Decreased emotional reactivity of rats exposed to repeated phase shifts of light–dark cycle
Introduction
The daily light–dark (LD) cycle is the most important environmental signal that entrains endogenous circadian rhythms of physiological and behavioural processes to the exact 24-hour rhythm throughout all living organisms. The internal synchrony is coordinated by the master circadian pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus and peripheral oscillators in other tissues and organs [1]. Altered timing of the external entraining cue results in misalignment between internal circadian clocks and external environment causing a disruption of phase relationships at different levels of circadian organisation [2], [3]. This phenomenon has become closely related to the modern lifestyle and is increasingly encountered especially by rotating shift workers, night workers and frequent travellers across time zones [4]. Subsequently, impaired circadian organisation can lead to negative health consequences and contribute to a higher incidence of diseases in shift workers [5], [6]. Epidemiological studies have indicated that shift work is associated with disturbed sleep–wake cycle [7], increased risk of cardiovascular diseases [8], several types of malignancies [9], [10] and psychological disorders [11] although the significance of these links is still disputable and varies among studies.
To further understand causality and underlying mechanisms linking circadian disruption and shift work to adverse health effects, animal studies have been performed [12]. Frequently explored experimental models of circadian disruption, which are mainly focused on the SCN, employ exposure of rodents to constant light [13], altered length of LD period [14] or repeated shifts in LD cycle [2], [15]. Disturbed circadian oscillations can induce causal pathways leading to an increased risk of disease development through physiological, psychosocial and behavioural mechanisms [16]. In rodents, physiological effects of altered light conditions are implicated in metabolic functions, especially in glucose metabolism [12]. Behavioural consequences of these experimental manipulations are primarily documented by changed rhythms of locomotor activity [17], [18]. Moreover, exposure to constant light results in deficient cognitive functions [19], reduced anxiety-like responses and increased depressive-like behaviours [20]. Similarly, hamsters submitted to phase shifts of LD cycle displayed impaired cognitive skills [21]. In mice, fast rotating shifts of LD cycle produced long-term neurobehavioural consequences such as hyperlocomotion and anxiety-like behaviour in an open-field test [18].
On the other hand, some findings showed that altered timing of light exposure does not have to directly trigger pathological processes but it can increase susceptibility of organisms to challenging factors [22] or negative heath consequence may depend on genetic predisposition [17]. Likewise, in our study with rats, rotating shifts of LD cycle did not elevate absolute levels of blood pressure (BP) and heart rate (HR) [23] but the treatment changed sensitivity of the animals to sympathetic stimulation as shown by higher BP response after norepinephrine administration in comparison with controls [24]. Since effective coping with stress represents an adaptive way to restore homeostasis in healthy individuals, the excessively high response to challenge may in the long term potentiate adverse effects. Thus, an augmented stress response can represent a mechanism, which mediates effects of circadian desynchrony resulting from disturbed LD conditions on disease development.
The present study extends our previous results, which demonstrated that chronic phase advance and delay shifts disturb circadian system functioning based on changed temporal organisation of locomotor activity, cardiovascular parameters and clock gene expression [23], [25]. In the current study, we analysed effects of repeated phase shifts of LD cycle on behaviour and the activity of autonomic nervous system (ANS) in response to different behavioural tests. We applied 8-h phase delay shifts every 2 days for 5 weeks to male Wistar rats and examined their emotional reactivity in the open-field, black–white box and elevated plus maze tests, which are considered to be mild stressors of novelty, light areas and open spaces, respectively. Besides behavioural measures of emotional reactivity, we evaluated stress-related changes of autonomic regulation of cardiovascular response by analysing HR and BP variability and baroreflex sensitivity.
Section snippets
Animals
Adult male Wistar rats were obtained from a breeding station at the Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences (Dobra Voda, Slovak Republic) at the age of 8–10 weeks. Rats were housed in groups of four animals in plastic cages at an ambient temperature of 21 ± 2 °C and humidity of 55 ± 10%. Food and water were provided ad libitum. Rats were kept under a LD cycle of 12L:12D (lights on 06:00; light intensity 150 lx) for more than 3 weeks before the experimental
Behaviour
In the open-field test, SHIFT rats travelled a longer distance (t(13) = − 2.277, p < 0.05; Fig. 3A), displayed longer time spent rearing (t(13) = − 5.177, p < 0.001; Fig. 3B) and in turn decreased time spent freezing (t(13) = 2.332, p < 0.05; Fig. 3C) as compared to CTRL rats. The percentage of distance travelled in the central zone (10.9 ± 2.8% vs. 14.7 ± 3.1% for CTRL and SHIFT rats, respectively; t(13) = − 0.909, p = 0.380) as well as grooming activity (t(13) = − 0.342, p = 0.738; Fig. 3D) did not differ between
Discussion
In the present study we examined the effects of repeated phase shifts of LD cycle on behavioural and cardiovascular response of male Wistar rats to mild emotional stressors. Five-week exposure to 8-h delay shifts altered emotional reactivity of rats resulting in hyperactivity in the open-field and black–white box tests and enhanced response of the ANS in the black–white box. The effects on anxiety measures were not homogenous across three test paradigms but considering results from black–white
Acknowledgement
This study was supported by the Slovak Research and Development Agency (APVV-0291-12) and the Scientific Grant Agency of the Ministry of Education of the Slovak Republic and of the Slovak Academy of Sciences (VEGA 1/0557/15).
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