The mechanism of acute fasting‐induced antidepressant‐like effects in mice

Acute fasting induced antidepressant‐like effects. However, the exact brain region and mechanism of these actions are still largely unknown. Therefore, in this study the antidepressant‐like effects of acute fasting on c‐Fos expression and BDNF levels were investigated. Consistent with our previous findings, immobility time was remarkably shortened by 9 hrs fasting in the forced swimming test. Furthermore, these antidepressant‐like effects of 9 fasting were inhibited by a 5‐HT_2A/2C receptor agonist (±)‐1‐(2, 5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride (DOI), and the effect of DOI was blocked by pretreatment with a selective 5‐HT_2A receptor antagonist ketanserin. Immunohistochemical study has shown that c‐Fos level was significantly increased by 9 hrs fasting in prefrontal cortex but not hippocampus and habenular. Fasting‐induced c‐Fos expression was further enhanced by DOI in prefrontal cortex, and these enhancements were inhibited by ketanserin. The increased BDNF levels by fasting were markedly inhibited by DOI in frontal cortex and hippocampus, and these effects of DOI on BDNF levels were also blocked by ketanserin. These findings suggest that the antidepressant‐like effects of acute fasting may be exerted via 5‐HT_2A receptor and particularly sensitive to neural activity in the prefrontal cortex. Furthermore, these antidepressant‐like effects are also mediated by CREB and BDNF pathway in hippocampus and frontal cortex. Therefore, fasting may be potentially helpful against depression.     

Rapid anti‐depressant‐like effects of ketamine and other candidates: Molecular and cellular mechanisms

Major depressive disorder takes at least 3 weeks for clinical anti‐depressants, such as serotonin selective reuptake inhibitors, to take effect, and only one‐third of patients remit. Ketamine, a kind of anaesthetic, can alleviate symptoms of major depressive disorder patients in a short time and is reported to be effective to treatment‐resistant depression patients. The rapid and strong anti‐depressant‐like effects of ketamine cause wide concern. In addition to ketamine, caloric restriction and sleep deprivation also elicit similar rapid anti‐depressant‐like effects. However, mechanisms about the rapid anti‐depressant‐like effects remain unclear. Elucidating the mechanisms of rapid anti‐depressant effects is the key to finding new therapeutic targets and developing therapeutic patterns. Therefore, in this review we summarize potential molecular and cellular mechanisms of rapid anti‐depressant‐like effects based on the pre‐clinical and clinical evidence, trying to provide new insight into future therapy.     

Proteomics‐based screening of the target proteins associated with antidepressant‐like effect and mechanism of Saikosaponin A

Depression is a commonly occurring neuropsychiatric disease with an increasing incidence rate. Saikosaponin A (SA), a major bioactive component extracted from Radix Bupleuri, possesses anti‐malignant cell proliferation, anti‐inflammation, anti‐oxidation and liver protective effects. However, few studies have investigated SA’s antidepressant effects and pharmacological mechanisms of action. Our study aimed to explore the anti‐depression effect of SA and screen the target proteins regulated by SA in a rat model of chronic unpredictable mild stress (CUMS)‐induced depression. Results showed that 8‐week CUMS combined with separation could successfully produce depressive‐like behaviours and cause a decrease of dopamine (DA) in rat hippocampus, and 4‐week administration of SA could relieve CUMS rats’ depressive symptoms and up‐regulated DA content. There were 15 kinds of significant differentially expressed proteins that were detected not only between the control and CUMS groups, but also between the CUMS and SA treatment groups. Proline‐rich transmembrane protein 2 (PRRT2) was down‐regulated by CUMS while up‐regulated by SA. These findings reveal that SA may exert antidepressant effects by up‐regulating the expression level of PRRT2 and increasing DA content in hippocampus. The identification of these 15 differentially expressed proteins, including PRRT2, provides further insight into the treatment mechanism of SA for depression.     

