The circadian syndrome is a predictor for cognition impairment in middle-aged adults: Comparison with the metabolic syndrome.

AIMS: Circadian syndrome (CircS) is considered a better predictor for cardiovascular disease than the metabolic syndrome (MetS). We aim to examine the associations between CircS and MetS with cognition in Chinese adults. METHOD: We used the data of 8546 Chinese adults aged ≥40 years from the 2011 China Health and Retirement Longitudinal Study. MetS was defined using harmonised criteria. CircS included the components of MetS plus short sleep and depression. The cut-off for CircS was set as ≥4. Global cognitive function was assessed during the face-to-face interview. RESULTS: CircS and MetS had opposite associations with the global cognition score and self-reported poor memory. Compared with individuals without the CircS and MetS, the regression coefficients (95%CI) for global cognition score were -1.02 (-1.71 to -0.34) for CircS alone and 0.52 (0.09 to 0.96) for MetS alone in men; -1.36 (-2.00 to -0.72) for CircS alone and 0.60 (0.15 to 1.06) for MetS alone in women. Having CircS alone was 2.53 times more likely to report poor memory in men (95%CI 1.80-3.55) and 2.08 times more likely in women (95%CI 1.54-2.81). In contrast, having MetS alone was less likely to report poor memory (OR 0.64 (0.49-0.84) in men and 0.65 (0.52-0.81) in women). People with CircS and MetS combined were more likely to have self-reported poor memory. CONCLUSIONS: CircS is a strong and better predictor for cognition impairment than MetS in Chinese middle-aged adults. MetS without short sleep and depression is associated with better cognition.

Changes in menstrual cycle length and in sleep-wake behaviors during COVID-19 related lockdown in Israel.

COVID-19 related lockdowns changed our life. Studies report that young women are more susceptible to lockdown-induced adverse effects and stress. As stress and menstrual cycle are associated, we hypothesized that menstrual cycle length might change during lockdown. We examined menstrual cycle length, and sleep-wake behaviors during lockdown in Israel. Participants were 97 women in their fertile years who used Tempdrop fertility sensor™ to track cycles. Data were collected before, during and after lockdown in Israel. Our main finding is that lockdown was associated with changes in menstrual cycle length of most participants, with either increased of decreased length. Changes were reversed when lockdown was terminated. Sleep duration increased during lockdown but we found no relationship between sleep and menstrual cycle. We suggest these findings contribute to the understanding of the relationship between stress, sleep, and menstrual cycle. Further studies should explore the sources for differential effects in sub-groups of women.

Proteinoid Nanocapsules as Drug Delivery System for Improving Antipsychotic Activity of Risperidone.

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.

Exploring test batteries for depression- and anxiety-like behaviours in female and male ICR and black Swiss mice.

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.

Mice Lacking the Transcriptional Coactivator PGC-1α Exhibit Hyperactivity.

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.

Mood-stabilizing effects of rapamycin and its analog temsirolimus: relevance to autophagy.

Accumulated data support a relationship between mood disorders and cellular plasticity and resilience, some suggesting relevance to autophagy. Our previous data show that pharmacological enhancement of autophagy results in antidepressant-like effects in mice. The current study was designed to further examine the effects of autophagy enhancement on mood by testing the effects of subchronic treatment with the mammalian target of rapamycin (mTOR) inhibitors and autophagy enhancers rapamycin and temsirolimus in a model for mania and in a model for antidepressant action, respectively. The results show that rapamycin reduced mania-like aggression and reward-seeking behaviors, with no effects on locomotion. Temsirolimus reduced depression-related immobility in the forced-swim test without effects on locomotion in the open field or on anxiety-related measures in the elevated plus maze. Taken together with our previous findings, these data support the notion that enhancing autophagy may have mood-stabilizing effects.

Chronic Stress May Not Be a Factor in the Behavioral Response to Chronic Lithium in ICR Mice.

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.

Individual responses of rodents in modelling of affective disorders and in their treatment: prospective review.

