Age-Related Changes in Murine Corneal Nerves

Reichard, Maria; Weiß, H.; Poletti, Enea; Ruggeri, Alfredo; Guthoff, Rudolf; Stachs, Oliver; Baltrusch, Simone

doi:10.3109/02713683.2015.1088952

Cited by 20 publications

(25 citation statements)

References 45 publications

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“…The disappearance of the majority of the sensory axons in the cornea by 24 months of age reported in our study is consistent with an earlier study (Reichard et al, 2016); but extends those data to show that corneal touch sensation is also reduced while apical axon extension is not affected by aging. The nerve terminals that targeted to the apical–most cell layers in the majority of corneas failed to initiate a blink in response in the corneal touch assay.…”

Section: Discussionsupporting

confidence: 93%

“…Advances in imaging allow the acquisition of high-resolution images of the ICNs on mouse corneas using confocal microscopy (Reichard et al, 2016; Stepp et al, 2017); similarly, advances in vivo confocal microscopy permit the study of the ICNs in human corneas (Patel and McGhee, 2009; Stachs et al, 2007). Altered morphology and numbers of the corneal sensory nerves have been reported by clinicians studying small fiber neuropathy and in diseases affecting the central nervous system including Multiple Sclerosis, Parkinson's Disease, and Fibromyalgia (Cruzat et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Allowing C57BL/6 mice to age is associated with development of chronic dry eye disease symptoms (McClellan et al, 2014) similar to those seen in young mice when subjected to treatments that induce dry eye disease acutely (Dursun et al, 2002). Sensory axon density has been reported to decrease in C57BL/6 mice (Reichard et al, 2016). A recent study shows that sensory axon density is reduced in a surgically induced chronic dry eye model where the lacrimal gland is removed (Yamazaki et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice

Stepp

Pal‐Ghosh

Tadvalkar

et al. 2018

Experimental Eye Research

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Dry Eye disease causes discomfort and pain in millions of patients. Using a mouse acute desiccating stress (DS) model we show that DS induces a reduction in intraepithelial corneal nerve (ICN) density, corneal sensitivity, and apical extension of the intraepithelial nerve terminals (INTs) that branch from the subbasal nerves (SBNs). Topical application of 0.02% Mitomycin C (MMC) or vehicle alone has no impact on the overall loss of axon density due to acute DS. Chronic dry eye, which develops progressively as C57BL/6 mice age, is accompanied by significant loss of the ICNs and corneal sensitivity between 2 and 24 months of age. QPCR studies show that mRNAs for several proteins that regulate axon growth and extension are reduced in corneal epithelial cells by 24 months of age but those that regulate phagocytosis and autophagy are not altered. Taken together, these data demonstrate that dry eye disease is accompanied by alterations in intraepithelial sensory nerve morphology and function and by reduced expression in corneal epithelial cells of mRNAs encoding genes mediating axon extension.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice

Stepp

Pal‐Ghosh

Tadvalkar

et al. 2018

Experimental Eye Research

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“…Such interest extends also to the eye, and in recent years, many publications have used mice to analyze normal and pathologic ocular processes, including those affecting the sensory innervation of the corneal surface. [1][2][3] As a result of these studies, the distribution and architecture of mouse corneal sensory innervation is reasonably well known, confirming that it follows the morphologic pattern of corneal nerve branching described in other mammalian species, 4,5 although remarkable differences exist in nerve density between mice strains. 4 Additionally, the corneal innervation of mice has been used to explore the origin and trophic dependence of peripheral sensory nerves during prenatal development 6 and postinjury nerve regeneration in adults, 3,7,8 as well as age-dependent changes in the architecture and function of corneal nerves.…”

supporting

confidence: 51%

“…[1][2][3] As a result of these studies, the distribution and architecture of mouse corneal sensory innervation is reasonably well known, confirming that it follows the morphologic pattern of corneal nerve branching described in other mammalian species, 4,5 although remarkable differences exist in nerve density between mice strains. 4 Additionally, the corneal innervation of mice has been used to explore the origin and trophic dependence of peripheral sensory nerves during prenatal development 6 and postinjury nerve regeneration in adults, 3,7,8 as well as age-dependent changes in the architecture and function of corneal nerves. 2,9 Moreover, mice have been extensively employed to define the morphologic alterations of corneal nerves caused by a number of pathologic conditions such as diabetes, 10 surgical injury, 1,11,12 herpes virus infections, 13,14 and dry eye disease.…”

