Electroacupuncture Prevents the Depression-Like Behavior by Inhibiting the NF-κB/NLRP3 Inflammatory Pathway in Hippocampus of Mice Subjected to Chronic Mild Stress

<b><i>Background:</i></b> The precise physiological mechanisms of acupuncture in the treatment of depression are still unknown. This study aimed to observe the effects of electroacupuncture (EA) on depression-like behavior of mouse in chronic mild stress (CMS) model and explore the underlying mechanism. <b><i>Methods:</i></b> The depression model was established by using CMS method for 6 weeks. After the third week of the CMS paradigm, EA treatment was performed daily for 15 min over a period of 3 weeks. The antidepressant-like effects of EA were evaluated using the sucrose preference test and the forced swimming test (FST). The protein levels of the nuclear factor-kappa B (NF-κB), p-NF-κB, inhibitor of NF-κB, p-IκBα, NOD-like receptor protein 3, interleukin (IL)-6, IL-1β, IL-18, and tumor necrosis factor-α (TNF-α) in hippocampus of mice were detected. <b><i>Results:</i></b> Sucrose preference was decreased after 6 weeks of CMS and the effects of CMS was reversed by EA. CMS increased immobility time and decreased latency to the first immobility in the FST test, but these effects were reversed by EA. CMS-induced nuclear entry of NF-κB (nuclear/cytoplasmic ratio of NF-κB) with an increase in protein levels of p-NF-κB and p-IκBα in the hippocampus. The CMS also increased NLRP3 levels in the hippocampus. However, these effects were reversed by EA. In addition, the levels of IL-6, IL-1β, IL-18, and TNF-α in the hippocampus were increased by CMS, and these effects of stress were reversed by EA. <b><i>Conclusion:</i></b> EA prevented CMS-induced depressive-like behaviors by inhibiting NF-κB/NLRP3 inflammatory pathway.

Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines

Rationale Major depressive disorder (MDD) is a leading cause of disability worldwide but currently prescribed treatments do not adequately ameliorate the disorder in a significant portion of patients. Hence, a better appreciation of its aetiology may lead to the development of novel therapies. Objectives In the present study, we have built on our previous findings indicating a role for protease-activated receptor-2 (PAR2) in sickness behaviour to determine whether the PAR2 activator, AC264613, induces behavioural changes similar to those observed in depression-like behaviour. Methods AC264613-induced behavioural changes were examined using the open field test (OFT), sucrose preference test (SPT), elevated plus maze (EPM), and novel object recognition test (NOR). Whole-cell patch clamping was used to investigate the effects of PAR2 activation in the lateral habenula with peripheral and central cytokine levels determined using ELISA and quantitative PCR. Results Using a blood–brain barrier (BBB) permeable PAR2 activator, we reveal that AC-264613 (AC) injection leads to reduced locomotor activity and sucrose preference in mice but is without effect in anxiety and memory-related tasks. In addition, we show that AC injection leads to elevated blood sera IL-6 levels and altered cytokine mRNA expression within the brain. However, neither microglia nor peripheral lymphocytes are the source of these altered cytokine profiles. Conclusions These data reveal that PAR2 activation results in behavioural changes often associated with depression-like behaviour and an inflammatory profile that resembles that seen in patients with MDD and therefore PAR2 may be a target for novel antidepressant therapies.

A Terrified Sound Stress Impairs Learning And Memory Ability of Adult Female

Stress, as an important environmental factor of mental health, cannot be ignored. The great physiological difference between males and females implies that the effects of stress may differ by gender. However, few studies have focused on the effects of stress on females. This study investigated the effects of a terrified sound stress on adult female mice.Methods: 32 adults female C57BL/6 mice were randomly divided into control group (n=16) and stress group (n=16). Sucrose preference test and open field test (OFT) were carried out to evaluate the anxiety and depression of mice. Spatial learning and memory ability were measured by Morris Water maze test (MWM). Endocrine hormones were determined by enzyme-linked immunosorbent assay (ELISA). Serum differential proteins were screened by mass spectrometry (MS). Results: Compared with control group, the sucrose preference of stress group was decreased; in MWM, the escape latency of the stress group was significantly prolonged (P<0.05), and the total swimming distance was significantly increased (P<0.05).Serum T (P<0.05), GnRH (P<0.05), FSH and LH levels decreased; thirty six differential peaks were found by MS, eight of them had high multiples of difference (> 1.2 or <0.8). Conclusion: terrified sound stress impairs spatial learning ability and mental health of adult female mice.

