Dualistic and inconsistent role of total and rapid-eye movement (REM) sleep deprivation on depressive-like behaviors in rats: a systematic review

Abstract

Sleep deprivation (SD) has deleterious effects on cognitive functions and mood state. Evidence has shown that total and rapid-eye movement (REM) SD may lead to mood disturbances, anxiety, and depressive-like behaviors in rodents. However, there are inconsistent reports showing the potential antidepressant effects of SD. The present systematic review study aimed to review all previously published studies (indexed in PubMed) to assess the effects of total and REM SD on depressive-like behavior in rats, with respect to rat model, rat strain, age or weight, sex, SD model, SD duration, SD method, and depression test. At first, 184 studies were identified. After removal of duplications and unrelated studies, 37 studies were included in the present systematic review. The results showed a wide range of inconsistent effects of total and REM SD (especially REM SD) on depressive-like behavior in control and model rats. Increased depressive-like behavior was the most effect seen induced by total and REM SD in control rats. However, REM SD in pathological conditions showed a therapeutic role via decreasing depression, but total SD did not show this effect. We also showed that sex and depression test may alter the effect of REM SD on depressive-like behavior (evidence is limited). We suggested that future studies should use various depression tests and both sexes to better investigate the effects of SD on depression. We also showed that chronic REM SD leads to manic-like behaviors in females, although this effect has not been well investigated in males.

Introduction

Sleep is a critical physiological phenomenon that is vital for physical and mental health. Evidence has shown the increasing rate of sleep restriction and insomnia in societies. It has been estimated that the prevalence of insomnia in the adult population vary from 10 to 40% [1]. A recent study has shown that approximately 10% of the adult population have insomnia and 20% of the adults have occasional insomnia-related symptoms [2]. Other recent study has reported that 6–10% of Europeans suffer from chronic insomnia [3]. Also, it has been shown that individuals with sleep disturbances or insomnia are 10 and 17 times more likely to experience depression and anxiety, respectively, than those without sleep problems [4]. A recent report has shown a 40–50% prevalence of comorbidity between insomnia and various neuropsychiatric diseases [5].

Sleep deprivation (SD) and rapid-eye movement (REM) SD have deleterious effects on the mood state in preclinical models [6–8]. However, a wide range of inconsistent effects of SD on mood and cognition have been reported. It has been shown that total and REM SD have inconsistent effects on cognition and behavior. For example, it has been declared that total and REM SD induce a wide range of inconsistent effects on learning, memory, and neurogenesis [9]. Inconsistent effects of SD on the mood state have also been shown. Evidence has shown that total and REM SD can significantly lead to anxiety- and depressive-like behaviors in rats [10–12]. Some studies have also shown that REM SD may lead to the induction of manic-like and obsessive–compulsive-like behaviors in rats [6, 13, 14]. But on the contrary, many studies have demonstrated that total and REM SD may induce therapeutic effects for the treatment of depression [15–17]. A previous systematic review has suggested that SD may be considered as a non-drug treatment for depression [18]. It has also been shown that SD in mice exposed to chronic restraint stress alleviates depressive-like behaviors [19]. Other study has shown the antidepressant effect of REM SD in rats exposed to chronic unpredictable mild stress [20]. Therefore, we are faced with a wide range of SD effects on depression.

According to the mentioned findings, there is no systematic review study to investigate the wide range of inconsistent effects of SD and REM SD on depression. The present study aimed to review all previously published studies (indexed in the PubMed electronic database) to assess the effects of SD and REM SD on depressive-like behavior in rats. We hypothesized that the SD model and method, SD duration, rat model, or the depression test may be involved in the induction of inconsistent effects.

