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Emerging evidence suggests that disruption of circadian rhythmicity contributes to development of comorbid depression, cardiovascular diseases (CVD), and type 2 diabetes mellitus (T2DM). Physical exercise synchronizes the circadian system and has ameliorating effects on the depression- and anxiety-like phenotype induced by circadian disruption in mice and sand rats. We explored the beneficial effects of voluntary wheel running on daily rhythms, and the development of depression, T2DM, and CVD in a diurnal animal model, the fat sand rat (Psammomys obesus). Voluntary exercise strengthened general activity rhythms, improved memory and lowered anxiety- and depressive-like behaviors, enhanced oral glucose tolerance, and decreased plasma insulin levels and liver weight. Animals with access to a running wheel had larger heart weight and heart/body weight ratio, and thicker left ventricular wall. Our results demonstrate that exercising ameliorates pathological-like daily rhythms in activity and blood glucose levels, glucose tolerance and depressive- and anxiety-like behaviors in the sand rat model, supporting the important role of physical activity in modulating the "circadian syndrome" and circadian rhythm-related diseases. We suggest that the utilization of a diurnal rodent animal model may offer an effective way to further explore metabolic, cardiovascular, and affective-like behavioral changes related to chronodisruption and their underlying mechanisms., (© 2022. The Author(s).)

Objective and rationale: Animal models are critical for the study of mental disorders and their treatments but are repeatedly criticized for problems with validity and reproducibility. One approach to enhance validity and reproducibility of models is to use test batteries rather than single tests. Yet, a question regarding batteries is whether one can expect a consistent individual behavioural phenotype in mice across tests that can be presumed to be part of the same construct. This study was designed to explore the relationship between the behaviours of mice across tests in some variations of test batteries for depression- and anxiety-like behaviours. Methods: Female and male healthy, intact, and untreated mice from the ICR and black Swiss strains were used in four separate experiments. With some variations, mice were exposed to a battery of behavioural tests representing affective- and anxiety-like behaviours. Data were analysed for differences between sexes and for correlations between behaviours within and across the tests in the battery. Results: No differences were found between the sexes. With very few exceptions, we found correlations within tests (when one test has more than one measure or is repeated) but not across different tests within the battery. Conclusions: The results cast some doubt on the utility of behavioural test batteries to represent different facets of emotional behaviour in healthy intact outbred mice, without any interventions or treatments. Additional studies are designed to explore whether stronger relationship between the tests will appear after manipulations or drug treatments.

It was recently suggested that the Metabolic Syndrome should be renamed to "Circadian Syndrome". In this context, we explored the effects of living under standard laboratory conditions, where light is the only cycling variable (relevant to human modern life), in a diurnal mammal, on the relationships between affective-like pathology, type 2 diabetes mellitus (T2DM), and cardiac hypertrophy. After 20 weeks, some of the animals spontaneously developed T2DM, depressive and anxiety-like behavior and cardiac hypertrophy. There were significant correlations between levels of anxiety-like behavior and glucose tolerance, and between heart/total body weight ratio and glucose tolerance. Our data suggest a relationship between the development of T2DM, emotional and cardiac pathology as seen in diurnal humans. Furthermore, our data show a possible relationship between reduced daily cycling cues in the laboratory and what has been regularly termed "Metabolic Syndrome" and recently proposed by us to be renamed to "Circadian Syndrome".

Although type 2 diabetes (T2DM) and depression are associated with disturbances in circadian rhythms, most studies of these diseases use nocturnal mice and rats while modeling diurnal humans. We suggest that the development of T2DM and depression are related to changes that accompany the switch from the mammalian ancestral nocturnal activity to the current diurnal one. We show that diurnal sand rats ( Psammomys obesus) held outdoors in laboratory cages (where they are exposed to natural environmental conditions) and fed a standard rodent diet do not develop T2DM in contrast to animals held indoors (where the only cycling environmental condition is light) fed the same diet. Moreover, keeping sand rats under a short photoperiod dampened behavioral and molecular daily rhythms, resulted in anxiety- and depressive-like behavior, and accelerated the development of T2DM. We suggest that the disturbed rhythms disrupt the internal temporal order and metabolic pathways controlled by feeding and the circadian system, resulting in the development of T2DM and depressive-like behavior. We further suggest that using nocturnal mice and rats as sole model animals may limit research, especially when studying circadian rhythm-related diseases.

