Activation of GABAB receptors alleviates depressive-like behavior induced by chronic cerebral ischemia via upredulation of BDNF in rats

Aim To investigate the mechanisms underlying depressive-like behavior induced by chronic cerebral is- chemia in rats. Methods In the present study, a chronic cerebral hypoperfusion model was established by perma- 2VO） in rats. Two weeks after 2VO, GAB- nent bilateral common carotid arteries occlusion （two-vessel occlusion, AB receptor agonist baclofen （25 mg · kg^-1 . d^-1 i p ） was administrated for 21 days. The FST was performed to evaluate depressive-like behavior in which the immobility time was recorded. In addition, the expression of brain derived neurotrophic factor （BDNF） in hippocampal CA1 was measured by Western blot. Results The immobility time of 2VO group was significantly prolonged and the expression of BDNF was decreased by 28.95% compared with sham group. After activation of GABAB receptors by baclofen, the immobility time was significantly reduced and the expression of BDNF was increased by 47.91% compared with 2VO group. Conclusion 2VO induced ob- vious depressive-like behavior in rats. Activation of GABAB receptors alleviates the depressive-like behavior in- duced by chronic cerebral ischemia via upredulation of BDNF in hippocampal CA1 in rats.

Effect and regulation ofα-dstroglycan glyco⁃sylation on chronic social defeat induced depressive-like behaviors of mice

OBJECTIVEα-Dstroglycan(α-DG)is a predominant component in the dystrophin-glycoprotein complex(DGC)and a recently char⁃acterized receptor for several extracellular matrix components with high affinity.Recent research⁃es have reported that hypoglycosylation ofα-DG is associated with the pathophysiology of diseas⁃es,especially muscular dystrophy,but little is known about major depressive disorder(MDD).Like-acetylglucosaminyl transferase(Large)is a key enzyme for glycosylation ofα-DG,which mainly modifies two points in the middle domain ofα-DG:Thr-317 and Thr-319.Glycosylatedα-DG(GLY-α-DG)can bind with high affinity to extracellular matrix(ECM)molecules that con⁃tain laminin globular(LG)domains,including per⁃lecan,agrin and neurexin.Agrin is mainly derived from neurons rather than glial cells.In cultured hippocampal neurons,it was found that agrin could regulate the homeostatic plasticity of inhibi⁃tory neurons by acting on GLY-α-DG.Mdx mice are transgenetic models for the investigation of Duchenne muscular dystrophy.Many studies have shown that the expression of GLY-α-DG in the peripheral and brain tissues of Mdx mice is significantly down-regulated.Mdx mice show cognitive impairment and high levels of anxiety.In this study,we employed chronic social defeat stress(CSDS)to establish an animal model of depression and detected the expression of GLY-α-DG among the brain areas associated with the pathophysiology of depression.METHODS So⁃cial interaction test(SIT)and sucrose preference test(SPT)were used to evaluate depressive-like behavior.Open field(OF)and elevated plus maze(EPM)test were used to determine the anxiety-like behavior of Mdx mice.Novelty-sup⁃pressed feeding test(NSFT)forced swim test(FST)and tail suspension test(TST)were used to detect the depressive-like behavior of Mdx mice.Novel object recognition test(NOR)was applied to evaluate the cognition of Mdx mice.Subthreshold social defeat stress was used to explore the susceptibility to stress in Mdx mice.Stereotactic infusion of agrin into the ventral hippocampus(vHip),FST and TST were used to investigate the antidepressant effects of agrin.Adeno-associated virus(AAV)-mediated overex⁃pression techniques,behavior tests and whole-cell path-clamp technique were conducted to determine the impact of Large overexpression on CSDS susceptible mice.RESULTS The expres⁃sion ofα-DG and GLY-α-DG were significantly decreased in the vHip of CSDS susceptible mice.Mdx mice showed decreased expression of GLY-α-DG and increased anxiety-like behav⁃iors.Mdx mice displayed some depressive-like behaviors,and the susceptibility to stress was significantly increased.Downregulation of the expressionα-DG in the vHip by lentivirus increased the susceptibility to stress.Administra⁃tion of agrin to CSDS susceptible mice exerted antidepressant effects,and this effect could par⁃tially sustain for a week.The expression of Large was decreased in vHip.Overexpression of Large through AAV-Large reversed the depressive-like behaviors and restored the decreased frequency and amplitude of mIPSC.CONCLUSION GLY-α-DG and its glycosylase are significantly decreased in CSDS susceptible mice.Adminis⁃tration of agrin and overexpression of Large displays antidepressant effect,which may be related to its promotion of inhibitory synaptic transmission.

