Opposing expression gradients of calcitonin‐related polypeptide alpha (Calca/Cgrpα) and tyrosine hydroxylase (Th) in type II afferent neurons of the mouse cochlea

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The mammalian cochlea contains two types of afferent neurons, distinguished by their morphology and innervation pattern. The majority (95%) are larger diameter, myelinated type I afferents postsynaptic to single inner hair cells (IHCs). In contrast, a much smaller number of thinner, unmyelinated type II afferents extend dendrites hundreds of microns along the cochlear spiral, contacting many outer hair cells (OHCs). These distinct innervation patterns suggest distinct functional roles. Type I afferents transmit acoustic information, as proven by many decades of research (Young, 2008). The functional role of type II afferents is less certain. Their contribution to acoustic analysis is presumed to be minimal, due to their small number, relative insensitivity to sound (Brown, 1994; Robertson, 1984; Robertson, Sellick, & Patuzzi, 1984) and weak excitation by OHC transmitter release (Weisz, Lehar, Hiel, Glowatzki, & Fuchs, 2009). Instead, evidence suggests that type II afferents may signal cochlear damage (Flores et al., 2015; Liu, Glowatzki, & Fuchs, 2015), and so are postulated to be “cochlear nociceptors”.
Identifying genes that are differentially expressed in type II versus type I afferent neurons would enable genetic manipulation to isolate the effects of type II afferents from those of the much larger population of type I afferents. Understanding the cellular actions of these selectively expressed genes also could shed light on the overall function of type II afferents. In previous work, tyrosine hydroxylase (Th), a marker for C‐type low threshold mechanoreceptors in the somatosensory system, was shown to express in lateral olivocochlear (LOC) efferents and in type II but not type I afferent neurons, particularly in the apical cochlea (Vyas, Wu, Zimmerman, Fuchs, & Glowatzki, 2016). This observation suggested a previously underappreciated heterogeneity among type II afferent neurons. Indeed, in contrast to the much‐diversified groups of ganglion neurons in other sensory systems such as vision and somatosensation (Abraira & Ginty, 2013; Basbaum, Bautista, Scherrer, & Julius, 2009; Sanes & Masland, 1992), little is known beyond the type I and type II dichotomy for spiral ganglion neurons (SGNs) and activity differences among type I afferents. Therefore, the identification of additional genetic markers that could label type II afferent neurons in the basal cochlea is desirable. In view of the proposed role of type II afferents in detecting tissue damage, we continued to screen recombinant mouse lines labeling subpopulations of ganglion neurons in the somatosensory system, especially nociceptors, for their expression patterns in the cochlea.
One such gene, Calca, encoding for calcitonin gene‐related peptide alpha (CGRPα), is expressed in a wide variety of neuronal and non‐neuronal cell types, ranging from keratinocytes to primary afferent neurons and spinal motor neurons (Russell, King, Smillie, Kodji, & Brain, 1987). CGRP is a potent vasodilator and mediates neuronal‐immune system communication (Assas, Pennock, & Miyan, 2014). CGRP is expressed specifically in small C and Aδ neurons of dorsal root ganglia. The release of CGRP from sensory terminals is thought to intensify pain sensation, in part through its induction of vasodilation and inflammation, but also by facilitating central transmission. CGRP's most infamous role is in migraine pathogenesis, where again, a combination of effects on vasodilation, inflammation, and central plasticity is thought to occur. CGRP has long been known to be expressed in cochlear efferent neurons (Kitajiri et al., 1985). Its involvement in nociception makes the expression in type II cochlear afferents shown here particularly interesting in the context of acoustic trauma and associated “gain of function” pathologies such as hyperacusis.
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