Sexual Dimorphism in the Response of Adipose Mass and Cellularity to Graded Caloric Restriction

Objective: To investigate the effects of mild to moderate caloric restriction on parameters of body growth, fat mass, and adipose tissue cellularity in female and male Wistar rats. Research Methods and Procedures: Three‐month‐old female and male Wistar rats were subjected to a chronic, mild to moderate caloric restriction paradigm (5%, 10%, or 20% reduction in caloric intake from ad libitum values) for 6 months. This was accomplished using a unique automated feeder system tailored to the food consumption levels of individual rats. Body weight and length, weight of lean organs, regional adipose mass, and adipose cellularity were measured before and after the diet restriction. Results: Caloric restriction produced proportional decelerations in body weight increases in both genders, without significant changes in body length or lean organ mass. Marked and disproportional reductions in regional adipose tissue mass were produced at all levels of food restriction (even at 5% restriction). An unexpected finding was that in response to graded caloric restriction, female rats preserved adipose fat cell number at the expense of fat cell volume, whereas the converse was seen for male rats. Discussion: These studies demonstrate a sexual dimorphism in the response to mild to moderate degrees of chronic caloric restriction. At low levels of caloric restriction, it is possible to affect regional adipose mass and cellularity while preserving lean organ mass.     

A single dose of S‐ketamine induces long‐term antidepressant effects and decreases oxidative stress in adulthood rats following maternal deprivation

Ketamine, an antagonist of N‐methyl‐d ‐aspartate receptors, has produced rapid antidepressant effects in patients with depression, as well as in animal models. However, the extent and duration of the antidepressant effect over longer periods of time has not been considered. This study evaluated the effects of single dose of ketamine on behavior and oxidative stress, which is related to depression, in the brains of adult rats subjected to maternal deprivation. Deprived and nondeprived Wistar rats were divided into four groups nondeprived + saline; nondeprived + S‐ketamine (15 mg/kg); deprived + saline; deprived + S‐ketamine (15 mg/kg). A single dose of ketamine or saline was administrated during the adult phase, and 14 days later depressive‐like behavior was assessed. In addition, lipid damage, protein damage, and antioxidant enzyme activities were evaluated in the rat brain. Maternal deprivation induces a depressive‐like behavior, as verified by an increase in immobility and anhedonic behavior. However, a single dose of ketamine was able to reverse these alterations, showing long‐term antidepressant effects. The brains of maternally deprived rats had an increase in protein oxidative damage and lipid peroxidation, but administration of a single dose of ketamine reversed this damage. The activities of antioxidant enzymes superoxide dismutase and catalase were reduced in the deprived rat brains. However, ketamine was also able to reverse these changes. In conclusion, these findings indicate that a single dose of ketamine is able to induce long‐term antidepressant effects and protect against neural damage caused by oxidative stress in adulthood rats following maternal deprivation. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1268–1281, 2015     

A model of emotional stress‐induced binge eating in female mice with no history of food restriction

Overeating is a major contributing factor to obesity and related health complications. For women, in particular, negative emotions such as stress strongly influence eating behavior and bingeing episodes. Modeling this type of binge eating in rodents presents challenges: firstly, stress‐induced anorexia is commonly observed in rodents therefore a mild stressor is required in order to observe an orexigenic effect. Second, many studies report using calorie restriction to observe the required behavior; yet this does not necessarily reflect the human condition. Thus, the aim of this study was to develop a model of emotional stress‐induced bingeing independent of caloric restriction. Female and male C57BL/6J mice were divided into ad libitum (n = 20 per sex) and food‐restricted (n = 20 per sex) groups which were both further split into a control group and a group exposed to frustration stress (n = 10 per group). All mice were provided intermittent access to a highly palatable food in 2 cycles. At the end of each cycle the stress group was subjected to a 15‐minute frustration episode where highly palatable food was within the home cage but inaccessible. Both groups were then given free access for 15 minutes. Frustrated female mice from the ad libitum displayed binge‐like behavior compared with controls (P = .0001). Notably, this behavior was absent in males. Ovariectomy had no impact on binge‐like behavior. Collectively, these data validate a novel model of emotional stress‐induced binge eating specific to female mice which does not require caloric restriction and is not driven by ovarian hormones.     

