High Impact Original ResearchLight cycle phase advance as a model for jet lag reprograms the circadian rhythms of murine extraorbital lacrimal glands
Introduction
The tear film is the critical interface between the ocular surface and the external environment that maintains ocular surface homeostasis and corneal optical function [1]. Any factor that causes a change in the quality and quantity of the tear film can interfere with the imaging of external objects in the retina by decreasing contrast sensitivity and functional visual acuity. The tear film consists of three layers, namely, the lipid layer, aqueous layer, and mucin layer, from front to back. The aqueous layer is primarily derived from the secretion of the main lacrimal glands located in the orbital lacrimal fossa and the accessory lacrimal glands located in the palpebral and fornix conjunctivae. In addition to water and electrolytes, the aqueous layer also contains enzymes, such as peroxidase and lysozyme, lipids, lactoferrin, antimicrobial peptides [2], growth factors [3], lacritin [4], and cytokines [5]. These elements provide protection and support for the normal ocular surface through various mechanisms to avoid chemical, mechanical, and microbial damage from the outer environment [6].
The secretion of lacrimal glands is affected by a variety of internal and external factors [7]. Endogenous factors, such as menopause [8] and diabetes [9], reduce the secretion function of the lacrimal glands, which causes individuals to be prone to having dry eyes. Common external factors that affect secretion include cold, dryness, mechanical irritation, physical damage, toxic chemicals, and infections caused by various microbes [10]. However, whether and how alterations of the external light cycle disrupt the circadian clock system is not completely clear.
In mammals, virtually all aspects of physiological systems oscillate during the day under the control of the circadian clock system [11]. The synchronization of circadian oscillators is governed by the suprachiasmatic nucleus (SCN) in the hypothalamus, the central circadian pacemaker, after receiving light signal inputs from the retina [12]. Similarly, the metabolism and secretion of the lacrimal glands also have a robust rhythm during the day [[13], [14], [15]]. Human lacrimal glands secrete more tears during the daytime than at night [13]. Some tear film parameters, including pH [16], osmolarity [17,18], and tear volume [13,19], diurnally variate through the day. Circadian rhythm disturbances caused by shift work lead to instability of the tear film for night-shift workers and exacerbate dry eye symptoms [20]. The disturbance of normal circadian rhythms through sleep deprivation can also impair the structure and function of the lacrimal glands and, thus, induce dry eyes [21]. Moreover, we have systemically provided detailed information regarding the circadian characteristics of murine lacrimal glands with respect to cell size, secretion response, and transcriptomic profile [15,22]. We further demonstrated that metabolic stress induced by short-term high fructose intake [22] and streptozotocin-induced hyperglycemia [15] significantly reprograms the circadian rhythm of lacrimal glands at different levels.
Jet lag, which is caused by rapidly traversing numerous time zones, is a common desynchrony between an endogenous circadian clock and the external environment caused by shifts in the ambient light-dark cycle [[23], [24], [25]]. Acute jet lag can disrupt the normal circadian rhythm and lead to a series of psychological and physiological consequences, including sleep disturbances, daytime fatigue, decreased mental and physical performance, decreased alertness, headaches, and gastrointestinal disturbances [26,27]. However, to what extent jet lag affects the secretion response and molecular regulators of circadian rhythmicity in the lacrimal glands remains to be established.
Based on the discoveries described above, we hypothesized that circadian disruption by jet lag is sufficient to induce short-term lacrimal gland dysfunction, instability of tear film, and possible dry eye by fueling metabolic, immune, and neural dysfunction in the lacrimal glands. This study demonstrates that jet lag significantly influences alterations in the mass, cell size, secretion response, and circadian transcriptional profile of murine extraorbital lacrimal glands (ELGs) on a daily basis. These observations might contribute to our understanding of the molecular mechanism of the impairments in lacrimal gland physiology caused by jet lag as well as to the development of specific therapies for preventing jet lag-associated ocular surface diseases.
Section snippets
Overall study scheme and jet lag protocol
The flow chart of the experimental design and analysis for this study is presented in Fig. 1. In order to conduct this experiment, light cycle phase advance as a model for jet lag was established as previously described [26,28]. Briefly, C57BL/6J male mice were subjected to a 12-h light/12-h dark (LD) cycle for control group, and the LD cycle was advanced by 8-h for jet lag group (Fig. 1A). Locomotor activity and core body temperature were recorded as previously reported [26,28] (Fig. 1B). A
Jet lag alters general animal behavior
To determine the effects of jet lag on general murine phenotypes, the locomotor activity and core body temperature of the mice during light cycle phase advance as a model for jet lag were recorded by the Emitter-Telemetry System. As shown in Fig. 2A, the locomotor activity of the mice exhibited a diurnal rhythm, which increased during the dark phase, before the 8-h phase advance in the LD cycle. However, the locomotor activity of the mice gradually shifted after the changed light regimen, and
Discussion
To the best of our knowledge, this is the first report to confirm that light cycle phase advance as a model of jet lag globally disrupts the normal circadian rhythm of murine ELGs. This conclusion is based on the following observations: (1) the circadian patterns of murine ELGs in terms of weight, cell size, and secretion response after jet lag were significantly altered; (2) the composition of rhythmic genes and the phase of rhythmic gene expression were significantly altered in jet
Author contributions
Conceptualization, Z.L.; Methodology, S.H., D.Q., and X.P.; Investigation, X.J., D.L., X.P., D.Q., and S.H.; Analysis and visualization, S.H. and X.P.; Writing, Review and Editing, Z.L. and S.H.; Funding, Resources, and Supervision, Z.L., S.H., and X.J.
Declaration of competing interest
The authors declare no competing financial interest.
Acknowledgements
Research support was provided by the National Natural Science Foundation of China (grant numbers 81470603 and 81770962 to Z.L.), the Ministry of Science and Technology of the Peoples Republic of China (grant number 2018YFC0114500 to Z.L.), the Basic Science Project for Youth of Henan Eye Institute/Henan Eye Hospital (grant numbers 20JCQN003 to S.H. and 20JCQN002 to X.J.), the Doctoral Research and Development Foundation of Henan Provincial People's Hospital (grant number ZC20190146 to S.H.),
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