The acute antidepressant effects of ketamine provide hope for the development of a fast acting approach to treat depression but the consequences of chronic treatment with ketamine are still unclear. One theory regarding the acute effect is that ketamine acts through activation of mTOR but chronic activation of mTOR may lead to reduced autophagy and reduced autophagy could have negative consequences on neuronal plasticity and survival and on affect. To study the interaction between chronic ketamine administration, autophagy and depression the present study tested the effects of 3 weeks daily administration of 5 or 10mg/kg ketamine in both female and male ICR mice on behavior in the open field and the forced swim test and on frontal cortex levels of beclin-1 and p62, two proteins that serve as markers of autophagy. The results show that acute administration of ketamine results in an antidepressant-like effect in the FST, chronic ketamine had no effects in the behavioral tests. There was no difference in the acute or chronic groups between female and male mice. Additionally, chronic ketamine did not alter frontal cortex levels of autophagy markers. The present study suggests that in ICR mice, chronic ketamine does not have the same clear effects that are seen after acute treatment. The lack of difference between females and males and the lack of effects on autophagy after chronic treatment is discussed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Preclinical Research Most neuropsychiatric research, including that related to the circadian system, is performed using nocturnal animals, mainly laboratory mice and rats. Mood disorders are known to be associated with circadian rhythm abnormalities, but the mechanisms by which circadian rhythm disruptions interact with depression remain unclear. As the circadian system of diurnal and nocturnal mammals differs, we previously suggested that the utilization of diurnal animal models may be advantageous for understanding these relations. During the last 10 years, we and others established the validity of several diurnal rodent species as a model for the interactions between circadian rhythms and depression. Diurnal rodents respond to photoperiod manipulation in a similar way to humans, the behavioral outcome is directly related to the circadian system, and treatment that is effective in patients is also effective in the model. Moreover, less effective treatments in patients are also less effective in the model. We, therefore, suggest that using diurnal animal models to study circadian rhythms-related affective disorders, such as depression, will provide new insights that will hopefully lead to the development of more effective treatments. Drug Dev Res 77 : 347-356, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The relationships between biological rhythms and affective disorders are known but their underlying biology not clear. There is difficulty in studying circadian rhythms in humans and appropriate animal models are hard to identify or develop. Some studies show that diurnal rodents can be advantageous model animals for the study of interactions between biological rhythms and affective disorders but previous studies did not include females whereas in humans there are sex differences in affective disorders. The present study tested the effects of short photoperiods in both males and females of the diurnal golden spiny mouse (Acomys russatus). Adult, female and male spiny mice were housed in either neutral photoperiod (12:12 light/dark; NP), or short photoperiod (5:19 light/dark; SP) conditions. After 3weeks acclimatization, animals were tested for spontaneous activity in an open field, elevated plus maze (EPM), sweet solution preference (SSP) and the forced swim test (FST). Both sexes responded to the SP, but while SP males showed increased anxiety-like behavior in the EPM and depression-like behavior in the FST, females showed increased activity, reduced anxiety-like behavior in the EPM, depression-like response in the SSP and no effect in the FST. Differences between sexes were previously demonstrated in behavioral tests that followed a variety of manipulations, and were usually explained in the context of sex hormones. Yet, the current results cannot be compared with previous data from diurnal rodents and further testing of females from other diurnal rodents are needed to explore whether these differences are a general phenomenon or possibly unique to golden spiny mice., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Physical exercise is a non-pharmacological treatment for affective disorders. The mechanisms of its effects are unknown although some suggest a relationship to synchronization of circadian rhythms. One way to explore mechanisms is to utilize animal models. We previously demonstrated that the diurnal fat sand rat is an advantageous model for studying the interactions between photoperiods and mood. The current study was designed to evaluate the effects of voluntary exercise on activity rhythms and anxiety and depression-like behaviors in sand rats as a step towards better understanding of the underlying mechanisms. Male sand rats were housed in short photoperiod (SP; 5h light/19 h dark) or neutral light (NP; 12h light/12h dark) regimens for 3 weeks and divided into subgroups with or without running wheels. Activity was monitored for 3 additional weeks and then animals were tested in the elevated plus-maze, the forced swim test and the social interaction test. Activity rhythms were enhanced by the running wheels. As hypothesized, voluntary exercise had significant effects on SP animals' anxiety- and depression-like behaviors but not on NP animals. Results are discussed in the context of interactions between physical exercise, circadian rhythms and mood. We suggest that the sand rat model can be used to explore the underlying mechanism of the effects of physical exercise for mood disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The lack of appropriate animal models for affective disorders is a major factor hindering better understanding of the underlying pathologies and the development of more efficacious treatments. Because circadian rhythms play an important role in affective disorders, we recently suggested that diurnal rodents can be advantageous as model animals. We found that in diurnal rodents, short photoperiod induces depression- and anxiety-like behaviors, with similarities to human seasonal affective disorder. In a pilot study we also found that these behaviors are ameliorated by morning bright light administration. In the present study we further evaluated the effects of morning and evening bright light administration on short photoperiod-induced depression- and anxiety-like behaviors in diurnal fat sand rats. Animals were maintained under short (5L:19D) or neutral (12L:12D) photoperiod and treated with morning or evening bright light or red dim light as control. Morning bright light ameliorated the behavioral deficits in the elevated plus maze and social interaction tests whereas evening bright light was effective only in the social interaction test. This is the first detailed presentation of the effects of bright light treatment in an animal model and a clear demonstration to the advantages of utilizing diurnal rodents to study interactions between circadian rhythms and affect.