Method

Search strategy

The search strategy of the present systematic review was designed according to preferred notification items for systematic reviews and meta-analyses (PRISMA) guidelines [21, 22]. All related published studies were investigated and identified in PubMed electronic database. Boolean operator guideline was also utilized to identify the relevant keywords [23]. Keywords used to search in this systematic review were as follows:

((sleep deprivation[Title/Abstract]) AND (rats[Title/Abstract])) AND (depressive[Title/Abstract]);

((sleep deprivation[Title/Abstract]) AND (rats[Title/Abstract])) AND (depression[Title/Abstract]);

((sleep deprivation[Title/Abstract]) AND (rat[Title/Abstract])) AND (depressive[Title/Abstract]);

((sleep deprivation[Title/Abstract]) AND (rat[Title/Abstract])) AND (depression[Title/Abstract]);

((sleep restriction[Title/Abstract]) AND (rats[Title/Abstract])) AND (depressive[Title/Abstract]);

((sleep restriction[Title/Abstract]) AND (rats[Title/Abstract])) AND (depression[Title/Abstract]);

((sleep restriction[Title/Abstract]) AND (rat[Title/Abstract])) AND (depression[Title/Abstract]);

((sleep restriction[Title/Abstract]) AND (rat[Title/Abstract])) AND (depressive[Title/Abstract]).

Of note, there was no limitation on publication date in the search strategy. The search period was between 20th October–5th November 2024.

Inclusion/exclusion criteria

Inclusion criteria: Only rat studies were selected. Only original (research) papers were selected. All studies conducted total SD or REM SD model. All studies assessed depressive-like behaviors using various tests. All articles were in English. Also, the selected articles were checked for consistency. Each article included all these factors: (1) Total SD or REM SD, (2) depression test, (3) rats.

Exclusion criteria: All forms of thesis dissertations, conference papers, review articles, and patents were excluded. Clinical studies or preclinical studies not using rats (for example, mice) were excluded. Studies in other languages were excluded. Studies that used total SD or REM SD but did not assess depression were excluded.

Data extraction and management

Literature screening was performed according to Fig. 1. At first, the title and abstract of each article were checked by two authors (H.M. and Z.N.). All the full texts were evaluated by (A.M., N.T., and P.F.). In the next step, any differences in the search strategy and selection of articles were resolved by discussion and consultation with other authors (F.H.). The other author (S.V.) reviewed the manuscript preparation process and cited references. After selecting the articles, a standardized note-taking form was used for data extraction purposes. The data extraction form has this information: (1) rat model, (2) sex, (3) age or weight, (4) SD model, (5) SD duration, (6) SD method, (7) depression test(s), (8) effect(s), (9) reference.

Fig. 1.

Flowchart of the study selection process (PRISMA flow chart)

Strategy for data extraction

All the selected published studies with their results have been provided in the data extraction table (Table 1), while the study outcome has been discussed in “Results”. The analyses of the results have also been generally explained in “Discussion”.

Table 1.

The effect of total and REM SD on depressive-like behavior in rats with respect to the rat model, sex, age or weight, SD model, SD method, SD duration, and depression test

