Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation.
Leng Lige,Zhuang Kai,Liu Zeyue,Huang Changquan,Gao Yuehong,Chen Guimiao,Lin Hui,Hu Yu,Wu Di,Shi Meng,Xie Wenting,Sun Hao,Shao Zhicheng,Li Huifang,Zhang Kunkun,Mo Wei,Huang Timothy Y,Xue Maoqiang,Yuan Zengqiang,Zhang Xia,Bu Guojun,Xu Huaxi,Xu Qi,Zhang Jie
Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1β production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1β receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1β production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.
Deficiency Reduces Anxiety- and Depression-Like Behaviors in Mice via Alterations in Gut Microbiota.
Sun Lijuan,Ma Lanjing,Zhang Haohao,Cao Ying,Wang Chenchen,Hou Nannan,Huang Niu,von Deneen Karen M,Zhao Changhai,Shi Yupeng,Pan Yan,Wang Meixia,Ji Gang,Nie Yongzhan
Depression and obesity have high concurrence within individuals, which may be explained by sharing the same risk factors, including disruption of the intestinal microbiota. However, evidence that delineated the causal connections is extremely scarce. Mice lacking fat mass- and obesity-associated gene () were generated. -deficient and wild-type control mice were subjected to novel conditions with or without chronic unpredictable mild stress (CUMS) for 6 weeks. Some mice were treated with antibiotics via their drinking water for 6 weeks in order to deplete their microbiota. Behavioral tests were performed to evaluate anxiety- and depression-like behaviors. 16S rRNA amplicon and metagenomic sequencing were employed to analyse fecal microbiota. Plasma levels of inflammatory cytokines and lipopolysaccharides (LPS) were also compared. Deletion of led to lower body weight and decreased anxiety- and depression-like behaviors, +/- mice were also less susceptible to stress stimulation, highlighting the essential role of in pathogenesis of depression. With regard to gut microbiota, deficiency mice harbored specific bacterial signature of suppressing inflammation, characterized with higher abundance of , lower Porphyromonadaceae and . Critically, behavioral alterations of mice are mediated by shift in gut microbiota, as such changes can be partially attenuated using antibiotics. Exposure to CUMS increased serum IL-6 level while deficiency reduced its level, which may be explained by a lower LPS concentration. Together, our findings uncover the roles of on depression and provide insights into microbiota-related biological mechanisms underlying the association between obesity and depression.
Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels.
Aceto Giuseppe,Colussi Claudia,Leone Lucia,Fusco Salvatore,Rinaudo Marco,Scala Federico,Green Thomas A,Laezza Fernanda,D'Ascenzo Marcello,Grassi Claudio
Proceedings of the National Academy of Sciences of the United States of America
Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3β in spike timing-dependent long-term potentiation (tLTP) in the chronic unpredictable mild stress (CUMS) mouse model of depression. To assess the specific role of GSK3β in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3β. In addition, we examined the role of the voltage-gated potassium Kv4.2 subunit, a molecular determinant of A-type K currents, as a potential downstream target of GSK3β. We found increased levels of active GSK3β and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3β knockdown. Furthermore, knockdown of GSK3β in the NAc ameliorated depressive-like behavior in CUMS mice. Electrophysiological, immunohistochemical, biochemical, and pharmacological experiments revealed that inhibition of the Kv4.2 channel through direct phosphorylation at Ser-616 mediated the GSK3β-dependent tLTP changes in CUMS mice. Our results identify GSK3β regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3β-Kv4.2 axis may be an attractive therapeutic target for MDD.
Amygdala-hippocampal innervation modulates stress-induced depressive-like behaviors through AMPA receptors.
