Anatomy and Neuroscience - Theses
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ItemRelationship between structure, molecular phenotype and function of corneal sensory neurons and their nerve terminal endings( 2017)The ability to sense and react to our environment is governed by activity in peripheral sensory neurons, which are widely distributed in the different body tissues. Embedded in their membrane there are specific types of ion channels and receptors that are responsible for the transduction of the different stimulus modalities. This thesis has used immunohistochemistry, in situ hybridization and electrophysiology to explore the structure and molecular phenotype of the different functional sub-types of sensory neurons innervating the cornea, and their nerve terminal endings in guinea pigs and mice. In addition, the thesis has investigated the effects of metabolic stress induced by a high fat diet and diabetes on the nerves fibres of sensory neurons in the corneal epithelium of mice. Previous studies have shown that corneal afferent neurons have heterogeneous molecular identities(Bron et al., 2014; Ivanusic et al., 2013). The results presented in Chapter 2 confirmed this heterogeneity and found that the majority of corneal afferent neurons could be subdivided into the 3 functionally defined corneal receptors on the basis of their selective expression of sensory transducer molecules. Transient receptor potential cation channel subfamily V member 1 (TRPV1) was expressed in polymodal nociceptors, transient receptor potential cation channel subfamily M member 8 (TRPM8) was expressed in cold thermoreceptors and Piezo2 was expressed in mechano-nociceptors. Furthermore, the TRPV1-IR corneal afferent neurons were further subdivided into three sub-populations on the basis of their molecular phenotype. These findings led to the hypothesis that the neurochemically defined sub-populations of TRPV1-IR corneal afferent neurons form morphologically distinct nerve terminal endings that terminate at different locations within the corneal epithelium. The results in Chapter 3 confirmed this hypothesis, showing that CGRP expressing TRPV1-IR nerve terminals in the guinea pig cornea had simple endings that terminated in the basal or wing cell layers, whereas the TRPV1-IR nerve terminals that did not express CGRP had ramifying endings that terminated in squamous cell layer. A previous study had demonstrated that the TRPM8-IR nerve terminals of putative cold thermoreceptors form complex endings that terminate in the wing and squamous cell layers(Ivanusic et al., 2013). The results presented in Chapter 4 confirmed that functionally identified polymodal nociceptors and cold thermoreceptors in the corneal epithelium have distinct nerve terminal morphologies and neurochemical phenotypes. The experiments in Chapter 5 investigated the effects of high fat-diet and Type 2 diabetes on the density of TRPV1-IR and TRPM8-IR nerve fibres in the corneal epithelium. It was demonstrated that TRPV1-IR and TRPM8-IR fibres in the corneal epithelium were affected differently by the metabolic stress associated with these pathological conditions. The findings of this thesis define the different sub-populations of corneal afferent neurons and show morphological and/or neurochemical specialisation of the TRPV1 expressing corneal nerve terminals in normal cornea. Furthermore, the findings demonstrate directly for the first time that pathology induced by metabolic stress can differentially affect some of these sub-populations of corneal sensory neurons.