Rat model	Strain	Sex	Age or weight	SD model	SD duration	SD method	Depression test(s)	Effect(s)	References
Control	Wistar	Male	3 months	REM SD	72 h	Multiple platform	SPT, FST, TST	Depressive behaviors	[12]
Control	Wistar	Female	7–8 weeks	REM SD	6 h/day/2 weeks	Multiple platform	FST	No depressive behavior	[6]
Control	Wistar	Both	3 weeks	REM SD	Various durations in 3 weeks	Multiple platform	SPT, FST	No effect in SPT Depressive behavior in males in FST Antidepressant effect in females in FST	[35]
Control	Wistar	Female	7–8 weeks	REM SD	6 h/day/2 weeks	Multiple platform	FST	No depressive behavior	[13]
Laparotomy	Sprague–Dawley	Male	24 months	Total SD	12 h/3 days	Gentle handling	TST	Increases depressive behavior	[36]
Control	Wistar	Male	200–250 g	REM SD	18 h/day/3 weeks	–	FST	Depressive behavior	[74]
Control	Wistar	Male	6 weeks	–	–	–	FST	Depressive behavior	[75]
Control	Sprague–Dawley	Male	2 months	Total SD	28d	Insomnia model of chronic unpredictable stress	FST	Depressive behavior	[25]
Control	Wistar	Male	6 weeks	REM SD	6 h/day/4 weeks	Modified multiple platform	SPT, FST	Depressive behaviors	[76]
Control	Sprague–Dawley	Male	15 weeks	REM SD	12 h/day/3 weeks	Multiple platform	SPT	Depressive behavior	[77]
CUMS	–	–	–	–	18 h/day/3 weeks	–	–	Improvement of depressive behavior	[39]
Control	Sprague–Dawley	Male	19 days	Total SD	Various durations in 2 weeks	Pinnacle automated	SST	Depressive behavior	[26]
Control	Wistar	Male	6 weeks	REM SD	18 h/day/4 weeks	Modified multiple platform	SPT, FST	Depressive behaviors	[32]
CUMS	–	–	–	REM SD	–	Multiple platform	–	Improvement of depressive behavior	[20]
Control	Wistar	Male	240 g	REM SD	7 days	Multiple platform	SPT, FST, TST	Depressive behaviors	[78]
Control	Wistar	Male	200–280 g	REM SD	72 h	Multiple platform	FST	Depressive behavior	[44]
Control	Wistar	Male	180–220 g	Total SD	24 h	The Water box	FST	No effect	[33]
Control	Sprague–Dawley	Male	200–220 g	REM SD	16 h/day/4 weeks	Multiple platform	SPT, TST	Depressive behaviors	[79]
Control	–	–	–	–	–	–	FST, TST	Depressive behaviors	[7]
CUS	Sprague–Dawley	Male	3 months	REM SD	28 days	Multiple platform	SPT	Improvement of depressive behavior	[38]
Control	Wistar	Male	200–250 g	Total SD	48 h	The Water box	FST	Depressive behavior	[27]
Control	Sprague–Dawley	Male	180–220 g	REM SD	19 h/day/1 week	Multiple platform	SPT, FST	Depressive behaviors	[80]
Control	Wistar	Male	230–250 g	REM SD	7 days	Modified multiple platform	FST, TST	Depressive behaviors	[81]
Control	Sprague–Dawley	Male	19 days	Total SD	Various durations in 2 weeks	Pinnacle automated	FST	Depressive behavior	[28]
Control	Sprague–Dawley	Male	6–8 weeks	Total SD	48 h	Automated apparatus	SPT, FST	Depressive behaviors	[29]
Control	Wistar	Male	230–250 g	REM SD	72 h	Multiple platform	FST, TST	Depressive behaviors	[82]
Control	Wistar	Male	200–220 g	REM SD	24 h	Multiple platform	FST	Depressive behavior	[31]
Control	Sprague–Dawley	Both	6–8 weeks	Total SD	6 h/15–21 gestational days	Gentle handling	FST	Depressive behavior	[24]
Control	Wistar	Male	18 days	REM SD	18 h/day/3 weeks	Multiple platform	SNCT	No effect	[10]
Control	Sprague–Dawley	Both	6–8 weeks	Total SD	6 h/1–7 gestational days	Gentle handling	FST	Depressive behavior	[11]
Control	Long-Evans	Male	600–700 g	REM SD	24 h	Columns in water model	FST	Depressive behavior	[30]
CUPS	Sprague–Dawley	Male	3 months	REM SD	48 h	Multiple platform	SPT	Improvement of depressive behavior	[37]
OB	Wistar	Male	280–320 g	REM SD	72 h	Single platform	FST	Improvement of depressive behavior	[16]
MT2 blockade	Wistar	Male	280–320g	REM SD	24 h	Single platform	FST	Potentiated the antidepressant effect	[41]
CCI	Wistar	Male	3 months	REM SD	96 h	Single platform	SPT	Improvement of depressive behavior	[40]
Control	Wistar	Female	3 months	REM SD	72 h	Single platform	FST	Antidepressant effect	[43]
Control	Sprague–Dawley	Male	330–340 g	Total SD	24 h	Disk over water method	FST	Antidepressant effect	[42]

