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Chronotype determines morningness-eveningness preference over a 24-h period. Significant data indicates meaningful differences between evening types (ET) and morning types (MT) in behavior, personality traits, health and well-being. The aim of this study was to investigate cortisol response and subjective perceived stress of MT and ET individuals in response to an acute natural stressor. Twenty six definite MT and twenty six definite ET college students were recruited for this study. Participants were instructed to evaluate their perceived subjective stress and to provide saliva samples for cortisol levels at four different time points: Morning of regular school day, morning immediately before a final exam, afternoon of a regular school day and afternoon immediately before a final exam. For general mood assessment, the participants were also asked to fill out the Positive and Negative Affect Schedule (PANAS) questionnaire. The most outstanding finding of this study was the blunting of cortisol increase in response to acute stress in the morning in the ET group: Salivary cortisol was higher before a final exam only in MT but not in ET. However, no differences between the groups were found in the subjective stress measure. In the PANAS scale, ET showed lower positive affect, and a trend towards a higher negative affect. Overall, our results suggest dysregulation of the HPA axis in ET individuals, possibly due to their daily struggle to function in a morning-oriented society. These results further highlight the challenges faced by ET individuals and raise the question of possible interventions to assist them.

While the importance of the circadian system to health and well-being is extensively studied, the role of daylight exposure in these interactions is relatively poorly understood. Here we show, using a diurnal animal model naturally exposed to daylight, that daily morning exposure to 3000 lux, full spectrum electric light has beneficial health effects. Compared with controls, sand rats (Psammomys obesus) subjected to morning light treatment demonstrate daily rhythms with high peak to trough difference in activity, blood glucose levels and per2 gene expression in the suprachiasmatic nucleus, pre-frontal cortex, kidney and liver. The treated animals were also healthier, being normoglycemic, having higher glucose tolerance, lower body and heart weight and lower anxiety- and depression-like behavior. Our results suggest that exposure to high intensity light is important for the proper function of the circadian system and well-being, and are important in face of human's low exposure to daylight and extensive use of artificial light at night.

Animal models in neuropsychiatric research need validation. One way to address external validity is systematic reviews and meta-analyses. The present study presents a meta-analysis of the effects of antidepressants in the mouse tail suspension test (TST). A PubMed search identified studies that examined imipramine and fluoxetine effects in the TST. Inclusion criteria were testing in the light phase; trial duration was six minutes; immobility time scored 6 or (last) 4 min; adult mice; acute intraperitoneal (IP) administration. Effect sizes (ES) were estimated using Cohen's d, heterogeneity of ES with Cochran's Q test, correlations between dose and ES with Pearson's correlation and differences between strains with Analysis of variance. Results show that antidepressants decrease immobility time in the TST and a correlation between drug dose and ES but no effects of strain. We suggest that the TST is a valid tool to quantitatively, consistently and reproducibly capture the immobility-reducing aspects of fluoxetine and imipramine and that the lack of strain effects is due to small number of experiments in many of the strains.

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.

In attempts to slow down the spread of COVID-19 pandemic, countries took different measures including lockdowns. Several studies reported the effects of lockdowns on sleep mostly suggesting an increase in sleep duration during lockdowns. This is an interesting outcome as life in the modern world were associated with insufficient sleep. The present study is a systematic review and meta-analysis of work regarding sleep duration during lockdowns. We searched PubMed using the terms “COVID-19”, “SARS-CoV-2”, “lockdown”, “stay at home”, “quarantine” and “sleep” and found 262 papers. After applying exclusion criteria, we identified 26 papers (with 35 discrete studies) for the meta-analysis. A fixed effect model was used with effect sizes estimated using Cohen’s d and heterogeneity of effect sizes tested using the Cochran’s Q test statistics. Most studies (31/35) report an increase in sleep duration during lockdown periods with a mean (± STD) of 31.5 ± 21.2 minutes. Effect sizes (Cohen’s d) ranged between 0.08 and 3.34, which are considered between very small and huge. Q statistics was 4859.3 (p