Artificial Light at Night Reduces Anxiety-Like Behavior in Female Mice with Exacerbated Mammary Tumor Growth

Artificial light at night (ALAN) is a pervasive phenomenon. Although initially assumed to be innocuous, recent research has demonstrated its deleterious effects on physiology and behavior. Exposure to ALAN is associated with disruptions to sleep/wake cycles, development of mood disorders, metabolic disorders, and cancer. However, the influence of ALAN on affective behavior in tumor-bearing mice has not been investigated. We hypothesize that exposure to ALAN accelerates mammary tumor growth and predict that ALAN exacerbates negative affective behaviors in tumor-bearing mice. Adult (> 8 weeks) female C3H mice received a unilateral orthotropic injection of FM3A mouse mammary carcinoma cells (1.0 × 105 in 100 μL) into the fourth inguinal mammary gland. Nineteen days after tumor inoculation, mice were tested for sucrose preference (anhedonia-like behavior). The following day, mice were subjected to an open field test (anxiety-like behavior), followed by forced swim testing (depressive-like behavior). Regardless of tumor status, mice housed in ALAN increased body mass through the first ten days. Tumor-bearing ALAN-housed mice demonstrated reduced latency to tumor onset (day 5) and increased terminal tumor volume (day 21). Exposure to ALAN reduced sucrose preference independent of tumor status. Additionally, tumor-bearing mice housed in dark nights demonstrated significantly increased anxiety-like behavior that was normalized via housing in ALAN. Together, these data reaffirm the negative effects of ALAN on tumorigenesis and demonstrate the potential anxiolytic effect of ALAN in the presence of mammary tumors.

Influence of high energy diet and polygenic predisposition for obesity on postpartum health in rat dams

It is estimated that 30% of pregnant women worldwide are overweight or obese, which leads to adverse health effects for both the mother and child. Women with obesity during pregnancy are at higher risk for developing both metabolic and mental disorders, such as diabetes and depression. Numerous studies have used rodent models of maternal obesity to understand its consequences on the offspring, yet characterization of changes in the dams is rare, and most rodent models rely solely on a high fat diet to induce maternal obesity, without regarding genetic propensity for obesity. Here we present the influence of both peripartum high energy diet (HE) and obesity-proneness on maternal health using selectively-bred diet-resistant (DR) and diet-induced obese (DIO) rat dams. Outbred Sprague-Dawley rats were selected and bred according to their propensity to gain weight. From F1 onward, dams consuming a HE diet displayed higher body weight gain during pregnancy, and HE diet had a strong effect on meal patterns. Sensitivity to the hormone amylin was preserved during pregnancy, regardless of diet. After several rounds of selective breeding, dams from generation F3 were assessed for their postpartum physiology and behaviors. We observed strong diet and phenotype effects on gestational weight gain, with DIO-HE dams gaining 119% more weight than DR-chow. A high-resolution analysis of maternal behaviors on postpartum day 2 (P2) did not detect main effects of diet or phenotype, but a subset of DIO dams showed decreased pup-related behaviors. During a sucrose preference test (SPT) on P14, all DR dams consumed at least 70% sucrose, while a subset of DIO dams preferred water. In generation F6/F7 dams, effects on gestational weight gain persisted, and we observed a main effect of phenotype of SPT, with DIO-chow dams showing the lowest sucrose preference. Both DIO and DR dams consuming HE diet had severe postpartum liver lipidosis and exhibited reduced leptin sensitivity in the arcuate nucleus at the time of pup-weaning. These data demonstrate that both diet and genetic obesity-proneness have consequences on maternal health.

Beneficial effects of running exercise on hippocampal microglia and neuroinflammation in chronic unpredictable stress-induced depression model rats

Running exercise has been shown to relieve symptoms of depression, but the mechanisms underlying the antidepressant effects are unclear. Microglia and concomitant dysregulated neuroinflammation play a pivotal role in the pathogenesis of depression. However, the effects of running exercise on hippocampal neuroinflammation and the number and activation of microglia in depression have not been studied. In this study, rats were subjected to chronic unpredictable stress (CUS) for 5 weeks followed by treadmill running for 6 weeks. The depressive-like symptoms of the rats were assessed with a sucrose preference test (SPT). Immunohistochemistry and stereology were performed to quantify the total number of ionized calcium-binding adapter molecule 1 (Iba1)+ microglia, and immunofluorescence was used to quantify the density of Iba1+/cluster of differentiation 68 (CD68)+ in subregions of the hippocampus. The levels of proinflammatory cytokines in the hippocampus were measured by qRT-PCR and ELISA. The results showed that running exercise reversed the decreased sucrose preference of rats with CUS-induced depression. In addition, CUS increased the number of hippocampal microglia and microglial activation in rats, but running exercise attenuated the CUS-induced increases in the number of microglia in the hippocampus and microglial activation in the dentate gyrus (DG) of the hippocampus. Furthermore, CUS significantly increased the hippocampal levels of inflammatory factors, and the increases in inflammatory factors in the hippocampus were suppressed by running exercise. These results suggest that the antidepressant effects of exercise may be mediated by reducing the number of microglia and inhibiting microglial activation and neuroinflammation in the hippocampus.

