TEAR DEFICIENCY INDUCED BY LACRIMAL GLAND EXCISION CAUSES DEPRESSIVE-LIKE BEHAVIORS IN MICE
Authors: Masuoka *Takayoshi , Nakazawa Hitomi , He Qiang , Nakano Katsuya , Zheng Shijie , Kiyoi Takeshi , Uwada Junsuke 
Published: February 2025

Abstract

Background
Dry eye is an ocular surface disease with tear film instability accompanied by corneal epithelial damage, ocular discomfort, pain, and visual disturbance. Nerve terminals in the cornea are reported to show firing abnormalities in dry eye model animals elicited by surgical excision of the lacrimal gland (Ková cs et al., 2016; Masuoka et al., 2018); the mechanisms of neuropathic pain might underly ocular uncomfortable sensation in dry eyes. Clinical studies have implicated that dry eye, which is the same as other chronic pain disorders, is strongly correlated with psychiatric disorders such as anxiety and depression (Bitar et al., 2019).

Aims & Objectives
In the present study, we examined (1) whether two types of dry eye model mice with different severities produce behavioral changes in the open-field, sucrose preference, and forced swim tests and (2) whether spontaneous motor activity with running wheel helps improve behavioral disorders.

Method
The bilateral exorbital lacrimal glands (ELG) or exorbital and intraorbital lacrimal glands (ELG+ILG) were removed from male C57BL/6J mice. As the control group, sham-operated mice were made. Tear volume and corneal damage were measured every two weeks by phenol red thread and fluorescein staining, respectively. The open-field, sucrose preference, and forced swim tests were carried out 6 or 12 weeks after surgery.

Results
The ELG and ELG+ILG excision persistently decreased tear volume and aggravated the corneal damage. The cornea in the ELG+ILG excision mice was more severely impaired than that in the ELG excision mice. Excision of the lacrimal glands decreased in the staying time in the inner zone of the open field, whereas it showed no significant effect on the total travel distance. The gland excision mice exhibited lower preference in the sucrose preference test, and longer immobility and shorter climbing times in the forced swim test than sham-operated mice, which appeared earlier in the ELG+ILG excision mice. After performing the spontaneous wheel-running, the longer immobility times and the shorter climbing times in the forced swim were completely canceled in lacrimal gland excision mice.

Discussion & Conclusion
These results suggest that chronic tear deficiency might directly induce depressive-like behaviors, which depend on the severity and duration of the corneal impairment. In addition, motor activity could help ameliorate depression-like behaviors caused by ocular dryness.

References
Bitar MS, Olson, DJ, Li M, Davis RM (2019) The Correlation Between Dry Eyes, Anxiety and Depression: The Sicca, Anxiety and Depression Study. Cornea 38:684–689.
Ková cs I, Luna C, Quirce S, Mizerska K, Callejo G, Riestra A Ferná ndez-Sá nchez L, Meseguer VM, Cuenca N, Merayo-Lloves J, Acosta MC, Gasull X, Belmonte C, Gallar J (2016) Abnormal activity of corneal cold thermoreceptors underlies the unpleasant sensations in dry eye disease. Pain 157:399-417.
Masuoka T, Gallar J, Belmonte C (2018) Inhibitory Effect of Amitriptyline on the Impulse Activity of Cold Thermoreceptor Terminals of Intact and Tear-Deficient Guinea Pig Corneas. J Ocul Pharmacol Ther 34:195-203.