Brain-derived neurotrophic factor (BDNF), its receptors and epigenetic modulators, are implicated in the pathophysiology of affective disorders, T2DM and the circadian system function. We used diurnal sand rats, which develop type 2 diabetes (T2DM), anxiety and depressive-like behavior under laboratory conditions. The development of these disorders is accelerated when animals are maintained under short photoperiod (5:19L:D, SP) compared to neutral photoperiod (12:12L:D, NP). We compared rhythms in plasma BDNF as well as BDNF and PER2 expression in the frontal cortex and suprachiasmatic nucleus (SCN) of sand rats acclimated to SP and NP. Acclimation to SP resulted in higher insulin levels, significantly higher glucose levels in the glucose tolerance test, and significantly higher anxiety- and depression-like behaviors compared with animals acclimated to NP. NP Animals exhibited a significant daily rhythm in plasma BDNF levels with higher levels during the night, and in BDNF expression levels in the frontal cortex and SCN. No significant BDNF rhythm was found in the plasma, frontal cortex or SCN of SP acclimated animals. We propose that in sand rats, BDNF may, at least in part, mediate the effects of circadian disruption on the development of anxiety and depressive-like behavior and T2DM.

The Metabolic Syndrome is a cluster of cardio‐metabolic risk factors and comorbidities conveying high risk of both cardiovascular disease and type 2 diabetes. It is responsible for huge socio‐economic costs with its resulting morbidity and mortality in most countries. The underlying aetiology of this clustering has been the subject of much debate. More recently, significant interest has focussed on the involvement of the circadian system, a major regulator of almost every aspect of human health and metabolism. The Circadian Syndrome has now been implicated in several chronic diseases including type 2 diabetes and cardiovascular disease. There is now increasing evidence connecting disturbances in circadian rhythm with not only the key components of the Metabolic Syndrome but also its main comorbidities including sleep disturbances, depression, steatohepatitis and cognitive dysfunction. Based on this, we now propose that circadian disruption may be an important underlying aetiological factor for the Metabolic Syndrome and we suggest that it be renamed the ‘Circadian Syndrome’. With the increased recognition of the ‘Circadian Syndrome’, circadian medicine, through the timing of exercise, light exposure, food consumption, dispensing of medications and sleep, is likely to play a much greater role in the maintenance of both individual and population health in the future.

Animal models are critical for the study of disease mechanisms and the screening of potential novel treatments. In the context of bipolar disorder, amphetamine-induced hyperactivity (AIH) is a frequently used screening model for antimanic effects. Yet, the utility of screening models depends on their predictive (or pharmacological) validity and it is expected that such models will respond to effective treatments. Lithium is the prototypic mood stabilizer but previous data regarding the effects of lithium in the AIH model are not clear and most data comes from studies using acute lithium administration that is not relevant to the therapeutic regimen in patients. To evaluate the pharmacological validity of AIH as a model for mania-like behavior we tested the interaction between chronic oral administration of lithium and amphetamine in ICR (CD-1®) mice and in black Swiss mice. We conducted 4 different experiments where chronic lithium was followed by an acute injection of amphetamine and one experiment where chronic amphetamine was combined with chronic lithium. The results show that amphetamine result in hyperactivity (experiments 1-4) and that lithium has no effects. Moreover, chronic amphetamine (experiment 5) result in sensitization that is not attenuated by lithium. The results clearly show that the predictive validity of the AIH model in ICR or black Swiss mice is problematic and possibly cast doubt on the utilization of the AIH as a screening model for novel mood stabilizers in other strains of mice.

Background The challenges to embody the complexity of symptoms and biological mechanism of affective disorders question the value of animal models as well as their reproducibility and validity. Validity is further hindered by large individual variability in many models. Whereas individual variability presents a challenge, it can also be used to study susceptibility and resistance. One of the frequently used models for screening antidepressants and interventions related to depression is the forced swim test (FST). The FST is typically performed only once. Methods The current study was designed with a number of objectives: (1) Examine the group effects of repeated FST (2) Examine the interaction between sex and repeated FST and (3) examine the consistency of individual variability across test and retest in the FST. We exposed ICR female and male mice to the FST 3 or 5 times with two days between exposures. Immobility time was analyzed across exposures at the group and the individual levels using repeated measures ANOVA as well as Pearson's correlations. Results As expected, repeated exposure to the FST resulted in increased immobility across exposures with no consistent effect of sex. At the level of individual mice, immobility time showed correlation across exposures. Discussion The current study demonstrates the effects of repeating the FST in both sexes with attention to individual variability. The results suggest that the FST can be used more than once and that mice show a consistent individual pattern of responding in the test.