Results

Twenty-two studies showed that SD leads to depressive-like behavior in rats. All these studies used control rats. Also, 20 studies used male rats, while only 2 studies [11, 24] used both sexes. Therefore, female studies are sparse. All depression tests [forced swim test (FST), sucrose preference test (SPT), tail suspension test (TST)] were allocated. Seven studies used total SD [11, 24–29], while the other studies used REM SD. The duration of SD was between at least 24 h (for REM SD) [30, 31] or 48 h (for total SD) [27, 29] to 18 h/day for 4 weeks (for REM SD) [32] or 28 days (for total SD) [25]. Of note, this study [25] used an insomnia model induced by chronic stress.

There were 4 studies that showed no depressive-like effect. This study [33] used 24 h of total SD in male rats, this study [10] used 18 h/day for 3 weeks of REM SD in male rats. Two studies [6, 13] showed no depressive-like, but manic-like behaviors in female rats exposed to REM SD for 6 h/day for 14 days. Although other studies have shown manic-like behaviors induced by REM SD, while they did not assess depressive-like behaviors or use any depression tests [14, 34].

Importantly, one study [35] reported that increasing the duration of REM SD in 3 weeks in male rats had no effect on depressive-like behavior in SPT, while it induced depressive-like behavior in male rats in FST, but, on the contrary, it induced an antidepressant effect in female rats in FST. Therefore, this study showed that the effect of REM SD (using multiple platform device) on depressive-like behavior is inconsistent and may be related to sex and depression test.

SD in other studies that not used control rats showed antidepressant effects, except one study [36]. It has been shown that REM SD in male rats exposed to chronic stress [20, 37–39], in a rat model of olfactory bulbectomy [16], in a rat model of chronic constrictive injury [40], and in a rat model of MT2 blockade [41] improved depression. While this study [36] showed that total SD aggravates depressive-like behavior in a rat model of laparotomy.

Eventually, two studies showed that total [42] and REM [43] SD induced an antidepressant effect in male and female rats, respectively. In addition, this study [35] showed this effect only in females exposed to REM SD in FST. (Table 2).

Table 2.

Categorizing all studies according to their effects on depressive-like behavior with respect to rat and SD models

Number of studies	Rat model	SD model	Depressive-like behavior
22	Control	Both	Increase
4	Control	Both	No depressive effect
2	Control	Both	Antidepressant
7	Chronic stress, MT2 blockade, Chronic constrictive injury, Olfactory bulbectomy	REM SD	Improvement of depression
1	Laparotomy	Total SD	Aggravates depression
1	Control	REM SD	No effect in SPT Depressive behavior in males in FST Antidepressant effect in females in FST

Discussion

Overview

According to Table 2, increased depressive-like behaviors in control rats following total and REM SD are the most common findings of previous studies. However, we showed that REM SD but not total SD improves depressive-like behaviors in different rat models of depression (or other models). But on the contrary, total SD aggravates depression in a rat model of laparotomy. Also, one study using REM SD for 72 h in females and one study using total SD for 24 h in males showed an antidepressant effect. One study using total SD for 24 h and one study using REM SD for 18 h/day for 3 weeks showed no effect on depressive-like behavior, while both used male rats, but the first study used FST and the second used sucrose negative contrast test (SNCT). Two studies showed no depressive-like using FST, but manic-like behavior in female rats exposed to REM SD for 6 h/day for 2 weeks. Importantly, one study showed inconsistent effects of REM SD on depressive-like behavior, depending on sex and the depression test. It seems that chronic durations of REM SD do not lead to depressive-like state. In addition, REM but not total SD may show therapeutic effects on non-control rats. However, there are few studies that showed antidepressant effects of total (24 h) or REM (72 h) SD in control rats. Therefore, the effects of total and REM SD may depend on the duration, sex, depression test, and the subjects (control or disease model). Although female studies are so sparse, one recent study showed a significant sex-dependent effect of chronic REM SD [35]. The result of this study [35] is consistent with previous studies [6, 13] that showed chronic REM SD does not induce depressive-like behavior in female rats. Therefore, the role of SD duration and sex may be more important. Importantly, REM SD significantly shows a dual effect on depressive-like behavior, because in controls, REM SD often induces depressive-like behavior; while in models, REM SD improves depression. This effect has not been observed by total SD, although there is only one study.