Long Term Low Salt Feeding Led to the Changes in Food Intake, Body Weight and Depressive-Like Behavior in Mice

Low salt intake is associated with depression, but the experimental evidence is not clear. Sixty adult mice were randomly divided into four groups (mild, moderate and severe salt deficiency groups and control) during the seasonal splitting from winter to spring. The mice in the control group were fed with standard ordinary diet (salt content 0.26%), while in the mild, moderate and severe groups, the mice were fed with 10%, 30% and 50% salt deficient feedstuff, lasting for approximately 3 months. The results showed that the salt content of feed was negatively correlated with the food intake and body weight of mice. The sucrose preference test found that only the mild salt deficiency group had no differ-ence between the beginning and the end of the experiment, and the other three groups in-cluding the control, showed a significant decrease. These results suggest that dietary salt content has an impact on the food intake and body weight of mice and is associated with the emergence of depressive-like behavior. Furthermore, the seasonal splitting from winter to spring may also have a differential synergistic effect on the change of depression-like behavior associated with low salt intake in mice.

Restraint Induces Sickness Responses Independent of Injection with Epstein-Barr Virus (EBV)-Encoded dUTPase

Most adult humans have been infected by Epstein-Barr virus (EBV), a putative cause of chronic fatigue syndrome, and carry latent EBV. The EBV-encoded dUTPase can induce sickness responses in mice and chronic stress exacerbates this response. Because individuals often adapt to chronic stress, we tested the hypothesis that acute restraint stress would potentiate these sickness responses elicited by EBV-encoded dUTPase. Male CD-1 mice were injected daily for one or three days with either saline or EBV-encoded dUTPase. Additionally, mice from each condition were either restrained for three hours daily or left undisturbed during the light phase when mice are inactive. Restraint decreased weight gain during the one- and three-day experiments. Restraint in saline injected mice increased anxiety-like behavior in the open field during the three-day experiment. There were no behavioral differences during the one-day experiment. Restraint stress had no effect when experienced acutely on one day, but did produce a sickness response after three days of exposure regardless of saline or dUTPase injection. In contrast to the effects of chronic stress and EBV-encoded dUTPase on the sickness response, acute stress did not affect sickness responses in association with EBV-encoded dUTPase. Thus, dUTPase does not appear to provoke the same sickness responses after acute stress as compared to chronic stress.

Dopamine D₁- and D₂-Receptors in Immunostimulation under Activation of Mu-Opioid Receptors in Mice with Different Psychoemotional States

The purpose of the present study was to analyze the effect of activation of mu-opioid receptors (mu-OR) on the immune response under blockade of postsynaptic D1-and D2-receptors in mice of the C57BL/6J strain displaying either aggressive or depressive-like behaviors in the social conflict model. It is shown that activation of activation of mu-OR with a highly selective agonist DAGO (100 μg/kg) increased significantly IgM-immune response not only in C57BL/6J mice with an unchanged psychoemotional state but also in mice displaying aggressive or depressive-like behaviors in the social stress model (10 days of agonistic confrontations). Selective blockade of DA receptors of the D1-type with SCH-23390 (1.0 mg/kg with DAGO administration) caused a more pronounced elevation of IgM-immune response than DAGO alone while DAGO effect was completely blocked by prior administration of D2-receptor antagonist haloperidol (1.0 mg/kg). At the same time, both SCH-23390 and haloperidol prevented the immune response increase induced by DAGO injection in mice engaged in aggressive or depressive-like behaviors. Thus, in animals not subjected to social stress DAGO-induced immunostimulation is provided only by D2-receptors, whereas in animals with altered psychoemotional state mu-opioid immunostimulation is mediated by both types of DA receptors—D1 and D2. These data provide evidence for different impacts of the main subtypes of DA receptors in the mediation of immunomodulating effects of mu-opioid system under normal and stressful conditions.