Sirtuin inhibitor Ex‐527 causes neural tube defects,ventral edema formations,and gastrointestinal malformations in Xenopus laevis embryos

Chemical reagent Ex‐527 is widely used as a major inhibitor of Sirtuin enzymes, which are a family of highly conserved protein deacetylases and have been linked with caloric restriction and aging by modulating energy metabolism, genomic stability, and stress resistance. However, the extent to which Ex‐527 controls early developmental events of vertebrate embryos remains to be understood. Here, we report an examination of Ex‐527 effects during Xenopus early development, followed by a confirmation of expressions of xSirt1 and xSirt2 in embryonic stages and enhancement of acetylation by Ex‐527. First, we found that reductions in size of neural plate at neurula stages were induced by Ex‐527 treatment. Second, tadpoles with short body length and large edematous swellings in the ventral side were frequently observed. Moreover, Ex‐527‐treated embryos showed severe gastrointestinal malformations in late tadpole stages. Taken together with these results, we conclude that the Sirtuin family start functioning at early embryonic stages and is required for various developmental events.     

Beneficial Effects of Caloric Restriction on Chronic Kidney Disease in Rodent Models: A Meta-Analysis and Systematic Review

Background

Numerous studies have demonstrated the life-extending effect of caloric restriction. It is generally accepted that caloric restriction has health benefits, such as prolonging lifespan and delaying the onset and progression of CKD in various species, especially in rodent models. Although many studies have tested the efficacy of caloric restriction, no complete quantitative analysis of the potential beneficial effects of reducing caloric intake on the development and progression of CKD has been published.

Methods

All studies regarding the relationship between caloric restriction and chronic kidney diseases were searched in electronic databases, including PubMed/MEDLINE, EMBASE, Science Citation Index (SCI), OVID evidence-based medicine, Chinese Bio-medical Literature and Chinese science and technology periodicals (CNKI, VIP, and Wan Fang). The pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by using fixed- or random-effects models.

Results

The data from 27 of all the studies mentioned above was used in the Meta analysis. Through the meta-analysis, we found that the parameter of blood urea nitrogen, serum creatinine and urinary protein levels of the AL group was significant higher than that of the CR group, which are 4.11 mg/dl, 0.08mg/dl and 33.20mg/kg/24h, respectively. The incidence of the nephropathy in the caloric restriction (CR) group was significantly lower than that in the ad libitum—fed (AL) group. We further introduced the subgroup analysis and found that the effect of caloric restriction on the occurrence of kidney disease was only significant with prolonged intervention; the beneficial effects of CR on the 60%-caloric-restriction group were greater than on the less-than-60%-caloric-restriction group, and caloric restriction did not show obvious protective effects in genetically modified strains. Moreover, survival rate of the caloric restriction group is much higher than that of the ad libitum—fed (AL) group.

Conclusions

Our findings demonstrate for the first time that compared with the AL group, the caloric restriction indeed decreased urea nitrogen, creatinine, urine protein, incidence of kidney diseases and increased the survival rate on 700~800 days.     