Depressive effects of SD

The most expected result was the induction of depressive-like behavior induced by total or REM SD. As mentioned, most studies showed this effect. Previous studies have shown that 72 h REM SD leads to depressive- and anxiety-like behaviors in rats [12, 44]. Total SD also leads to depressive- and anxiety-like behaviors in rats [26, 28]. It has been suggested that SD attenuates neurogenesis and synaptic plasticity, leading to cognitive impairments and mood disturbances [11, 45, 46]. Also, SD potently affects the function of brain-derived neurotrophic factor (BDNF), the most important neurotrophin in the central nervous system involved in the modulation of neuroplasticity, mood, and cognition [9, 47, 48]. As we know, attenuated neuroplasticity is an important mechanism underlying mood disturbances. It has been shown that decreased BDNF in the hippocampus in female rats may underlie manic- and obsessive–compulsive-like effects induced by chronic REM SD [6]. Other study has shown that 72-h SD leads to decreased BDNF protein levels in male Sprague–Dawley rats [49]. It has also been reported that SD decreases BDNF levels and induces depressive-like behaviors in male C57BL/6J mice [50]. On the contrary, a previous study has shown greater levels of BDNF in the hippocampus induced by chronic REM SD, along with depressive- and anxiety-like behaviors [10]. It has also been revealed that REM SD triggers antidepressant mechanisms, including the increment of BDNF levels in a rat model of olfactory bulbectomy [16]. Inconsistent effects of SD on BDNF levels and neurogenesis have been reported in a previous review study [9]. Therefore, inconsistent effects of SD on the mood state may be related to its inconsistent effects on neurogenesis and BDNF function. In addition, changes in the function of corticotropin-releasing hormone (CRH) following SD may be important. CRH is a peptide hormone that plays a central role in the body’s stress response and is a key hormone that regulates humoral and behavioral adaptation to stress [51]. It has been reported that brain-derived CRH increases REM sleep via activating CRH receptor type 1 [51]. Other study has shown that increased CRH immunoreactivity in specific hypothalamic nuclei may underlie some of the metabolic changes induced by paradoxical SD [52]. Previous study has also shown increased CRH levels in the hypothalamus of rats exposed to REM SD [53]. Furthermore, increased serum level of CRH has been reported following total SD in rats in a previous study [54]. On the other hand, depression is often described as a condition with HPA axis overactivity on the basis of increased CRH and cortisol levels [55], showing a significant relationship between CRH and depression. It has also been noted that chronically elevated CRH levels gradually desensitize the CRH receptors, which in turn may be responsible for the attenuated pituitary responsiveness [8], leading to a blunted pituitary ACTH response [56]. Also, previous study has declared that the HPA axis is hyperactive in major depressive disorder, probably as a result of a primary hyperdrive of CRH [57]. Therefore, changes in CRH levels may underlie the depressive effects of total or REM SD; however, no study has reported the contradictory effects of SD on CRH.