Methyl Donors Supplementation Attenuates the Adverse Effects of Maternal High Fructose Diet of Offspring Emotional and Cognitive Behaviors

Free Fatty acid is an end-product of hepatic metabolism of fructose. Most of past studies have demonstrated significant relationship between gestational high fat diet and metabolic and physiology outcomes in offspring. However, there is a scarce of data extended to the effects of high fructose diet-fed dams on juveniles’ progeny. Therefore, the present experiment was designed to examine the later effects of maternal high fructose diet intake during pregnancy and lactation on juvenile offspring rats emotional behaviors and memory abilities. We tested whether methyl donors supplemented to that high fructose diet could reverse the adverse effects. We found at two months of age, anxiety-like behavior and depression-like behavior were elevated in off springs of mother fed to high fructose diet and a sex difference effect with males were more affected than females. In addition, behavioral outcomes indicated that the high fructose diet also impaired spatial working and recognition memories in the Y-maze and object recognition test respectively. Blood glucose intolerance increased significantly in juvenile males rats of dams fed with high fructose diet when compared to females. However, a supplementation of the maternal diet with methyl donors attenuated all these changes. Our study suggested a controlled fructose diet supplemented to methyl donors during critical period of brain developing (in utero and pre-weaning stage), otherwise that could induced irreversible detrimental effects on offspring behavior and cognitive health.

Pre-mating nitenpyram exposure in male mice leads to depression-like behavior in offspring by affecting tryptophan metabolism in gut microbiota

Several studies have confirmed that the health status of the paternal affects the health of the offspring,however,it remains unknown whether paternal exposure to pesticides affect the offspring health.Here,we used untargeted metabolomics and 16S rRNA sequencing technology,combined with tail suspension test and RT-qPCR to explore the effects of paternal exposure to nitenpyram on the neurotoxicity of offspring.Our results found that the paternal exposure to nitenpyram led to the offspring’s depressive-like behaviors,accompanied by the reduction of tryptophan content and the disorder of microbial abundance in the gut of the offspring.Further,we determined the expression of tryptophan metabolism-related genes tryptophanase(tnaA)and tryptophan hydroxylase 1(TpH1)in gut bacteria and colonic tissues.We found that tryptophan is metabolized to indoles rather than being absorbed into colonocytes,which coursed the reduce of tryptophan availability after nitenpyram exposure.In conclusion,our study deepens our understanding of the intergenerational toxic effects of pesticides.

Neuron stem cell NLRP6 sustains hippocampal neurogenesis to resist stress-induced depression

Neurogenesis decline in hippocampal dentate gyrus(DG)participates in stress-induced depressive-like behaviors,but the underlying mechanism remains poorly understood.Here,we observed low-expression of NOD-like receptor family pyrin domain containing 6(NLRP6)in hippocampus of stress-stimulated mice,being consistent with high corticosterone level.NLRP6 was found to be abundantly expressed in neural stem cells(NSCs)of DG.Both Nlrp6 knockout(Nlrp6^(-/-))and NSCconditional Nlrp6 knockout(Nlrp6CKO)mice were susceptible to stress,being more likely to develop depressive-like behaviors.Interestingly,NLRP6 was required for NSC proliferation in sustaining hippocampal neurogenesis and reinforcing stress resilience during growing up.Nlrp6 deficiency promoted esophageal cancer-related gene 4(ECRG4)expression and caused mitochondrial dysfunction.Corticosterone as a stress factor significantly down-regulated NLRP6 expression,damaged mitochondrial function and suppressed cell proliferation in NSCs,which were blocked by Nlrp6 overexpression.ECRG4 knockdown reversed corticosterone-induced NSC mitochondrial function and cell proliferation disorders.Pioglitazone,a well-known clinical drug,up-regulated NLRP6 expression to inhibit ECRG4 expression in its protection against corticosterone-induced NSC mitochondrial dysfunction and proliferation restriction.In conclusion,this study demonstrates that NLRP6 is essential to maintain mitochondrial homeostasis and proliferation in NSCs,and identifies NLRP6 as a promising therapeutic target for hippocampal neurogenesis decline linked to depression.

