic, and mint leaves selectively activate TRP channels (TRPV1, TRPA1, and TRPM8, respectively). The psychophysical effects of these compounds directly correlate with the environmental stimuli to which these TRP channels are responsive. Activation of TRPV1 by either capsaicin from chili peppers or heat evokes a burning sensation, activation of TRPA1 by mustard oil and environmental irritants evokes a stinging pain, and activation of TRPM8 by menthol from mint leaves or cold evokes the sensation of cooling. (B) TRP channels are differentially expressed in somatosensory neurons. Two-color fluorescent in situ hybridization demonstrates little overlap between TRPM8 and TRPV1 (left hand image). Meanwhile, TRPA1 is expressed in a subset of TRPV1 neurons (right hand image). Image courtesy of Mark Hoon, NIH/NIDCD.
Figure 3
Figure 3
TRPV1 Reporter mice reveal the anatomy of neurons that expressed TRPV1 throughout their lineage. (A) Skin section from TRPV1-Cre × YFP reporter strain showing primary afferent arborizations in the various epidermal layers. (B) DRG section from adult TRPV1-PLAP-nlacZ mouse, showing minimal overlap between β-Gal reaction product (green) and IB4 (red). (C) DRG section from adult TRPV1-Cre × LacZ reporter strain. Anti-LacZ (green) shows significantly more overlap with IB4 (red) since the entire TRPV1 lineage is marked. Image courtesy of Danial Cavanaugh and Allan Basbaum, Department of Anatomy UCSF.
Figure 4
Figure 4
Venn diagram illustrating the distribution of markers across different classes of C fibers (not to scale). Numbers reference the mouse lines listed in Table 2.
Figure 5
Figure 5
Delta opioid receptor (DOR-eGFP mice, green) rarely overlaps with TRPV1 (red). Image courtesy of Grégory Scherrer, Stanford University.

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