The unprecedented restrictions imposed due to the COVID-19 pandemic, including movement control orders and lockdowns, altered our daily habits, and severely affected our well-being and physiology. The effect of these changes is yet to be fully understood. Here, we analyzed highly detailed data on 169 participants for 2-6 months, before and during the second COVID-19 lockdown in Israel. Our entire study was conducted during the COVID-19 pandemic, and therefore is the first to decipher the specific effects of the lockdown from the general effects of the pandemic. We extracted 12 well-being indicators from sensory data of smartwatches and from self-reported questionnaires, filled on a daily basis using a designated mobile application. We used a mixed ANOVA model to study the interplay between age, gender, and chorotype on well-being before and after lockdowns. We found that at the population level, lockdowns resulted in significant changes in mood, sleep duration, sport duration, social encounters, resting heart rate, and the number of steps. The lockdown's adverse effects were greater for young early chronotypes who did not increase their sleep duration, reduced activity level and suffered from significantly reduced mood, and for women, who further suffered an increase in stress levels and a greater decline in social encounters. Our findings underscore that while lockdowns severely impacted our well-being and physiology in general, greater damage has been identified in certain subpopulations. Based on the observed effects, special attention should be given to younger people, who are usually not in the focus of social support, and to women.

Background To compare the predictive value of the circadian syndrome (CircS) and Metabolic syndrome (MetS) for cardiovascular disease. Method We used the data of 9360 Chinese adults aged >= 40 years from the 2011 China Health and Retirement Longitudinal Study (CHARLS). Of the participants, 8253 people were followed in the 2015 survey. MetS was defined using the harmonized criteria. CircS was based on the components of the International Diabetes Federation (IDF) MetS plus short sleep and depression. The cut-off for CircS was set as >= 4. Multivariable logistic regression analysis was used to examine the associations. Results The prevalence of CircS and MetS was 39.0% and 44.7%. Both MetS and CircS were directly associated with prevalent CVD. The odds ratios for prevalent CVD comparing CircS with MetS, respectively, were 2.83 (95%CI 2.33-3.43) and 2.34 (1.93-2.83) in men, and 2.33 (1.98-2.73) and 1.79 (1.53-2.10) in women. Similar associations were found for incident CVD. The five-year incidence of CVD was 15.1% in CircS and 14.0% in MetS. The number of CircS components has a better predictive power for both prevalent and incident CVD than those of Mets components as indicated by the area under the ROC (AUC). AUC values for CVD in 2011 were higher for CircS than MetS in both men (0.659 (95%CI 0.634-0.684) vs 0.635 (95%CI 0.610-0.661)) and women (0.652 (95%CI 0.632-0.672) vs 0.619 (95%CI 0.599-0.640)). Conclusion The circadian syndrome is a strong and better predictor for CVD than the metabolic syndrome in Chinese adults.

Background There is a desperate need for in-vivo behavioral screening tests for anti-manic effects. The frequently used psychostimulant-induced hyperactivity test appears to have lower validity than previously described, but other quick, simple and high throughput tests are currently unavailable. New method In the context of modeling the behavioral facets of mania, we previously suggested that the sweet solution preference test (SSP) in naive mice might have predictive validity for screening anti-manic effects. The current study further examined this proposal by testing the effects of lithium, valproate and imipramine on SSP in three strains of mice (male mice from the black Swiss, ICR and C57bl/6 strains) and an exploratory test in females (black Swiss strain). Results Data demonstrate that lithium and valproate at appropriate dosing schedules significantly and reliably reduce SSP in all three strains (including in females) but that the antidepressant imipramine has no effects. Comparison with existing methods The results support the utilization of the SSP as mice screening model for anti-manic effects of drugs with stronger predictive validity compared with other methods. Conclusions The SSP is not a comprehensive model for bipolar disorder but it has good predictive validity and strong practical value that can be applied towards simple and fast screening of large numbers of animals, without the need for specialized equipment or complicated/prolonged procedures. We therefore propose that the SSP is an advantageous screening assay for testing novel mood stabilizing drugs for anti-manic properties.

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.