IntroductionLack of good animal models for affective disorders, including major depression and bipolar disorder, is noted as a major bottleneck in attempts to study these disorders and develop better treatments. We suggest that an important approach that can help in the development and use of better models is attention to variability between model animals. RESULTS: Differences between mice strains were studied for some decades now, and sex differences get more attention than in the past. It is suggested that one factor that is mostly neglected, individual variability within groups, should get much more attention. The importance of individual differences in behavioral biology and ecology was repeatedly mentioned but its application to models of affective illness or to the study of drug response was not heavily studied. The standard approach is to overcome variability by standardization and by increasing the number of animals per group. CONCLUSIONS: Possibly, the individuality of specific animals and their unique responses to a variety of stimuli and drugs, can be helpful in deciphering the underlying biology of affective behaviors as well as offer better prediction of drug responses in patients.

Endogenous cardiac steroids in animal models of mania.

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 naïve 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'ß-dihydroxy-5'ß-estran-17'ß-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.

Utilization of Diurnal Rodents in the Research of Depression.

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.

Effects of repeated asenapine in a battery of tests for anxiety-like behaviours in mice.

OBJECTIVE: A number of atypical antipsychotic drugs were demonstrated to have anxiolytic effects in patients and in animal models. These effects were mostly suggested to be the consequence of the drugs' affinity to the serotonin system and its receptors. Asenapine is a relatively new atypical antipsychotic that is prescribed for schizophrenia and for bipolar mania. Asenapine has a broad pharmacological profile with significant effects on serotonergic receptors, hence it is reasonable to expect that asenapine may have some anxiolytic effects. The present study was therefore designed to examine possible effects of asenapine on anxiety-like behaviour of mice. METHOD: Male ICR mice were repeatedly treated with 0.1 or 0.3 mg/kg injections of asenapine and then tested in a battery of behavioural tests related to anxiety including the open-field test, elevated plus-maze (EPM), defensive marble burying and hyponeophagia tests. In an adjunct experiment, we tested the effects of acute diazepam in the same test battery. RESULTS: The results show that diazepam reduced anxiety-like behaviour in the EPM, the defensive marble burying test and the hyponeophagia test but not in the open field. Asenapine has anxiolytic-like effects in the EPM and the defensive marble burying tests but had no effects in the open-field or the hyponeophagia tests. Asenapine had no effects on locomotor activity. CONCLUSION: The results suggest that asenapine may have anxiolytic-like properties and recommends that clinical trials examining such effects should be performed.

Diurnal rodents as an advantageous model for affective disorders: novel data from diurnal degu (Octodon degus).

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 effects of the atypical antipsychotic asenapine in a strain-specific battery of tests for mania-like behaviors.

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.

Introducing Female Black Swiss Mice: Minimal Effects of Sex in a Strain-Specific Battery of Tests for Mania-Like Behavior and Response to Lithium.

Black Swiss (BS) mice were shown to be an advantageous strain to model behavioral domains of mania, but to date only male mice were tested, whereas bipolar disorder (BPD) is equally prevalent in women and men. This study was therefore designed to examine the possibility of using both male and female BS mice in future studies. Groups of male and female BS mice were compared with each other, with or without lithium treatment, in tests for domains of mania-like behavior including activity in an open field, sweet solution preference, elevated plus maze, forced swim and amphetamine-induced hyperactivity. The results indicate mostly a similarity between female and male BS mice, both naïve and after chronic lithium treatment. The results are discussed in the context of the deficiency in utilizing female mice in animal models research and suggest that both male and female BS mice can be used to model domains of mania-like behavior.

Chronic oral carbamazepine treatment elicits mood-stabilising effects in mice.

OBJECTIVE: The underlying biology of bipolar disorder and the mechanisms by which effective medications induce their therapeutic effects are not clear. Appropriate use of animal models are essential to further understand biological mechanisms of disease and treatment, and further understanding the therapeutic mechanism of mood stabilisers requires that clinically relevant administration will be effective in animal models. The clinical regimens for mood-stabilising drugs include chronic oral administration; however, much of the work with animal models includes acute administration via injection. An effective chronic and oral administration of the prototypic mood stabiliser lithium was already established and the present study was designed to do the same for the mood stabiliser carbamazepine. METHODS: Mice were treated for 3 weeks with carbamazepine in food. ICR mice were treated with 0.25%, 0.5% and 0.75%, and C57bl/6 mice with 0.5% and 0.75%, carbamazepine in food (w/w, namely, 2.5, 5.0 or 7.5 g/kg food). Mice were then tested for spontaneous activity, forced swim test (FST), tail suspension test (TST) and amphetamine-induced hyperactivity. RESULTS: Oral carbamazepine administration resulted in dose-dependent blood levels reaching 3.65 µg/ml at the highest dose. In ICR mice, carbamazepine at the 0.5% dose had no effect on spontaneous activity, but significantly reduced immobility in the TST by 27% and amphetamine-induced hyperactivity by 28%. In C57bl/6 mice, carbamazepine at the 0.75% dose reduced immobility time in the FST by 26%. CONCLUSIONS: These results demonstrate a behaviourally effective oral and chronic regimen for carbamazepine with mood stabilising-like activity in a standard model for mania-like behaviour and two standard models for depression-like behaviour.