Ma Hui,Li Chenyang,Wang Jinpeng,Zhang Xiaochen,Li Mingyue,Zhang Rong,Huang Zhuo,Zhang Yong
Proceedings of the National Academy of Sciences of the United States of America
Chronic stress is one of the most critical factors in the onset of depressive disorders; hence, environmental factors such as psychosocial stress are commonly used to induce depressive-like traits in animal models of depression. Ventral CA1 (vCA1) in hippocampus and basal lateral amygdala (BLA) are critical sites during chronic stress-induced alterations in depressive subjects; however, the underlying neural mechanisms remain unclear. Here we employed chronic unpredictable mild stress (CUMS) to model depression in mice and found that the activity of the posterior BLA to vCA1 (pBLA-vCA1) innervation was markedly reduced. Mice subjected to CUMS showed reduction in dendritic complexity, spine density, and synaptosomal AMPA receptors (AMPARs). Stimulation of pBLA-vCA1 innervation via chemogenetics or administration of cannabidiol (CBD) could reverse CUMS-induced synaptosomal AMPAR decrease and efficiently alleviate depressive-like behaviors in mice. These findings demonstrate a critical role for AMPARs and CBD modulation of pBLA-vCA1 innervation in CUMS-induced depressive-like behaviors.
Hippocampal Salt-Inducible Kinase 2 Plays a Role in Depression via the CREB-Regulated Transcription Coactivator 1-cAMP Response Element Binding-Brain-Derived Neurotrophic Factor Pathway.
Jiang Bo,Wang Hao,Wang Jin-Liang,Wang Ying-Jie,Zhu Qing,Wang Cheng-Niu,Song Lu,Gao Ting-Ting,Wang Yuan,Meng Guo-Liang,Wu Feng,Ling Yong,Zhang Wei,Li Jun-Xu
BACKGROUND:Developing novel pharmacological targets beyond monoaminergic systems is now a popular strategy for finding new ways to treat depression. Salt-inducible kinase (SIK) is a kinase that regulates the nuclear translocation of cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator (CRTC) by phosphorylation. Here, we hypothesize that dysfunction of the central SIK-CRTC system may contribute to the pathogenesis of depression. METHODS:Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioral tests, viral-mediated gene transfer, Western blotting, coimmunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immunohistochemistry were used in this study (for in vivo studies, n = 10; for in vitro studies, n = 5). RESULTS:Both CSDS and CUMS markedly increased the expression of hippocampal SIK2, which reduced CRTC1 nuclear translocation and binding of CRTC1 and CREB in the hippocampus. Genetic overexpression of hippocampal SIK2 in naïve mice simulated chronic stress, inducing depressive-like behaviors in the forced swim test, tail suspension test, sucrose preference test, and social interaction test, as well as decreasing the brain-derived neurotrophic factor signaling cascade and neurogenesis in the hippocampus. In contrast, genetic knockdown and knockout of hippocampal SIK2 protected against CSDS and CUMS, exerting significant antidepressant-like effects that were mediated via the downstream CRTC1-CREB-brain-derived neurotrophic factor pathway. Moreover, fluoxetine, venlafaxine, and mirtazapine all significantly restored the effects of CSDS and CUMS on the hippocampal SIK2-CRTC1 pathway, which was necessary for their antidepressant actions. CONCLUSIONS:The hippocampal SIK2-CRTC1 pathway is involved in the pathogenesis of depression, and hippocampal SIK2 could be a novel target for the development of antidepressants.
Early-life stress leads to impaired spatial learning and memory in middle-aged ApoE4-TR mice.
Lin Lan-Yan,Zhang Jing,Dai Xiao-Man,Xiao Nai-An,Wu Xi-Lin,Wei Zhen,Fang Wen-Ting,Zhu Yuan-Gui,Chen Xiao-Chun
BACKGROUND:Apolipoprotein E (ApoE) is a major lipid carrier that supports lipid transport and injury repair in the brain. The APOE ε4 allele is associated with depression, mild cognitive impairment (MCI) and dementia; however, the precise molecular mechanism through which ApoE4 influences the risk of disease development remains unknown. To address this gap in knowledge, we investigated the potential effects of chronic unpredictable mild stress (CUMS) on ApoE3 and ApoE4 target replacement (ApoE3-TR and ApoE4-TR) mice. RESULTS:All ApoE-TR mice exposed to CUMS at 3 months old recovered from a depression-like state by the age of 12 months. Of note, ApoE4-TR mice, unlike age-matched ApoE3-TR mice, displayed impaired spatial cognitive abilities, loss of GABAergic neurons, decreased expression of Reelin, PSD95, SYN and Fyn, and reduced phosphorylation of NMDAR2B and CREB. CONCLUSION:These results suggest that early-life stress may mediate cognitive impairment in middle-age ApoE4-TR mice through sustained reduction of GABAergic neurons and Reelin expression, which might further diminish the activation of the Fyn/NMDAR2B signaling pathway.
