Molecular and cellular changes underlying plasticity and regeneration of intact, injured and aged cold corneal nerves

Abstract

The peripheral nerve endings from trigeminal neurons that innervate the cornea are key neural structures to detect and encode the features of the physical and chemical external stimuli at the ocular surface. These neurons are functionally diverse and have been classified into polymodal nociceptors, mechano‐nociceptors and cold thermoreceptors. Each functional type evokes qualitative different conscious sensations. The sensory modality that is generated from a nerve ending is determined by the type and specific characteristics of the ion channels involved in stimulus transduction and encoding. Among them, TRPM8 channels transduce both cold and osmotic stimuli in corneal cold nerve terminals. These cold thermoreceptors mediate sensations of ocular surface cooling and dryness, and play an important role in the regulation of basal tearing and blinking. Morphologically, cold thermosensitive neurons display a more complex branching of their peripheral nerve endings innervating the cornea in comparison to the other functional classes of sensory neurons.With aging, TRPM8‐expressing cold sensory neurons innervating the mouse cornea experience morphological and functional alterations. These changes occur earlier and are more prominent at the nerve terminal than at the neuron cell body. A drastic reduction of the nerve terminal branching complexity in addition to lower background impulse activity is observed in cold nerves of aged mice. Similarly, after performing photorefractive keratectomy (PRK) in the adult mouse cornea, both the nerve terminal branching and background activity are reduced in a fraction of the cold nerve terminals. An altered morphological configuration along with an aberrant transducing and coding ion channels expression at corneal cold nerve terminals are likely to contribute to the discomfort sensations experienced after corneal surgery and to the age‐related abnormal tearing in the elderly.(Supported by PID2021‐124460OB‐I00 from DOI: MCIN/AEI/ 10.13039/501100011033, and CIPROM/2021/48 from the Generalitat Valenciana, Spain)