Antidepressant effects of SD

The antidepressant effect of REM SD has been shown in rat models of depression and stress. As we showed, REM SD potently induces antidepressant effects in rat models of chronic stress [37, 39]. This effect has also been observed in other models, including chronic constrictive injury, olfactory bulbectomy, and MT2 blockade [16, 40, 41]. Therefore, it seems that REM SD in pathological conditions may be a reliable antidepressant option for the alleviation of depressive-like behavior. However, total SD has not been used as much as REM SD in rat models of depression, stress, or other models. We found only one study that used total SD in a rat model of laparotomy, which aggravated depression [36]. But also, two past studies have shown the antidepressant effects of total SD (male) and REM SD (female) in control rats [42, 43]. Increased cAMP responsive element binding protein 1 (CREB1) levels and adenosine receptor activation have been suggested as underlying mechanisms for the antidepressant effect of REM SD in a rat model of chronic stress [20]. A higher BDNF expression has also been shown following 48 h REM SD, leading to an antidepressant effect in a rat model of chronic stress [37]. Furthermore, another study has shown that REM SD increases serotonin levels in the hippocampus of the bilateral olfactory bulbectomy rat model, leading to an antidepressant effect [16]. It has also been shown that REM SD via improvement of apoptotic status (decrease of apoptotic factor and increase of antiapoptotic factor) induces an antidepressant effect in a rat model of chronic stress [38]. Therefore, a wide range of mechanisms has been shown underlying the antidepressant effects of REM SD, although there is no “one” specific mechanism. Therefore, REM SD can play a dual role in the modulation of depression, because evidence has shown that REM SD can increase apoptosis and attenuate neurogenesis in controls [11, 12].

Inconsistent effects of SD

One study showed the inconsistent effect of chronic REM SD. This study [35] showed that chronic REM SD induces depressive-like behavior only in males and in the FST. However, in the SPT, both males and females did not show depressive-like behavior. In addition, REM SD showed an antidepressant effect in females in the FST, suggesting the important role of sex and the depression test. Both total and REM SD induce dual effects on neurogenesis and BDNF levels, while the role of SD duration seems to be critical [9]. It has been shown that short-term total SD may stimulate neurogenesis, while long-term total SD attenuates it [9]. For example, 12 h total SD may stimulate neurogenesis [58, 59], while 48 h, 72 h, or 96 h of total or REM SD impairs neurogenesis [46, 60, 61]. It has also been shown that 24 h REM SD decreases BDNF levels [62], while 48 h REM SD increases BDNF levels [63]. Importantly, previous study has shown the inconsistent effects of total SD on oxidative factors in the serum of rats, showing that long- but not short-term total SD increases oxidative stress and impairs memory [64], suggesting the important role of SD duration. Therefore, it seems that SD duration may be a determining factor for the effect of total and REM SD on depression. Although the number of studies that compare the different durations of SD on depression is limited. Evidence on the role of sex and the depression test is also very limited, but we showed that these two factors may alter the effect of REM SD on depressive-like behaviors in both sexes of rats.

Potential effects of stress associated with SD procedures

Importantly, SD procedures (SD method, apparatus, etc.) can act like stressors. As we know, stress is one of the most important underlying causes of depression [65, 66]. As shown in Table 1, many of the REM SD studies used multiple (or modified multiple) platform and single platform devices. In these studies, the rats were placed inside a water tank containing a single circular platform or multiple platforms with water up to 1–2 cm below the surface of the platform(s). These methods can stress the rats, such as the inability to move, having little space to rest, being surrounded by water, and difficulty drinking water and eating food. On the other hand, total SD methods such as the water box, and pinnacle automated, can induce more stress. For example, in the water box, the rat should constantly change its platform to avoid drowning. In the pinnacle automated method, the rat is places in a bar that is rotated continuously by a motor at approximately 3 rpm with random reversals in rotational direction to prevent the rat from acquiring brief sleep periods through adaptation to the pattern of rotation. Therefore, SD procedures can lead to the induction of stress, and SD procedure-induced stress can affect the mood state, leading to depressive-like behaviors. However, many of these studies designed a sham of REM SD group; for example, placing the rats inside a water tank with larger platforms. The rats of sham-REM SD groups experience normal sleep; however, the stress of the method still exists. Therefore, the results of sham-REM SD groups show the potential effect of SD procedure-induced stress on behavioral alterations in rats. Of note, the results of some of these studies showed no significant differences between control and sham-REM SD rats, suggesting that SD procedure-induced stress could not significantly affect the mood state [6, 13]. However, most of these studies did not design sham-REM SD group and only used REM SD rats [16, 37, 38, 44]. It should be noted that there are other REM SD studies that assessed behavioral functions (not included in this review due to exclusion criteria) that showed a normal function of sham-REM SD or sham-total SD rats, or showed behavioral dysfunctions in REM SD rats compared with sham-REM SD rats [67–70]. Therefore, the potential role of SD procedure-induced stress on the mood state and depression is still an important challenge. This can be considered as an important limitation of REM SD-related studies, and also, the present systematic review study. It can be suggested that potential SD procedure-induced stress can affect depressive-like behaviors in previous related studies, because most of these studies did not design a sham-REM SD group. However, it’s important to note that gentle handling method has been introduced as the method with the least stress [71]. In this method, there is not any apparatus or environmental stressor. As Table 1 shows only three studies used this method, and all these studies showed the induction of depression following total SD.