One problem areas of animal models and tests for neuropsychiatric disorders is unclear reproducibility, including both internal and external validity. One way to examine external validity is with systematic reviews and meta-analyses, a standard practice in clinical research that is relatively neglected in preclinical research. Considering the need to evaluate the validity and reproducibility of frequently used animal models, this study presents a meta-analysis of the effects of prototypic benzodiazepines and specific serotonin reuptake inhibitors (SSRIs) in the mouse defensive marble burying test (MBT). These drug groups were selected because although they differ in their biological targets as well as in their clinical use, they are both commonly used for the treatment of anxiety disorders. A PubMed literature search was performed to identify studies that examined the effects of benzodiazepines (diazepam, alprazolam, chlordiazepoxide, clonazepam) or SSRIs (fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine) in the MBT in mice. For benzodiazepines, 73 experiments were included. Benzodiazepines effect size was 2.04 and Q statistics was 1959 with a significant correlation between dose and effect size (r = 0.31, p = 0.007). For SSRIs we identified 47 experiments. Effect size of SSRIs was 2.24 and Q statistics was 493.38. No correlation was found between dose and effect size (r = 0.23, p = 0.12). The current results support the external validity of the defensive marble burying test as a screening test for anxiolytic effects. However, these results indicate that significant attention should be given to the administration schedules of benzodiazepines and SSRIs.

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.

Background: Lithium (Li) is the prototypic mood-stabilizing drug, but the individual response to Li is highly heterogeneous. Some evidence suggest interactions between Li and stress, and it is possible to hypothesize that lithium’s effects are modified by stress conditions. The current study examines the interaction between 2 chronic stressors, constant light (CL) and restrain and the behavioral responses to chronic Li in female and male mice. Methods: Female and male ICR mice were exposed to 3 weeks of either (1) CL; (2) daily restrain or (3) no stress control. One week after the start of the stress intervention, mice started chronic oral Li treatment or control. After 2 weeks of stress and Li, mice were tested in a number of behavioral tests including spontaneous activity, sweet solution preference, plus-maze and forced swim test. Results: There were no effects of stressors on behavior. Effects of Li were demonstrated in males but not females with no interactions between stress and Li. Conclusions: The behavioral effects of Li in this study were not affected by stress. The lack of effects of the stressors themselves on behavior suggests that the application of more intrusive stressors might be needed to further explore the issue.

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.

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”.

Despite the common use of bright light exposure for treatment of seasonal affective disorder (SAD), the underlying biology of the therapeutic effect is not clear. Moreover, there is a debate regarding the most efficacious wavelength of light for treatment. Whereas according to the traditional approach full-spectrum light is used, recent studies suggest that the critical wavelengths are within the range of blue light (460 and 484 nm). Our previous work shows that when diurnal rodents are maintained under short photoperiod they develop depression- and anxiety-like behavioral phenotype that is ameliorated by treatment with wide-spectrum bright light exposure (2500 lux at the cage, 5000 K). Our current study compares the effect of bright wide-spectrum (3,000 lux, wavelength 420- 780 nm, 5487 K), blue (1,300 lux, wavelength 420-530 nm) and red light (1,300 lux, wavelength range 600-780 nm) exposure in the fat sand rat (Psammomys Obesus) model of SAD. We report results of experiments with six groups of sand rats that were kept under various photoperiods and light treatments, and subjected to behavioral tests related to emotions: forced swim test, elevated plus maze and social interactions. Exposure to either intense wide-spectrum white light or to blue light equally ameliorated depression-like behavior whereas red light had no effect. Bright wide-spectrum white light treatment had no effect on animals maintained under neutral photoperiod, meaning that light exposure was only effective in the pathological-like state. The resemblance between the effects of bright white light and blue light suggests that intrinsically photosensitive retinal ganglion cells (ipRGCs) are involved in the underlying biology of SAD and light therapy.

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.

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.