针刺应答是否随针刺剂量增加而增大:一项基于睡眠剥夺大鼠的临床前研究

Background:The effectiveness of acupuncture for insomnia and insomnia-related anxiety and depression has been widely investigated in clinical trials.However,whether higher dosage(more frequent)acupuncture can bring greater responses(a greater size of effect)is less understood.Objective:This study is designed to investigate whether a five-times weekly(5 Ts/w)electroacupuncture(EA)treatment is better than a three-times weekly(3 Ts/w)EA in alleviating sleep deprivation,and sleep disturbance-induced cognitive dysfunctions and negative emotions in rats through four various behavioral te sts.Methods:Forty-six male Sprague-Dawley rats were randomly divided into control group(n=10),model group(n=12),EA-3 Ts/w group(n=12),and EA-5 Ts/w group(n=12).Except for the control group,the other three groups were established as chronic sleep deprivation models via the modified multi-platform water environment methodology.Then,rats in both EA-3 Ts/w group and EA-5 Ts/w group received corresponding dosage of EA therapy,respectively.After modeling and interventions,all four groups received four behavioral tests as follows:(1)sleep behavioral monitoring and evaluation was achieved by Comprehensive Lab Animal Monitoring System(CLAMS).(2)Cognitive functions were assessed by Novel Object Recognition(NOR)test.(3)Depressive-like behaviors was evaluated by Open-Field(OF)test.(4)Anxietylike behaviors was appraised by Elevated Plus-Maze(EPM)test.After finishing the behavioral tests,the hippocampus of each rat was removed and its synaptic structure changes were observed under electron microscope.Results:(1)CLAMS:two EA groups derived more sleep time within 24 h than the model group(both P<0.05),and no statistical differences was found between these two EA groups(P>0.05).(2)NOR test:NOR ratio in the EA-3 Ts/w group was higher than that of the model group(P<0.05)but lower than that of either the control group(P<0.05)or the EA-5 Ts/w group(P<0.05).(3)OF test:the difference of horizontal movements between the EA-3 Ts/w group and the EA-5 Ts/w group was not significant(P>0.05),although both of them were lower than that of the control group(both P<0.05)but higher than that of the model group(P<0.05).(4)EPM test:no significant decline of open-arm total time(OT)was found in EA-3 Ts/w group(P>0.05)but was found in both the model group(P<0.05)and the EA-5 Ts/w group(P<0.05)compared to the control group.Conclusion:(1)Five-week EA treatment can partially mitigate cognitive dysfunctions,anxiety-like behaviors,and depressive behaviors in rats with sleep deprivation,and this effect might be associated with the repairs on mitochondrial damage in hippocampal neurons.(2)There is insufficient evidence supporting 3 Ts/w EA treatment is less effective than 5 Ts/w EA treatment in mitigating sleep deprivation symptoms and depressive behaviors induced by sleep deprivation among rats.(3)5 Ts/w EA treatment might be more effective than 3 Ts/w EA treatment in attenuating sleep deprivation-induced cognitive impairments while it might further increase rat’s anxiety-like behaviors at the same time.

Cymbopogon citratus aqueous leaf extract attenuates neurobehavioral and biochemical changes induced by social defeat stress in mice

Objective:Psychosocial stress has been implicated in the genesis of psychiatric disorders such as memory deficits,depression,anxiety and addiction.Aqueous leaf extract of Cymbopogon citratus(CYC)otherwise known as lemongrass tea has antidepressant,anxiolytic and anti-amnesic effects in rodents.This study was designed to evaluate if C citratus could reverse the neurobehavioral and biochemical derangements induced by social defeat stress(SDS)in the resident/intruder paradigm.Methods:Intruder male mice were divided into five groups(n=7):group 1 received saline(10 mL/kg,p.o.;non-stress control),group 2 also received saline(10 mL/kg,p.o.;SDS control)while groups 3-5 had C.citratus(50,100 and 200 mg/kg,p.o.)daily for 14 d.The SDS was carried out 30 min after each treatment from day 7 to day 14 by exposing each intruder mouse in groups 2-5 to a 10 min confrontation in the home cage of an aggressive resident counterpart.The neurobehavioral features(spontaneous motor activity-SMA,anxiety,memory,social avoidance and depression were then evaluated.The concentrations of nitrite,malondialdehyde and glutathione as well as acetylcholinesterase activity in the brain tissues were also determined.Results:C.citratus(50,100 and 200 mg/kg)attenuated hypolocomotion,heightened anxiety,depressive-like symptom,memory deficit and social avoidance induced by SDS.The altered levels of oxidative stress and acetyl-cholinesterase in SDS-mice were positively modulated by C.citratus.Conclusion:The results of this study suggest that C.citratus might mitigate psychosocial stress-induced neurologic diseases in susceptible individuals.