Most organisms (including humans) developed daily rhythms in almost every aspect of their body. It is not surprising that rhythms are also related to affect in health and disease. In the present review we present data that demonstrate the evidence for significant interactions between circadian rhythms and affect from both human studies and animal models research. A number of lines of evidence obtained from human and from animal models research clearly demonstrate relationships between depression and circadian rhythms including (1) daily patterns of depression; (2) seasonal affective disorder; (3) connections between circadian clock genes and depression; (4) relationship between sleep disorders and depression; (5) the antidepressant effect of sleep deprivation; (6) the antidepressant effect of bright light exposure; and (7) the effects of antidepressant drugs on sleep and circadian rhythms. The integration of data suggests that the relationships between the circadian system and depression are well established but the underlying biology of the interactions is far from being understood. We suggest that an important factor hindering research into the underlying mechanisms is the lack of good animal models and we propose that additional efforts in that area should be made. One step in that direction could be the attempt to develop models utilizing diurnal animals which might have a better homology to humans with regard to their circadian rhythms. This article is part of a Special Issue entitled 'Anxiety and Depression'., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Deficiencies in appropriate animal models are a significant factor hindering the research of affective disorders. Significant data suggest that systems related to circadian rhythms are strongly linked to affective changes, but study with animal models in this context had unclear and inconsistent results. Circadian physiology is significantly different in diurnal and nocturnal animals and a recent project showed that in diurnal rodents, short photoperiods induce depression and anxiety-like phenotypes. This study was designed to evaluate the possibility that using a similar methodology would also result in behavioral changes in nocturnal mice. Mice from two strains were maintained in either short photoperiod, neutral photoperiod or long photoperiod for 3 weeks and tested for depression or anxiety-related behaviors, as done earlier with the diurnal rodents. Tests included activity levels, sweet solution preference, elevated plus-maze, resident-intruder aggression, and forced swim test. Tests were conducted either during the light phase or during the dark phase of the mice. In contrast to the clear phenotype in diurnal rodents, the effects of photoperiod manipulations in nocturnal mice were inconsistent. These results suggest that diurnal rodents may be advantageous compared with nocturnal species for studies exploring the relationship between circadian rhythms and affective disorders.

Circadian rhythms are strongly implicated in affective disorders and some recent studies suggested that diurnal rodents might be advantageous model animals for them. In line with this possibility, previous work demonstrated that in the diurnal fat sand rat, short photoperiod conditions result in depression- and anxiety-like behavioral phenotype that is relieved with bright light treatment. To further explore the possibility of using diurnal species as model animals for affective disorders, the present study examined the effects of short photoperiod schedule in an additional diurnal rodent, the unstriped Nile grass rat. Results indicate that 6 weeks short photoperiod (5 h light/19 h dark) regimen induced depression-like behavior in the forced swim test and the saccharin preference test compared with animals maintained in a neutral photoperiod regimen (12 h light/12 h dark). No effects were shown in the light/dark box model of anxiety or in a test for spontaneous activity. These results demonstrate that photoperiod manipulations in diurnal rodents induce affective-like behavioral change and support the possibility that diurnal rodents might provide a good potential as model animals for depression spectrum disorders., (Copyright 2009 Elsevier B.V. All rights reserved.)