Objectives Bipolar disorder (BD) is a complex psychiatric disorder characterized by mania and depression. Alterations in brain Na(+) , K(+) -ATPase and cardiac steroids (CSs) have been detected in BD, raising the hypothesis of their involvement in this pathology. The present study investigated the behavioral and biochemical consequences of a reduction in endogenous brain CS activity in animal models of mania. Methods Amphetamine (AMPH)-induced hyperactivity in BALB/c and black Swiss mice served as a model of mania. Behavior was evaluated in the open-field test in naive mice or in mice treated with anti-ouabain antibodies. CS levels were determined by enzyme-linked immunosorbent assay (ELISA), using sensitive and specific anti-ouabain antibodies. Extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) phosphorylation levels in the frontal cortex were determined by western blot analysis. Results Administration of AMPH to BALB/c and black Swiss mice resulted in a marked increase in locomotor activity, accompanied by a threefold increase in brain CSs. The lowering of brain CSs by the administration of anti-ouabain antibodies prevented the hyperactivity and the increase in brain CS levels. AMPH caused an increase in phosphorylated ERK (p-ERK) and phosphorylated Akt (p-Akt) levels in the frontal cortex, which was significantly reduced by administration of the antibodies. A synthetic 'functional antagonist' of CSs, 4-(3'α-15'β-dihydroxy-5'β-estran-17'β-yl) furan-2-methyl alcohol, also resulted in attenuation of AMPH-induced hyperactivity. Conclusions These results are in accordance with the notion that malfunctioning of the Na(+) , K(+) -ATPase/CS system may be involved in the manifestation of mania and identify this system as a potential new target for drug development.

Risperidone (RSP) is an atypical antipsychotic drug widely used to treat schizophrenia and bipolar disorder. Nanoparticles (NPs) are being developed as in vivo targeted drug delivery systems, which cross the blood-brain barrier and improve pharmacokinetics and drug effectiveness. Here, biodegradable proteinoids were synthesized by thermal step-growth polymerization from the amino acids l-glutamic acid, l-phenylalanine and l-histidine and poly (l-lactic acid). Proteinoid NPs containing RSP were then formed by self-assembly, overcoming the insolubility of the drug in water, followed by PEGylation (poly ethylene glycol (PEG) conjugation to increase the stability of the NPs in the aqueous continuous phase. These NPs are biodegradable owing to their peptide and ester moieties. They were characterized in terms of diameter, size distribution, drug loading, and long-term storage. Behavioral studies on mice found enhanced antipsychotic activity compared to free RSP.

Significant evidence from various sources suggests that structural alterations in mitochondrial function may play a role in both the pathogenesis of mood disorders and the therapeutic effects of available treatments. PGC-1α is a distinct transcriptional regulator designed to mediate the synchronous release of neurotransmitter in the brain and thereby to coordinate a number of gene expression pathways to promote mitochondrial biogenesis and oxidative phosphorylation. The role of PGC-1α in the context of affective disorder phenotypes and treatments has been suggested but not studied in depth. To further investigate the possible involvement of PGC-1α in affective disorders, we generated conditional PGC-1α null mice through transgenic expression of cre recombinase under the control of a Dlx5/6 promoter; cre-mediated excision events were limited to γ-amino-butyric-acid (GABA)-ergic specific neurons. We tested these mice in a battery of behavioral tests related to affective change including spontaneous activity, elevated plus maze, forced swim test, and tail suspension test. Results demonstrated that mice lacking PGC-1α in GABAergic neurons exhibited increased activity across tests that might be related to a mania-like phenotype. These results suggest possible relevance of PGC-1α to affective change, which corresponds with data connecting mitochondrial function and affective disorders and their treatment.

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.

Background AMPA receptors are highly expressed throughout the central nervous system and are suggested to be involved in mood regulation. Studies found changes in glutamate, its metabolites and receptors in patients with bipolar disorder (BPD) or major depression (MD) and in animal models of stress. Additional data suggest that the glutamatergic system and AMPA receptors specifically, have an important role in modulating the therapeutic effects of mood stabilizers. Further research on the role of AMPA receptors in mood regulation can be done using AMPAkines, positive modulators of AMPA receptors. AMPAkines have been studied for cognitive enhancement in neurodegenerative disorders and some were also examined in preclinical studies of mood disorders. In that context, the present study was designed to test the effects of the AMPAkine CX717 in a strain specific battery of tests for mania-like behaviors. Methods Black Swiss male mice were sub-chronically treated with 5 different doses of CX717 or vehicle and tested in a battery of behavioral tests including spontaneous activity, sweet solution preference, resident-intruder, forced swim and amphetamine-induced hyperactivity. Results Data show that CX717 doses of 30 mg/kg and above, but not lower, reduce activity levels. Moreover, 45 mg/kg and above reduce interactions in the resident-intruder test and ameliorate amphetamine-induced hyperactivity. Conclusions The results therefore show a partial effect of CX717 on manic-like behavior, somewhat similar to previously demonstrated effects of atypical antipsychotic drugs in this strain. It is therefore suggested that further work related to AMPAkines in the treatment of affective disorders might be warranted.