Functional studies of menin through genetic manipulation of the Men1 homolog in mice.
Balasubramanian Dheepa,Scacheri Peter C
Advances in experimental medicine and biology
To investigate the physiological role of menin, the protein product of the MEN1 gene, several groups have utilized gene targeting strategies to delete one or both copies of the mouse homolog Men1. Mice that are homozygous null for Men1 die during embryogenesis. Heterozygous Men1 mice are viable and develop many of the same types of tumors as humans with MEN1. In addition to conventional knockouts of Men1, tissue-specific elimination of menin using cre-lox has been achieved in pancreatic beta cells, anterior pituitary, parathyroid, liver, neural crest and bone marrow, with varying results that are dependent on cell context. In this chapter, we compare the phenotypes of the different conventional Men1 knockouts, detail the similarities and differences between Men1 pathogenesis in mice and humans and highlight results from recent crossbreeding studies between Men1 mutants and mice with null mutations in genes within the retinoblastoma pathway, including p18(Inc4c), p27(Kip1) and Rb. In addition, we discuss not only how the Men1 mutants have shed light on the role of menin in endocrine tumor suppression, but also how Men1 mutant mice have helped uncover previously unrecognized roles for menin in development, leukemogenesis and gestational diabetes.
Role of Interleukin-6 in Depressive Disorder.
Ting Emily Yi-Chih,Yang Albert C,Tsai Shih-Jen
International journal of molecular sciences
Major depressive disorder (MDD), which is a leading psychiatric illness across the world, severely affects quality of life and causes an increased incidence of suicide. Evidence from animal as well as clinical studies have indicated that increased peripheral or central cytokine interleukin-6 (IL-6) levels play an important role in stress reaction and depressive disorder, especially physical disorders comorbid with depression. Increased release of IL-6 in MDD has been found to be a factor associated with MDD prognosis and therapeutic response, and may affect a wide range of depressive symptomatology. However, study results of the genetic effects in MDD are controversial. Increased IL-6 activity may cause depression through activation of hypothalamic-pituitary-adrenal axis or influence of the neurotransmitter metabolism. The important role of neuroinflammation in MDD pathogenesis has created a new perspective that the combining of blood IL-6 and other depression-related cytokine levels may help to classify MDD biological subtypes, which may allow physicians to identify the optimal treatment for MDD patients. To modulate the IL-6 activity by IL-6-related agents, current antidepressive agents, herb medication, pre-/probiotics or non-pharmacological interventions may hold great promise for the MDD patients with inflammatory features.
NLRP3 gene knockout blocks NF-κB and MAPK signaling pathway in CUMS-induced depression mouse model.
Su Wen-Jun,Zhang Yi,Chen Ying,Gong Hong,Lian Yong-Jie,Peng Wei,Liu Yun-Zi,Wang Yun-Xia,You Zi-Li,Feng Shi-Jie,Zong Ying,Lu Guo-Cai,Jiang Chun-Lei
Behavioural brain research
BACKGROUND:Abundant researches indicate that neuroinflammation has important roles in the pathophysiology of depression. Our previous study found that the NLRP3 inflammasome mediated stress-induced depression-like behavior in mice via regulating neuroinflammation. However, it still remains unclear that how the NLRP3 inflammasome influences related inflammatory signaling pathway to contribute to neuroinflammation in depression. METHODS:We used wild-type mice and NLRP3 gene knockout mice to explore the role of NLRP3 inflammasome and related inflammatory signaling pathways in chronic unpredictable mild stress (CUMS) induced depression mouse model. RESULTS:Both wild-type and NLRP3 knockout stress group mice gained less weight than control group mice after 4 weeks CUMS exposure. The wild-type mice subjected to 4 weeks CUMS displayed depression-like behaviors, including decreased sucrose preference and increased immobility time in the tail suspension test. The NLRP3 knockout stress group mice didn't demonstrate depression-like behaviors. The levels of interleukin-1β protein in serum and hippocampi of CUMS exposed wild-type mice were significantly higher, while the NLRP3 knockout stress group mice didn't show an elevation of interleukin-1β levels. Similarly to early researches, we found that CUMS led to promoted NLRP3 expression in hippocampi. In addition, the hippocampi in CUMS exposed wild-type mice had higher p-JNK and p-p38 protein expression, which indicated activation of the mitogen-activated protein kinases (MAPK) pathway. The knockout of NLRP3 gene inhibited CUMS-induced activation of the MAPK pathway. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein complex was activated in the hippocampi of wild-type mice after CUMS exposure, while knockout of NLRP3 gene hindered its activation. CONCLUSIONS:These data further proved that the NLRP3 inflammasome mediated CUMS-induced depression-like behavior. The NLRP3 inflammasome regulated CUMS-induced MAPK pathway and NF-κB protein complex activation in depression mouse model. Further researches targeting the NLRP3 inflammasome-signaling pathway might be under a promising future in the prevention and treatment of depression.