A possible relationship between circadian rhythms and affective disorders has been strongly implicated, but understanding of the biological basis of such a relationship demands the utilization of appropriate animal models. Most research is performed with nocturnal rodents while some of the effects of daylight cycles or melatonin levels in nocturnal animals may differ greatly from effects in diurnal species (including humans). Recent studies suggested the diurnal fat Sand rat as an appropriate model animal to study circadian mechanisms involvement in mood and anxiety disorders, especially seasonal affective disorder (SAD). These studies demonstrated that Sand rats chronically exposed to short daylight (SD), or to melatonin regimen mimicing short daylight, show anxiety- and depression-like behaviors. These findings established face and construct validity for the model. The present study evaluated predictive validity by testing the effects of bright light treatment in Sand rats exposed to chronic SD. Sand rats maintained on SD for 3 weeks were treated with 1h daily 3000lx light for 3 weeks, 1h after "lights on" (during the light phase of the light/dark cycle), and their behavior tested in the sweet solution preference test (SSP), elevated plus-maze (EPM) and forced swim test (FST) and compared with control animals without treatment. Results indicate that bright light treatment reduced anxiety-like behavior in the EPM and depression-like behavior in the FST but not SSP. It is suggested that the results support the possibility that the diurnal Sand rat might be a preferred model animal for the study of SAD.

Circadian rhythms are considered an important factor in the aetiology, expression and treatment of major affective disorders, including seasonal affective disorder (SAD). However, data on the effects of daylight length manipulation or melatonin administration are complex. It has been suggested that since diurnal and nocturnal mammals differ significantly in their physiological and behavioural responses to daylight, diurnal rodents offer a preferable model of disorders related to circadian rhythms in the diurnal human. We previously found that diurnal fat sand rats maintained under short daylight (SD), show depression-like behaviour in the forced swim test (FST). The present study was designed to test additional behaviours related to affective disorders and study the involvement of melatonin in these behaviours. Sand rats were divided into short-daylight (SD, 5 h light:19 h dark) and long-daylight (LD, 12 h light:12 h dark) groups, and received 100 microg melatonin or vehicle administration for 3 wk (5 h and 8.5 h after light onset in the LD room). Animals were then tested for reward-seeking behaviour (saccharin consumption), anxiety (elevated plus-maze), aggression (resident-intruder test), and depression-like behaviour (FST). SD or melatonin administration resulted in a depressed/anxious-like behavioural phenotype including reduced reward seeking, increased anxiety, decreased aggression and decreased activity in the FST, supporting the notion that in a diurnal animal, reduced light results in a variety of behavioural changes that may model depression and anxiety; and that melatonin may be a significant factor in these changes. We suggest that the sand rat may offer an excellent model species to explore the interactions between daylight, affective behaviour and the related underlying mechanisms.

The present study examined the effect of simulated change in day length on the behavior of a diurnal rodent, the fat sand rat (a species of gerbil). Animals were housed under a short photoperiod (5/19 light/dark cycle) for 3 weeks and compared with controls living under a 12/12 light/dark cycle. All sand rats then underwent the forced swim test for depression-like behavior, and the open-field test for overall activity. Sand rats exposed to the short photoperiod displayed a significantly earlier sinking in the swim test, but there was no difference between their open-field activity compared with controls. Taking these responses as indicative of depression-like behavior, we suggest that a short photoperiod may induce affective-like changes, and that the sand rat may thus offer an appropriate animal model to explore the effect of photoperiod on normal, and perhaps also abnormal, seasonal mood changes (e.g., SAD), which in humans is a prevalent disorder, with winter depression episodes and spring/summer remissions.

Inositol, a precursor of the PIP cycle that was reported to have therapeutic effects in depressive patients and to be effective in two animal models of depression, was evaluated in the forced swim test using the genetic Flinders Sensitive Line (FSL) rats model of depression. Groups of rats were tested in a 2 x 2 design with Strain (FSL or Control) as one factor and Drug (Inositol or Placebo) as the second factor. Rats received chronic treatment (daily for 14 days) with inositol (1.2 g/kg) or placebo (1:2 glucose/mannitol solution). On day 14 rats were exposed to the forced swim test for 5 min and their behavior videotaped. Tapes were analyzed for three levels of activity: immobility, swimming, and vigorous struggle. Inositol countered the exaggerated immobility of FSL rats in the forced swim test, without affecting control animals. Data support our previous suggestion of inositol as a potential antidepressant., (Copyright 2002 Wiley-Liss, Inc.)