Asenapine is indicated for the treatment of schizophrenia and manic episodes in bipolar disorder (BPD). There is a paucity of information on the effects of asenapine in animal models of BPD, but such work is essential to discover its scope of effects and its mechanisms of therapeutic action. This study evaluated the effects of asenapine in a validated test battery for manic-like behaviors in Black Swiss mice. Male Black Swiss mice received asenapine at 0.03, 0.1, and 0.3 mg/kg twice daily for 7 days and were tested for spontaneous activity, sweet solution preference, forced-swim test, social interaction, and amphetamine-induced hyperactivity. Asenapine treatment resulted in dose-dependent, clinically relevant plasma levels. Asenapine, at the 0.1 and 0.3 mg/kg doses, reduced activity, with the 0.3 mg/kg dose also resulting in increased time in the center of an open field, increased immobility in the forced-swim test, and reduced amphetamine-induced hyperactivity. Asenapine exerted no effects in the social interaction or sweet solution preference tests. The results suggest that asenapine exerts antimanic-like effects in some of the behavioral tests performed in Black Swiss mice. These data support the utilization of asenapine in the treatment of BPD.

Background One concern regarding animal models of psychopathology is unclear external validity. One way to establish external validity is to examine measures representing separate facets of the pathology with a battery of tests in the same cohort of animals. Additionally, utilizing the same animals in a battery of tests can help to reduce the number of animals in research. However, issues had been raised regarding the analysis of data coming from batteries and the standard practice is to analyze each test separately. This approach introduces two problems: (1) the analysis answers the question regarding separate tests but not regarding the general effect; (2) there is no correction for multiple comparisons. One way to overcome these challenges is to use transformations to Z-scores. We suggest an additional approach, analyzing test batteries with multivariate analysis of variance (MANOVA). Methods To compare the outcomes of Z-score analysis and MANOVA we re-analyzed two published studies where data were initially analyzed separately for each test. Additionally, we computed effect sizes. Results The first study tested interaction between sex and lithium in a battery of manic-like behaviors, the second study tested asenapine in a battery of anxiety-like behaviors. For the first study, the MANOVA analysis indicated no effects of sex and a significant antimanic-like effect of lithium and for the second study, the MANOVA indicated a significant anxiolytic effect of asenapine. Z-score analysis resulted in a significant general antimanic-like effect in the lithium study but failed to demonstrate the anxiolytic effects of asenapine in the second study. Conclusions It is possible to suggest that MANOVA is an appropriate way to analyze data from test batteries and that its use, when appropriate, can increase the validity, predictability and reproducibility of results.

There is a well-known deficiency in valid animal models for bipolar disorder. Developing the single ideal model for the disorder-one that will represent its full scope-will probably not be possible until we have a much better understanding of the underlying pathology. Yet, intermediate models, even with partial validity, are critical in order to advance our knowledge and put us into position to develop even better models. The present article discusses the various efforts under way to develop the best models based on our current level of understanding. These efforts include (1) identifying new tests, (2) developing models based on the endophenotypes approach, (3) identifying the best rodent strains, (4) identifying the most appropriate species, (5) segregating susceptible versus resilient animals, and (6) segregating animals that respond or do not respond to treatment. It is suggested that a combined approach that includes these directions and others can result in better models with higher validity that will offer significant help in advancing research on bipolar disorder and developing new and better treatments.

Background The inhibition of protein kinase C (PKC) was recently suggested as a novel approach for the development of mood stabilizing drugs. Methods To further evaluate this possibility, the aim of the present study was to test the effects of peripheral (intraperitoneal) administration of chelerythrine in a battery of mania-related behavioral tests in black Swiss mice, a strain specific battery that was previously demonstrated to distinguish differential effects of mood stabilizing drugs. Results Sub-chronic administration of 1.0 mg/kg or 2.0 mg/kg chelerythrine had marginal effects to reduce spontaneous activity and sweet solution preference in black Swiss mice which naturally show mania-like behaviors. Chelerythrine had no effects on the behavior of these mice in the elevated plus-maze, the forced swim test and the amphetamine-induced hyperactivity test. Conclusions The partial effects in the battery are not unique as previous studies showed that lithium, valproate and risperidone, all used in the treatment of bipolar disorder, have distinct profiles in the battery. It is therefore concluded that chelerythrine may have antimanic effects and additional dose and time response studies are warranted to further evaluate its range of activity.