Suppression of NLRP3 inflammasome attenuates stress-induced depression-like behavior in NLGN3-deficient mice.
Li Ze-Qun,Yan Zhi-Yuan,Lan Fu-Jun,Dong Yi-Qun,Xiong Ye
Biochemical and biophysical research communications
Depression, regulated by central nervous system (CNS), is a significant inflammatory disorder. Neuroligin3 (NLGN3) has been implicated in brain functions. In the study, a chronic unpredictable mild stress (CUMS) model in wild type (WT) or NLGN3-knockout (KO) mice was established to explore the role of NLGN3 in regulating depression and to reveal the underlying molecular mechanism. The results indicated that NLGN3-knockout markedly reversed the loss of body weight, the reduction of sucrose consumption, the decrease of immobile time in the forced swimming tests (FST) and tail suspension tests (TST) induced by CUMS paradigm. CUMS up-regulated corticosterone (CORT) in serum, and down-regulated serotonin (5-HT), norepinephrine (NE) and brain-derived neurotrophic factor (BDNF) in hippocampus of mice, which were significantly reversed by NLGN3 deficiency. The results further demonstrated that NLGN3-knockout improved the degenerative neurons in cortex and hippocampus of CUMS-treated mice, accompanied with a significant decrease of ionized calciumbinding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) expressions. Additionally, NLGN3-KO mice challenged with CUMS showed a significant reduction of pro-inflammatory cytokines and chemokine, including tumor necrosis factor-alpha (TNF-α), interleukin-18 (IL-18), interleukin-1 beta (IL-1β), interleukin-4 (IL-4), CC-chemokine ligand-1 (CCL-1) and CXC-chemokine ligand-1 (CXCL-1), in cortex, hippocampus and amygdala tissue samples. Western blot analysis suggested that NLGN3-knockout inhibited the activation of nod-like receptor protein 3 (NLRP3) inflammasome and its adaptor of apoptosis-associated speck like protein (ASC), and reduced the expression of Caspase-1, along with the inactivation of nuclear factor-κB (NF-κB) in CUMS-challenged mice. The role of NLGN3 in regulating depression in mice was confirmed in vitro using astrocytes stimulated by LPS that NLGN3 knockdown reduced LPS-induced inflammation. Importantly, the suppressive effects of NLGN3-knockdown on inflammatory response were reversed by NLRP3 or ASC over-expression in AST exposed to LPS. In sum, our findings indicated that suppressing NLGN3 played a potential antidepressant role in CUMS animal model by inactivating NLRP3 inflammasome, providing a new therapeutic avenue for depression.
Astrocytic Epoxyeicosatrienoic Acid Signaling in the Medial Prefrontal Cortex Modulates Depressive-like Behaviors.