Environmental Enrichment Ameliorates Psychological Dependence Symptoms and Voluntary Morphine Consumption in Morphine Withdrawn Rats Under Methadone Maintenance Treatment

Introduction: Previous studies have shown that physical and psychological dependence and the vulnerability to relapse are still present during MMT. Thus, this study examined whether Enriched Environment (EE) would attenuate anxiety, depressive, and obsessive-compulsive-like behaviors, as well as voluntary morphine consumption following Methadone Maintenance Treatment (MMT) in morphine withdrawn rats. Methods: The rats were injected bi-daily doses (10 mg/kg, 12-h interval) of morphine for 14 days. Then, the rats were reared in a Standard Environment (SE) or EE for 30 more days during morphine withdrawal, simultaneous with receiving MMT. The rats were tested for anxiety (the Elevated Plus Maze [EPM]) and depression (Sucrose Preference Test [SPT]), Obsessive-Compulsive Disorder (OCD) as grooming behavior, and voluntary morphine consumption using a Two-Bottle Choice (TBC) paradigm. Results: The findings revealed that EE experience in morphine withdrawn rats under MMT significantly increased the EPM open-arm time and higher sucrose preference than SE rats. Also, we found that the EE decreased the self-grooming behavior and morphine preference ratio in morphine withdrawn rats receiving MMT compared to the SE group. Conclusion: We conclude that exposure to EE decreased methadone-induced anxiety, depressive and OCD-like behaviors, and voluntary morphine consumption in morphine withdrawn rats under MMT. Thus, the EE seems to be one of the strategies for reducing MMT-induced behavioral dysfunction and the risk of relapse induced by morphine withdrawal.

Cafeteria diet decreases sucrose preference and increases the sensitivity of risperidone in the caloric intake of Wistar rats

Purpose The purpose of this study was to evaluate the increase in sensitivity of a single risperidone administration in relation to energy intake of Wistar rats treated with cafeteria diet from birth to adulthood (119 days). Design/methodology/approach During the lactation period, six litters of Wistar rats (dam + 8 pups each litter) were fed one of the following two diets: Control (n = 3) or Cafeteria (n = 3) diets and water ad libitum. After weaning, the males were placed in individual cages, receiving the same diet offered to their respective dams (Control = 18; or Cafeteria = 18) until adulthood (119 postnatal days). The following parameters were evaluated: food and energy intake; macronutrient intake; weight gain; adipose tissue relative weight; sucrose preference; food intake after an administration of risperidone (0.1 mg/kg body weight). Findings The Cafeteria group showed a higher energy intake in relation to the Control group (p < 0.001). The consumption of energy beyond the individual needs can be understood as a hyperphagic condition. Also, the Cafeteria group reported greater weight gain (p = 0.048) and accumulation of adipose tissue (p < 0.001) with respect to the Control group. These results indicate that the cafeteria diet generated obesity in animals. The Cafeteria group showed reduced sucrose preference (p = 0.031), which is associated with the development of anhedonia-like behavior. In the food intake test, risperidone showed a greater sensitivity in Cafeteria animals, promoting a decrease in their energy intake in relation to the Control group that received risperidone (p = 0.040). Originality/value The cafeteria diet promoted hyperphagia, anhedonia-like behavior and obesity in animals. Acute risperidone administration showed greater sensitivity in the Cafeteria group, with a decrease in energy intake. The reported effects may be related to a downregulation of the dopaminergic system in the NAc region.

Early Life Adversity in Male Mice Sculpts Reward Circuits.

Early life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In this study, we focused on the projections from the dorsal raphe (DR) to the ventral tegmental area (VTA) and on to the nucleus accumbens (NAcc), an important pathway within the reward circuit. We hypothesized that ELA alters connectivity within the DR-VTA-NAcc pathway, manifested behaviorally as anhedonia in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was acquired and processed for regional DTI metrics, including tractography to assess circuit organization. We found brain-wide changes in radial diffusivity (RD) and altered connectivity of the reward circuit in the ELA group. DR-VTA-NAcc circuit tractography and axial diffusivity (AD) along this tract exhibited dispersed organization where AD was increased in the VTA segment. Behaviorally, ELA elicited an anhedonic phenotype in adulthood with decreased direct social approach and time spent with peer but no overt differences in sucrose preference test. Our findings suggest that reward circuits, assessed using DTI, are altered following ELA and that these changes may drive enduring reward deficits.

Lane-maze for preference testing in flies

Drosophila melanogaster is a candidate species to replace rodents in some neurobiological studies, encouraging attempts to develop behavioural tests for these flies. This study aimed to develop a behavioural test to simultaneously evaluate ethological (categorical) aspects of the motor and fluid intake activities, which may be used to assess sucrose preference in flies. For that, a lane-maze was 3D-printed to accommodate up to 14 individual flies in a single trial. Each lane had a capillary filled with 5% sucrose solution attached to one of the extremities. To validate a 5-min lane-maze test, male and female flies (adults, 5-6 days of age) underwent 0, 2, 8 or 20 h of food deprivation (FD, n=9-11/group) before testing. Duration of locomotion, immobility and grooming in the lane or capillary were scored from the video-recorded trials using EthoWatcher software. Minor effects of sex or FD were observed in the behaviours of flies. Independent of sex or FD, flies spent proportionally longer on the capillary than on the lane. Flies exhibited a significantly higher preference than expected for the capillary zone when food-deprived for 2h (males) or 20 h (females). Data suggest that short lane-maze test is a feasibly high throughput assessment of sucrose preference in flies, which may be sexually dimorphic as in other species studied so far.