Induction of depressive‐like effects by subchronic exposure to cocaine or heroin in laboratory rats

The effect of psychoactive drugs on depression has usually been studied in cases of prolonged drug addiction and/or withdrawal, without much emphasis on the effects of subchronic or recreational drug use. To address this issue, we exposed laboratory rats to subchronic regimens of heroin or cocaine and tested long‐term effects on (i) depressive‐like behaviors, (ii) brain‐derived neurotrophic factor (BDNF) levels in reward‐related brain regions, and (iii) depressive‐like behavior following an additional chronic mild stress procedure. The long‐term effect of subchronic cocaine exposure was a general reduction in locomotor activity whereas heroin exposure induced a more specific increase in immobility during the forced swim test. Both cocaine and heroin exposure induced alterations in BDNF levels that are similar to those observed in several animal models of depression. Finally, both cocaine and heroin exposure significantly enhanced the anhedonic effect of chronic mild stress. These results suggest that subchronic drug exposure induces depressive‐like behavior which is accompanied by modifications in BDNF expression and increases the vulnerability to develop depressive‐like behavior following chronic stress. Implications for recreational and small‐scale drug users are discussed.

     

Antidepressant‐like effects and basal immobility depend on age and serotonin transporter genotype

Monoamine uptake inhibitors are common treatments for depression; however, the therapeutic efficacy of these drugs varies widely. Two factors that are commonly linked to clinical outcome are age and serotonin transporter (SERT) genotype. Mouse models provide powerful tools to study consequences of age and genotype on antidepressant‐like efficacy; however, to date, systematic studies of this nature are lacking. Here, we used the tail suspension test (TST), a preclinical assay for antidepressant efficacy, to gain insight into age and SERT genotype dependency of immobility time in the TST under control conditions (saline injection) and in response to the tricyclic antidepressant, desipramine (DMI). Immobility after saline injection in juvenile, adolescent, adult, mature adult and middle‐aged mice (postnatal days 21, 28, 90, 210 and 300, respectively) significantly increased with age; however, the rate of increase was slower for SERT null (?/?) mice than for wild‐type (+/+) or heterozygote (+/?) mice. Desipramine reduced immobility across ages and SERT genotypes. Middle‐aged, but not adult, SERT^?/? mice were significantly more sensitive to DMI than age‐matched SERT^+/+ or SERT^+/? mice. Desipramine was less potent in middle‐aged SERT^+/+ and SERT^+/? mice than in adult SERT^+/+ or SERT^+/? mice. Regardless of age, DMI's maximal effects were greater in SERT^?/? mice than in SERT^+/+ or SERT^+/? mice. These results show that immobility time in the TST varies as a function of age and SERT genotype, underscoring the utility of the TST as a potential model to examine age‐ and SERT genotype‐dependent influences on antidepressant response.     

Anti‐aging drugs reduce hypothalamic inflammation in a sex‐specific manner

Aging leads to hypothalamic inflammation, but does so more slowly in mice whose lifespan has been extended by mutations that affect GH/IGF‐1 signals. Early‐life exposure to GH by injection, or to nutrient restriction in the first 3 weeks of life, also modulate both lifespan and the pace of hypothalamic inflammation. Three drugs extend lifespan of UM‐HET3 mice in a sex‐specific way: acarbose (ACA), 17‐α‐estradiol (17αE2), and nordihydroguaiaretic acid (NDGA), with more dramatic longevity increases in males in each case. In this study, we examined the effect of these anti‐aging drugs on neuro‐inflammation in hypothalamus and hippocampus. We found that age‐associated hypothalamic inflammation is reduced in males but not in females at 12 months of age by ACA and 17αE2 and at 22 months of age in NDGA‐treated mice. The three drugs blocked indices of hypothalamic reactive gliosis associated with aging, such as Iba‐1‐positive microglia and GFAP‐positive astrocytes, as well as age‐associated overproduction of TNF‐α. This effect was not observed in drug‐treated female mice or in the hippocampus of the drug‐treated animals. On the other hand, caloric restriction (CR; an intervention that extends the lifespan in both sexes) significantly reduced hypothalamic microglia and TNF‐α in both sexes at 12 months of age. Together, these results suggest that the extent of drug‐induced changes in hypothalamic inflammatory processes is sexually dimorphic in a pattern that parallels the effects of these agents on mouse longevity and that mimics the changes seen, in both sexes, of long‐lived nutrient restricted or mutant mice.     