Xiong Wenchao,Cao Xiong,Zeng Yuanning,Qin Xihe,Zhu Minzhen,Ren Jing,Wu Zhou,Huang Qiyuan,Zhang Yuan,Wang Mengyao,Chen Lianwan,Turecki Gustavo,Mechawar Naguib,Chen Wenjun,Yi Guoliang,Zhu Xinhong
The Journal of neuroscience : the official journal of the Society for Neuroscience
Major depressive disorder is the most common mental illness. Mounting evidence indicates that astrocytes play a crucial role in the pathophysiology of depression; however, the underlying molecular mechanisms remain elusive. Compared with other neuronal cell types, astrocytes are enriched for arachidonic acid metabolism. Herein, we observed brain-region-specific alterations of epoxyeicosatrienoic acid (EET) signaling, which is an arachidonic acid metabolic pathway, in both a mouse model of depression and postmortem samples from patients with depression. The enzymatic activity of soluble epoxide hydrolase (sEH), the key enzyme in EET signaling, was selectively increased in the mPFC of susceptible mice after chronic social defeated stress and was negatively correlated with the social interaction ratio, which is an indicator of depressive-like behavior. The specific deletion of (encode sEH) in adult astrocytes induced resilience to stress, whereas the impaired EET signaling in the mPFC evoked depressive-like behaviors in response to stress. sEH was mainly expressed on lysosomes of astrocytes. Using pharmacological and genetic approaches performed on C57BL/6J background adult male mice, we found that EET signaling modulated astrocytic ATP release and Moreover, astrocytic ATP release was required for the antidepressant-like effect of deletion in adult astrocytes. In addition, sEH inhibitors produced rapid antidepressant-like effects in multiple animal models of depression, including chronic social defeated stress and chronic mild stress. Together, our results highlight that EET signaling in astrocytes in the mPFC is essential for behavioral adaptation in response to psychiatric stress. Astrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression. Astrocytes secrete adenosine ATP, which modulates depressive-like behaviors. Notably, astrocytes are enriched for arachidonic acid metabolism. In the present study, we explored the hypothesis that epoxyeicosatrienoic acid signaling, an arachidonic acid metabolic pathway, modulates astrocytic ATP release and the expression of depressive-like behaviors. Our work demonstrated that epoxyeicosatrienoic acid signaling in astrocytes in the mPFC is essential for behavioral homeostatic adaptation in response to stress, and the extent of astrocyte functioning is greater than expected based on earlier reports.
Metabolomics analysis of the antidepressant prescription Danzhi Xiaoyao Powder in a rat model of Chronic Unpredictable Mild Stress (CUMS).
Zhu Yong-Liang,Li Shuang-Long,Zhu Chun-Yang,Wang Wan,Zuo Wen-Fei,Qiu Xiang-Jun
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Danzhi Xiaoyao Powder (DZXY) is a classical prescription, that has been extensively used in traditional Chinese medicine (TMC) to treat depression for many years. However, the mechanism of DZXY is still unclear. AIM OF THE STUDY:The aim was to investigate the mechanism of the antidepressant effect of DZXY on a rat model of chronic unpredictable mild stress (CUMS). MATERIALS AND METHODS:Forty male SD (Sprague-Dawley) rats with similar open field test (OFT) results were randomLy divided into a control group (n = 10) and an experimental group (n = 30). A depression model was established in the experimental group using the CUMS method. After the CUMS model was established successfully, the rats were randomLy divided into a depression model group and a DZXY group. The DZXY group was fed DZXY, while the depression model group and control group were given an equal amount of 0.5% sodium carboxymethyl cellulose suspension. Intragastric administration was performed once daily for 14 consecutive days. Animal weight, the sugar preference test, the open field test and the forced swimming test were used to evaluate the modeling effect and the antidepressant effect of DZXY. After the experiment, the plasma of rats was collected and the changes in plasma metabolites were analyzed by UPLC/Q-TOF-MS. The UPLC/Q-TOF-MS spectra data were evaluated by pattern recognition analysis to determine the changes in endogenous metabolites in the rat plasma samples. RESULTS:The results of the behavioral investigation showed that the rat model of depression was successfully replicated and that DZXY had an antidepressant effect. Using the UPLC-MS/MS metabolomics platform, partial least squares (PLS) and orthogonal partial least squares (OPLS), metabolic profile models (R2 and Q2 ≥ 0.5) of rat plasma were successfully constructed. The model could distinguish among the control group, the depression model group and the DZXY group. Finally, 38 differential metabolites were identified in the plasma. According to KEGG (http://www.kegg.jp) pathway analysis, amino acid metabolism, lipid metabolism, purine metabolism, the prolactin signaling pathway and bile secretion were enriched and represented the main metabolic pathways influenced in the plasma. CONCLUSIONS:This study successfully established a CUMS depression model. A total of 38 differential metabolites associated with depression were identified in the plasma of rats, 24 of which were modulated by DZXY. These results suggest that DZXY can improve excitability and play an antidepressant role by regulating phenylalanine metabolism, arachidonic acid metabolism, porphyrin metabolism, D-arginine and D-ornithine metabolism, steroid hormone biosynthesis, unsaturated fatty acid biosynthesis and steroid biosynthesis.