Circadian rhythms are strongly associated with affective disorders and recent studies have suggested utilization of diurnal rodents as model animal for circadian rhythms-related domains of these disorders. Previous work with the diurnal fat sand rat and Nile grass rat demonstrated that short photoperiod conditions result in behavioral changes including anxiety- and depression-like behavior. The present study examined the effect of manipulating day length on activity rhythms and behavior of the diurnal degu. Animals were housed for 3 weeks under either a short photoperiod (5-h:19-h LD) or a neutral photoperiod (12-h:12-h LD) and then evaluated by sweet solution test and the forced swim test for depression-like behavior, and in the light/dark box and open field for anxiety-like behavior. Results indicate that short photoperiod induced depression-like behavior in the forced swim test and the sweet solution preference test and anxiety-like behavior in the open field compared with animals maintained in a neutral photoperiod. No effects were shown in the light/dark box. Short photoperiod-acclimated degu showed reduced total activity duration and activity was not restricted to the light phase. The present study further supports the utilization of diurnal rodents to model circadian rhythms-related affective change. Beyond the possible diversity in the mechanisms underlying diurnality in different animals, there are now evidences that in three different diurnal species, the fat sand rat, the grass Nile rat and the degu, shortening of photoperiod results in the appearance of anxiety- and depression-like behaviors.

The disaccharide trehalose protects cells from hypoxic and anoxic injury and suppresses protein aggregation. In vivo studies with trehalose show cellular and behavioral beneficial effects in animal models of neurodegenerative diseases. Moreover, trehalose was shown to enhance autophagy, a process that had been recently suggested to be involved in the therapeutic action of antidepressant and mood-stabilizing drugs.The present study was therefore designed to explore antidepressant and mood-stabilizing activity of trehalose in animal models for depression and mania.Trehalose 1 or 2% was administered for 3 weeks as a drinking solution to Black Swiss mice (a model of manic-like behaviors) or 2% to ICR mice and their behavior evaluated in a number of tests related to depression or mania. The effects of trehalose were compared with similar chronic administration of the disaccharide maltose as well as with a vehicle (water) control.Chronic administration of trehalose resulted in a reduction of frontal cortex p62/beclin-1 ratio suggesting enhancement of autophagy. Trehalose had no mood-stabilizing effects on manic-like behavior in Black Swiss mice but instead augmented amphetamine-induced hyperactivity, an effect similar to antidepressant drugs. In ICR mice, trehalose did not alter spontaneous activity or amphetamine-induced hyperactivity but in two separate experiments had a significant effect to reduce immobility in the forced swim test, a standard screening test for antidepressant-like effects.The results suggest that trehalose may have antidepressant-like properties. It is hypothesized that these behavioral changes could be related to trehalose effects to enhance autophagy.

The scarcity of good animal models for bipolar disorder (BPD) and especially for mania is repeatedly mentioned as one of the rate-limiting factors in the process of gaining a better understanding into its pathophysiology and of developing better treatments. Standard models of BPD have some value but usually represent only one facet of the disease and have partial validity. A number of new approaches for modeling BPD and specifically mania have been suggested in the last few years and can be combined to improve models. These approaches include targeted mutation models representing reverse translation, the identification of advantageous strains for components of the disorder, a search for the most homologous species to address specific human pathology, and the exploration of individual differences of response including the separation between susceptible and resilient animals. Additionally, recent efforts have identified and developed new tests to distinguish between "normal" and "BPD-like" animals including the different utilization of known tests and novel tests such as the female-urine-sniffing test and behavior pattern monitor analysis. Additional tests relating to further domains of BPD are still needed. An ideal model for BPD that will encompass the entire disease and be useful for every demand will probably not become available until we have a full understanding of the pathophysiology of the disorder. However, the current advances in modeling should lead to better comprehension of the disorder and therefore to the gradual development of increasingly improved models.