Effect of maternal diet on offspring coping styles in rodents: a systematic review and meta‐analysis

Maternal nutrition can have long‐term effects on offspring morphology, physiology and behaviours. However, it is unclear whether mothers ‘program’ offspring behavioural coping strategy (proactive/reactive) according to the predicted nutritional quality of their future environment. We conducted a systematic review on this topic and meta‐analytically synthesized relevant experimental data on mice and rats (46 studies). We included data from experiments where dams were subjected to caloric restriction, protein restriction or overfeeding around gestation and subsequently measured offspring activity, exploration, or anxiety. Overall, little evidence existed for effects of maternal nutrition on the three investigated behavioural traits. The high heterogeneity observed in the data set suggests that maternal programming may sometimes occur. However, because offspring had access to a balanced diet before testing, behaviours may have been reprogrammed. Our results may indicate that reprogrammed behaviours could ameliorate negative effects associated with sub‐optimal nutrition in early life. Further, our systematic review revealed clear knowledge gaps and fruitful future research avenues.     

Gender‐Specific Effects of Early Nutritional Restriction on Adult Obesity Risk: Evidence From Quasi‐Experimental Studies

In countries undergoing nutrition transition and historically poor minority groups in wealthy countries, obesity tends to be more common in women than men. A potential contributor to this female excess of obesity is a mismatch between perinatal nutritional restriction and a later calorie‐rich environment. Several epidemiologic and quasi‐experimental studies support a gender‐differential effect of early nutritional deprivation on adult obesity. The quasi‐experimental studies are of particular interest because results of quasi‐experimental studies are typically less vulnerable to confounding bias than observational studies. Four quasi‐experimental studies—exploiting 20th century famines that occurred in Europe, Africa, and Asia—provide evidence that perinatal nutritional restriction followed by relative caloric abundance may increase adult obesity risk to a greater extent in women than men. If the findings are accurate and generalizable to contemporary food environments, they suggest that the female offspring of poor, or otherwise nutritionally restricted, women in rapidly developing and wealthy countries may be at particularly high risk of adult obesity. Research into gender‐specific effects of early life nutritional deprivation and its interactions with later environmental exposures may provide insight into global gender differences in obesity prevalence.     

Remodelling of the intestinal ecosystem during caloric restriction and fasting

Benefits of fasting and caloric restriction on host metabolic health are well established, but less is known about the effects on the gut microbiome and how this impacts renewal of the intestinal mucosa. What has been repeatedly shown during fasting, however, is that bacteria utilising host-derived substrates proliferate at the expense of those relying on dietary substrates. Considering the increased recognition of the gut microbiome’s role in maintaining host (metabolic) health, disentangling host–microbe interactions and establishing their physiological relevance in the context of fasting and caloric restriction is crucial. Such insights could aid in moving away from associations of gut bacterial signatures with metabolic diseases consistently reported in observational studies to potentially establishing causality. Therefore, this review aims to summarise what is currently known or still controversial about the interplay between fasting and caloric restriction, the gut microbiome and intestinal tissue physiology.     

Reduced C/EBPβ‐LIP translation improves metabolic health

Inactivation of target of rapamycin complex 1 (TORC1) signaling is considered important for the beneficial effects of caloric restriction (CR) on metabolism and health span. It is however not fully elucidated which cellular processes downstream of TORC1 are the main regulators of metabolic health. In this issue of EMBO Reports, Zidek et al 1 describe that inhibition of mammalian TORC1 (mTORC1) leads to decreased translation of CCAAT/enhancer‐binding protein β (C/EBPβ)‐liver inhibitory protein (LIP). Moreover, loss of C/EBPβ‐LIP in mice improves metabolic health, similar to the effects of CR. Zidek et al 1 thus report that reduced C/EBPβ‐LIP translation is a novel mTORC1‐regulated process that could play a major role in mediating the beneficial metabolic effects of caloric restriction.