Decreased expression of AKAP4 and TyrPho proteins in testis, epididymis, and spermatozoa with low sexual performance of mice induced by modified CUMS.
Choowong-In Pannawat,Sattayasai Jintana,Poodendaen Chanasorn,Iamsaard Sitthichai
The molecular mechanism of chronic stress especially reduced motility, a major cause of male infertility, has not been proved. It is known that A-kinase anchor protein 4 (AKAP4) and tyrosine-phosphorylated (TyrPho) proteins are involved in progressive motility. This study aimed to investigate the effect of chronic unpredictable mild stress (CUMS) on sexual behaviours, sperm quality, and expressions of AKAP4 and TyrPho proteins in testis, epididymis, and spermatozoa. Sixteen male mice were divided into control and CUMS groups (n = 8/group). Animals were induced by a stressor from twelve stressors for 36 days. Sexual behaviours, corticosterone and testosterone, sperm parameters, and histopathology were observed. The expressions of AKAP4 and TyrPho proteins in testis, epididymis, and spermatozoa were examined. Results showed that CUMS significantly increased corticosterone while serum testosterone level was decreased. Sexual behaviours and sperm parameter quality were significantly decreased. CUMS mice showed vacuolisation and pyknotic cells in seminiferous epithelium and less sperm mass was observed within epididymal lumen. CUMS decreased expressions of AKAP4 and TyrPho proteins in testis, epididymis, and spermatozoa. In conclusion, the decreased expression of AKAP4 and TyrPho proteins may be a mechanism associated with low semen qualities particularly decrease of sperm motility in CUMS.
Differential Regulation of DNA Methylation at the CRMP2 Promoter Region Between the Hippocampus and Prefrontal Cortex in a CUMS Depression Model.
Xiang Dan,Xiao Jiawei,Sun Siqi,Fu Linyan,Yao Lihua,Wang Gaohua,Liu Zhongchun
Frontiers in psychiatry
Current evidence supports the idea that neural plasticity is a potential cause of depression. Abundant studies indicate that CRMP2 has important roles in neural plasticity. Moreover, CRMP2 may contribute to the etiology of depression. However, the regulatory mechanisms underlying the role of CRMP2 remain unclear. DNA methylation alteration is generally acknowledged to be involved in the development of depression. The aim of this study was to explore the relationship between the expression and DNA methylation of CRMP2 in the hippocampus and prefrontal cortex of a rat depression model. Chronic unpredictable mild stress (CUMS) was used to establish a rat depression model, and body weight and behavioral tests were used to evaluate the effects of stress. Real-time PCR and Western blotting were used to test CRMP2 mRNA and protein expression, respectively, in the hippocampus and prefrontal cortex of rats. DNA methylation levels of the CRMP2 promoter were analyzed by bisulfite sequencing PCR (BSP). CUMS caused depressive-like behavior in rats, as evidenced by: decreased body weight and sucrose preference rate; decreases in the total distance traveled, rearing frequency, velocity, and duration in the center in the open field test (OFT); and prolonged immobility in the forced swimming test (FST). CRMP2 mRNA and protein expression in the hippocampus and prefrontal cortex were significantly decreased in the CUMS group compared with the control group. The levels of CRMP2 promoter DNA methylation in the hippocampus of the CUMS group were significantly higher than those of the control group, while these changes were not observed in the prefrontal cortex of CUMS rats. Our data provide evidence that altered expression of CRMP2 in the hippocampus and prefrontal cortex is associated with the pathogenesis of depression. Moreover, the results also suggest regional differences in the regulation of DNA methylation in the CRMP2 promoter between the hippocampus and prefrontal cortex during the development of depression.
