Research reportDisruption of circadian rhythms due to chronic constant light leads to depressive and anxiety-like behaviors in the rat
Introduction
The suprachiasmatic nucleus (SCN) of the anterior hypothalamus which is considered the biological clock, drives circadian rhythmicity of mainly all processes of physiology and behavior [1]. The SCN exhibits daily cycles of neuronal activity, with highest activation during the day and low during the night, as observed with the expression of c-Fos, glucose uptake and electrical activity [2], [3], [4]. The oscillatory properties of the SCN are suggested to rely on a transcription posttranslation feedback loop of clock genes (per1, 2 and 3; cry1 and 2; clock and bmal1) that produce 24 h cycles in individual cells [5]. Classically, the SCN is differentiated in two regions [6]: a ventrolateral and a dorsomedial area. The ventrolateral area receives projections from the retina, with information of the light/dark (LD) cycle. This alternating light–dark input permits a correct synchrony between internal and external oscillations, process necessary for adaptation and for efficient behavioral and physiological responses to the demands of the daily changing environment. This area also receives input from other external and internal stimuli that can serve as weak Zeitgebers, including arousal and activity [7], which contribute in a lower range to the adjustment of circadian rhythms. The dorsomedial area expresses endogenous rhythmicity and projects to diverse brain areas to transmit time information to the body and peripheral tissues via hormonal and autonomic signals [8].
Artificial light for long intervals during the night promotes altered activity schedules and reduced hours of sleep [9]. Both, arousal and activity combined with light at night can lead to conflicting time signals to the biological clock and lead to disturbed expression of circadian rhythms [10]. Recent evidence has pointed out that light at night as well as shift work and jet lag lead to circadian disruption, fatigue, irritability, depression and anxiety [11], [12], [13].
Depressive-like symptoms in animal models can be induced by stressful conditions due to early maternal separation or by exposing adult rodents to chronic mild stress [14], [15], [16]. Other models have used lesions or biochemical imbalance of brain areas involved in affective regulation to induce depressive-like behavior [17], [18]. Rodent models based on disruption of circadian rhythms provide a new perspective to study the induction of depression due to factors associated with modern life style, including light pollution.
Disruption of circadian rhythms in experimental models is commonly induced by frequent shifts of the LD cycle [19], by long periods of constant light [20], [21] by altered photoperiods [22], [23] or forced activity during the normal sleep phase [24]. Such altered photoperiods as well as LL have shown to drive out of phase daily rhythms in SCN cells [25], [26], [27], which is suggested to be the mechanism that drives behavioral rhythmicity. Exposing rodents to such conditions, leads to disruption of the sleep–wake temporal patterns, and a loss of circadian rhythmicity as measured with automatic monitoring systems of spontaneous activity [23], [24]. Altered circadian rhythms in rodents also lead to depressive-like symptoms, anxiety and anhedonia, expressed by reduced sucrose intake, altered patterns of food intake and high plasma levels of corticosterone [28], [29], [30], indicating that entrainment of circadian rhythms is necessary for efficient physiological and behavioral integrity.
The aim of this study was to determine whether long term constant light, which produces circadian disruption, leads to depressive-like behaviors in rats and whether this condition is associated with altered activity of the SCN measured with c-Fos and circadian expression of corticosterone and melatonin, known to be driven by the SCN [31]. This study shows that circadian disruption due to chronic constant light results in loss of rhythmicity of general activity, anhedonia in the sucrose consumption test, and anxiety-like behaviors in an open field test. Circadian disruption by constant light induced a loss of circadian expression in plasma melatonin and corticosterone, and this last hormone exhibited higher levels along the 24 h cycle. Also, rats exposed to constant light exhibited decreased activity in the SCN as indicated by reduced c-Fos expression, confirming that an altered circadian system contributes to the development of depression.
Section snippets
Animals and general conditions
Male Wistar rats weighing 250–300 g were housed in individual transparent acrylic cages (50 cm × 30 cm × 20 cm) placed in isolated lockers that can house up to 8 cages each, in a soundproof monitoring room with controlled air supply and temperature (22 ± 1 ̊C). Animals had always free access to food and water (Rodent Laboratory Chow 5001) and bedding was changed every week. Lighting conditions were controlled independently for each locker, allowing in this way to have different schedules for each group.
General activity
During BL, all animals exhibited robust daily rhythms synchronized to the LD cycle, with general activity predominantly expressed during the night (Fig. 1A, B and C top of the actograms). All rats exposed to constant darkness (DD), developed a free running temporal pattern of general activity, characterized by a daily phase delay, the periodogram indicated a period ranging between 24.5 and 25 h (Fig. 1B right bottom). LL rats progressively lost circadian rhythmicity and developed a pattern of
Discussion
Results obtained in the present study indicate that chronic conditions of an altered photoperiod induce depression- and anxiety-like behavior and affect the immunoreactivity of c-Fos in the SCN, the biological clock. Chronic constant light significantly reduced sucrose consumption, increased grooming and fecal boli in the open field test, suggesting a depressive-like behavior and a high anxiety response. High levels of corticosterone and lower body weight gain confirmed a depressive like state,
Conclusions
Present results highlight the relevance of LD alternation and the risk implied in constant light conditions for a correct expression of circadian rhythms.
Light at night is an important problem of modern society that requires more attention. People commonly exposed to this condition are night-workers; however, modern life style promotes that people stay awake to late hours in the night, which increases the exposition to. The integrity of circadian rhythms for affective behavior is evident since
Acknowledgments
Authors are thankful to Estefanía Espitia-Bautista and Madahi Palma-Gómez, Facultad de Medicina, UNAM, who provided technical support in blood sampling and evaluating the open field test; also to Luis Abel León Mercado IIBM UNAM for corticosterone determinations. This study was supported by PAPIIT-UNAM IN-203907, IN-224911; CONACyT 82462 and CONACyT 102145: apoyo para investigadores nacionales para el fortalecimiento de actividades de tutoría y asesoría de estudiantes de licenciatura awarded to
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