Effects of photoperiod and food on glucose intolerance and subsequent ocular pathology in the fat sand rat.

Type 2 diabetes mellitus (T2DM) and its ocular complications, such as cataract and diabetic retinopathy (DR) have been linked to circadian rhythm-disturbances. Using a unique diurnal animal model, the sand rat (Psammomys obesus) we examined the effect of circadian disruption by short photoperiod acclimation on the development of T2DM and related ocular pathologies. We experimented with 48 male sand rats. Variables were day length (short photoperiod, SP, vs. neutral photoperiod NP) and diet (standard rodent diet vs. low-energy diet). Blood glucose, the presence of cataract and retinal pathology were monitored. Histological slides were examined for lens opacity, retinal cell count and thickness. Animals under SP and fed standard rodent diet (SPSR) for 20 weeks had higher baseline blood glucose levels and lower glucose tolerance compared with animals kept under NP regardless of diet, and under SP with low energy diet (SPLE). Animals under SPSR had less cells in the outer nuclear layer, a lower total number of cells in the retina, and a thickened retina. Higher blood glucose levels correlated with lower number of cells in all cellular layers of the retina and thicker retina. Animals under SPSR had higher occurrence of cataract, and a higher degree of cataract, which correlated with higher blood glucose levels. Sand rats kept under SPSR develop cataract and retinal abnormalities indicative of DR, whereas sand rats kept under NP regardless of diet, or under SPLE, do not. These ocular abnormalities significantly correlate with hyperglycemia.

Salivary cortisol concentration and perceived stress measure in response to acute natural stress: The role of morningness-eveningness preference.

Chronotype reflects the 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 (mean age 23.4 ± 1.7) and twenty six definite ET (mean age 23.8 ± 1.3) 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 cortisol response 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.

Real-time sensing of war's effects on wellbeing with smartphones and smartwatches.

BACKGROUND: Modern wars have a catastrophic effect on the wellbeing of civilians. However, the nature of this effect remains unclear, with most insights gleaned from subjective, retrospective studies. METHODS: We prospectively monitored 954 Israelis (>40 years) from two weeks before the May 2021 Israel-Gaza war until four weeks after the ceasefire using smartwatches and a dedicated mobile application with daily questionnaires on wellbeing. This war severely affected civilians on both sides, where over 4300 rockets and missiles were launched towards Israeli cities, and 1500 aerial, land, and sea strikes were launched towards 16,500 targets in the Gaza Strip. RESULTS: We identify considerable changes in all the examined wellbeing indicators during missile attacks and throughout the war, including spikes in heart rate levels, excessive screen-on time, and a reduction in sleep duration and quality. These changes, however, fade shortly after the war, with all affected measures returning to baseline in nearly all the participants. Greater changes are observed in individuals living closer to the battlefield, women, and younger individuals. CONCLUSIONS: The demonstrated ability to monitor objective and subjective wellbeing indicators during crises in real-time is pivotal for the early detection of and prompt assistance to populations in need.

This study investigated the impact of the May 2021 Israel-Gaza war on the wellbeing of Israeli civilians. To do so, 954 Israelis over the age of 40 were monitored for six weeks before and after the war using smartwatches and a mobile application that asked daily wellbeing questions. The researchers found that during the war, people experienced spikes in heart rate, decreased sleep quality and duration, and increased screen time. These changes were more significant in people living closer to the battlefield, women, and younger individuals. However, after the ceasefire, wellbeing indicators returned to baseline levels. The study shows that monitoring wellbeing in real-time during crises can help identify and assist populations in need.