The effect of inositol as an antidepressant was previously demonstrated in both animal models of depression-like behavior and in clinical trials. Unlike most antidepressant drugs, inositol does not have a clear target in the synapse and was not demonstrated to alter monoamine levels in the brain. The present study attempted to draw a psychopharmacological profile of inositol's behavioral effects by exploring the interactions between the drug and specific receptor agonists and antagonists in the forced swim test. Rats received inositol treatment (or control) in combination with the serotonergic metabolism inhibitor PCPA or with the noradrenergic neurotoxin DSP-4. Results indicated that PCPA but not DSP-4 abolished the ability of inositol to cause a reduction in immobility time in the forced swim test. In mice, the specific 5-HT(2A)/5-HT(2C) antagonist ritanserin, but not the 5-HT(1A)/5-HT(1B)/beta adrenergic antagonist pindolol, abolished inositol's effect in the forced swim test. The 5-HT(2A)/5-HT(2C) agonist DOI and the 5-HT(1A) agonist 8-OH-DPAT did not have any significant effects on inositol's activity. The present data indicates that the antidepressant effect of inositol may involve 5-HT(2) receptors. It is thus possible that the effects of reuptake antidepressant drugs and the effects of inositol may have a common final pathway.

Rationale: Myo-inositol is an isomer of glucose that is a precursor in the phosphatidylinositol (PIP) cycle, a source of two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP3). Clinical studies have reported that inositol is effective in relieving symptoms of depression., Objective: The present study examined the effects of inositol on two animal models of depression: the Porsolt forced swim test, a behaviorally based model; and the reserpine-induced immobility model, a pharmacologically based model., Methods and Results: Chronic inositol injections (daily for 14 days) of 1.2 g/kg (but not at lower doses) reduced immobility time and increased struggle time in the Porsolt test compared with control animals. The same dose and treatment schedule also reduced complete immobility time but did not affect ambulatory activity in the reserpine test compared with controls. Chronic oral treatment with inositol (10% in food for 14 days) had effects similar to IP inositol in the Porsolt test., Conclusions: The effect of inositol in animal models of depression supports its possible importance as a new treatment for the disorder, and permits research on its mechanisms of action.

One problem area regarding animal models for affective disorders is unclear reproducibility, including external validity or generalizability. One way to evaluate external validity is with systematic reviews and meta-analyses. The current study presents a meta-analysis of the effects of prototypic antidepressants in the mouse forced swim test (FST). We identified studies that examined effects of antidepressants in the FST in mice and used standard protocol, male mice and acute drug administration. We calculated Effect sizes using Cohen’s d, homogeneity using Q statistic and correlations using Pearson’s correlation. Results indicate that all drugs reduce immobility in the FST. However, effect sizes for most drugs are heterogeneous and do not show a consistent dose/response relationship across variability factors. Reducing variability by examining only one strain or data from individual laboratories partially increases dose response relationship. These findings suggest that whereas the FST is a valid tool to qualitatively screen antidepressant effects its validity in the context of hierarchical comparison between doses or compounds might be relevant only to single experiments. [ABSTRACT FROM AUTHOR]

Abstract: Lithium, the prototypic mood stabilizer, was recently demonstrated to enhance autophagy in cells. Recent hypotheses regarding the source of therapeutic effects of lithium as well as other mood stabilizers and antidepressants suggest that they may stem from increased neuroprotection, cellular plasticity and resilience. Hence it is clearly a possibility that enhanced autophagy may be involved in the therapeutic action by contributing to increased cellular resilience. A well-documented mechanism to induce autophagy is by inhibition of mTOR, a negative modulator of autophagy and rapamycin (sirolimus) is a commonly used inhibitor of mTOR. Accordingly, the present study was designed to evaluate the effects of rapamycin in animal models of antidepressant activity. A dose-response experiment in the mice forced swim test was performed and followed by additional testing of mice and rats in an open field, the forced swim test and the tail suspension test. Results show that sub-chronic, but not acute, administration of rapamycin doses of 10mg/kg and above, have an antidepressant-like effect in both mice and rats and in both the forced swim and the tail suspension tests with no effects on the amount or distribution of activity in the open field. Whereas it is tempting to conclude that the antidepressant-like effects are related to mTOR inhibition, they may also be the consequences of interactions with other intracellular pathways. Additional studies are now planned to further explore the behavioral range of rapamycin''s effects as well as the biological mechanisms underlying these effects. [Copyright &y& Elsevier]