The role of strain differences

As Table 1 shows 20 studies used Wistar rats, 13 studies used Sprague–Dawley rats, and 1 study used Long-Evans rats (for 3 studies, we had no access to full-text). Therefore, the results of Table 1 showed that different rat strains (particularly Wistar and Sprague–Dawley) has been used in related studies, while there are no significant differences in the results of these studies. Strain-dependent SD effects refer to how different genetic strains of animals, particularly rodents, respond to SD differently, meaning that the effects of SD, such as cognitive impairments, behavioral changes, or changes in gene expression, can vary depending on the specific genetic background of the animal [72]. It has been noted that animals of different strains may have variations in their DNA sequences, which affect different biological processes, including sleep regulation, and maybe, SD side effects. Strain-dependent effects of total or REM SD on behavioral changes (particularly depressive-like behavior) in rats have not been studied. However, previous studies have reported that different strains of animals exhibit variations in sleep patterns, gene expression related to sleep, and behavioral responses to SD. For example, it has been revealed that some strains of mice show greater impairments in cognitive tasks after SD, while others might show more pronounced changes in gene expression related to circadian rhythms [73]. Understanding strain-dependent differences in SD is crucial for research purposes, as it highlights the importance of considering genetic background when investigating the effects of SD. As we found, there is no evidence on the potential role of strain differences in modulating SD effects on depressive-like or other behaviors in rodents (particularly rats). This can be considered as another limitation of previous related studies and the present systematic review. Eventually, there is another limitation in the present systematic review. This study is limited to rats and no other animal models, such as mice.

Conclusion

In conclusion, the present systematic review showed a wide range of inconsistent effects of total and REM SD (especially REM SD) on depressive-like behavior in control and model rats. We showed that both total and REM SD often lead to depressive-like behaviors. However, REM SD in pathological conditions shows a therapeutic role and alleviates depression, but total SD does not show this effect (although evidence for total SD is so limited). Therefore, future studies should assess the potential therapeutic role of total SD in different models of rats, including chronic stress and depression. We also showed that sex and depression test may alter the effect of REM SD on depressive-like behavior, although there was only one study in this field. Therefore, future studies should use different depression tests (but not only one test), and also, both sexes to better investigate the effects of SD on depression in rats. Furthermore, the mechanisms underlying SD effects are so inconsistent. Controversial changes in neurogenesis, oxidative stress, apoptosis, and the molecular factors may underlie the inconsistent effects of total and REM SD. We also suggest that future studies should assess the effects of SD on depression in both sexes of rats, because evidence on females is so limited. We also showed that chronic REM SD does not induce depressive-like behavior, but, on the contrary, leads to manic-like behavior in females, although this effect has not been approved in males.

Authors contributions

H.M. and Z.N. reviewed the title and abstracts. A.M., N.T., and P.F. reviewed all the full-texts. F.H. reviewed any differences in the search strategy and selection of articles. B. G. supervised the research process. S.V. designed the study, writing, and drafting. All the authors approved the final version.

Funding

There is no providing financial support to this project.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.