supporting

confidence: 51%

Functional Properties of Sensory Nerve Terminals of the Mouse Cornea

González-González

Bech

Gallar

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To define the firing properties of sensory nerve terminals innervating the adult mouse cornea in response to external stimuli of differing modality.METHODS. Extracellular electrical activity of single corneal sensory nerve terminals was recorded in excised eyes of C57BL/6J mice. Eyes were placed in a recording chamber and were continuously superfused with warm saline solution. Nerve terminal impulse (NTI) activity was recorded by means of a glass pipette (tip~50 lm), applied on the corneal surface. Nerve terminal impulse discharges were stored in a computer for offline analysis.RESULTS. Three functionally distinct populations of nerve terminals were identified in the mouse cornea. Pure mechanonociceptor terminals (9.5%) responded phasically and only to mechanical stimuli. Polymodal nociceptor terminals (41.1%) were tonically activated by heat and hyperosmolal solutions (850 mOsmÁkg À1 ), mechanical force, and/or TRPV1 and TRPA1 agonists (capsaicin and allyl isothiocyanate [AITC], respectively). Cold-sensitive terminals (49.4%) responded to cooling. Approximately two-thirds of them fired continuously at 348C and responded vigorously to small temperature reductions, being classified as high-background activity, low-threshold (HB-LT) cold thermoreceptor terminals. The remaining one-third exhibited very low ongoing activity at 348C and responded weakly to intense cooling, being named low-background activity, high-threshold (LB-HT) cold thermoreceptor terminals.CONCLUSIONS. The mouse cornea is innervated by trigeminal ganglion (TG) neurons that respond to the same stimulus modalities as corneal receptors of other mammalian species. Mechano-and polymodal endings underlie detection of mechanical and chemical noxious stimuli while HB-LT and LB-HT cold thermoreceptors appear to be responsible for basal and irritation-evoked tearing and blinking, respectively.

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Morphological and functional changes in TRPM8‐expressing corneal cold thermoreceptor neurons during aging and their impact on tearing in mice

Alcalde

Íñigo-Portugués

González-González

et al. 2018

J of Comparative Neurology

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Morphological and functional alterations of peripheral somatosensory neurons during the aging process lead to a decline of somatosensory perception. Here, we analyze the changes occurring with aging in trigeminal ganglion (TG), TRPM8-expressing cold thermoreceptor neurons innervating the mouse cornea, which participate in the regulation of basal tearing and blinking and have been implicated in the pathogenesis of dry eye disease (DED). TG cell bodies and axonal branches were examined in a mouse line (TRPM8 -EYFP) expressing a fluorescent reporter. In 3 months old animals, about 50% of TG cold thermoreceptor neurons were intensely fluorescent, likely providing strongly fluorescent axons and complex corneal nerve terminals with ongoing activity at 34°C and low-threshold, robust responses to cooling. The remaining TRPM8 corneal axons were weakly fluorescent with nonbeaded axons, sparsely ramified nerve terminals, and exhibited a low-firing rate at 34°C, responding moderately to cooling pulses as do weakly fluorescent TG neurons. In aged (24 months) mice, the number of weakly fluorescent TG neurons was strikingly high while the morphology of TRPM8 corneal axons changed drastically; 89% were weakly fluorescent, unbranched, and often ending in the basal epithelium. Functionally, 72.5% of aged cold terminals responded as those of young animals, but 27.5% exhibited very low-background activity and abnormal responsiveness to cooling pulses. These morpho-functional changes develop in parallel with an enhancement of tear's basal flow and osmolarity, suggesting that the aberrant sensory inflow to the brain from impaired peripheral cold thermoreceptors contributes to age-induced abnormal tearing and to the high incidence of DED in elderly people.

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Age-Related Changes in Murine Corneal Nerves

Cited by 20 publications

References 45 publications

Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice

Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice

Functional Properties of Sensory Nerve Terminals of the Mouse Cornea

Morphological and functional changes in TRPM8‐expressing corneal cold thermoreceptor neurons during aging and their impact on tearing in mice

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