EA Ameliorated Depressive Behaviors in CUMS Rats and Was Related to Its Suppressing Autophagy in the Hippocampus.
Zhang Zhinan,Cai Xiaowen,Yao Zengyu,Wen Feng,Fu Zhiyi,Zhang Jiping,Zhong Zheng,Huang Yong,Qu Shanshan
Autophagy is confirmed to be involved in the onset and development of depression, and some antidepressants took effect by influencing the autophagic process. Electroacupuncture (EA), as a common complementary treatment for depression, may share the mechanism of influencing autophagy in the hippocampus like antidepressants. To investigate that, sixty Sprague-Dawley rats firstly went through chronic unpredictable mild stress (CUMS) model establishment, and 15 rats were assigned to a control group. After modeling, 45 successfully CUMS-induced rats were randomly divided to 3 groups: CUMS, selective serotonin reuptake inhibitor (SSRI), and EA groups (15 rats per group), to accept different interventions for 2 weeks. A sucrose preference test (SPT), weighing, and open field test (OFT) were measurement for depressive behaviors of rats. Transmission electron microscope (TEM), immunohistochemistry (IHC), and western blot analysis were used to evaluate the autophagic changes. After that, depression-like behaviors were successfully induced in CUMS models and reversed by SSRI and EA treatments (both < 0.05), but these two therapies had nonsignificant difference between each other ( > 0.05). Autolysosomes observed through TEM in the CUMS group were more than that in the control group. Their number and size in the SSRI and EA groups also decreased significantly. From IHC, the CUMS group showed enhanced positive expression of both Beclin1 and LC3 in CA1 after modeling ( < 0.05), and the LC3 level declined after EA treatments, which was verified by decreased LC3-II/LC3-I in western blot analysis. We speculated that CUMS-induced depression-like behavior was interacted with an autophagy process in the hippocampus, and EA demonstrated antidepressant effects by partly inhibiting autophagy with a decreased number of autolysosomes and level of LC3 along with LC3-II/LC3-I.
Melatonin ameliorated CUMS-induced depression-like behavior via restoring endoplasmic reticulum stress in rat hippocampus.
Wang Shengdong,Xu Xiaohong,Ju Xuan,Wang Shuqi,Li Jing,Yan Pan,Yu Zhenghe,Song Mingfen
Melatonin is a hormone synthesized and secreted by the pineal gland with the effect of regulating sleep rhythm. Circadian and sleep disturbances may be central for understanding the pathophysiology and treatment of depression. Recently, the melatonergic system has been implicated in the pathophysiology and treatment of depression. In this study, we observed the effects of melatonin on depression-like behavior induced by chronic unpredictable mild stress (CUMS) in rats, and its molecular mechanism was explored. Adult male Sprague-Dawley rats were exposed to CUMS for 4 weeks. Melatonin or saline was injected intraperitoneally. Behavioral changes of Sprague-Dawley rats were detected by the open field test, sugar preference test, elevated O maze test and forced swimming test. In addition, the plasma corticosterone level and the expression of endoplasmic reticulum stress-related protein in the hippocampus of rats were measured. Compared with the control group, the CUMS-exposed Sprague-Dawley rats showed depression-like behavior, which was significantly improved by melatonin treatment. Moreover, CUMS induced endoplasmic reticulum stress and JNK phosphorylation in the hippocampus. Melatonin treatment could significantly reverse the endoplasmic reticulum stress and JNK phosphorylation induced by CUMS. These results suggest that melatonin improves depression-like behavior by inhibiting endoplasmic reticulum stress induced by CUMS. This study demonstrates that melatonin can improve depression-like behavior induced by CUMS, which may be related to the inhibition of endoplasmic reticulum stress and JNK phosphorylation in rat hippocampus.
Ifenprodil rapidly ameliorates depressive-like behaviors, activates mTOR signaling and modulates proinflammatory cytokines in the hippocampus of CUMS rats.
Yao Yamin,Ju Peijun,Liu Hongmei,Wu Xiaohui,Niu Zhiang,Zhu Yuncheng,Zhang Chen,Fang Yiru
RATIONALE:The rapid-onset and long-lasting antidepressant properties of ketamine have prompted investigations into a variety of agents that target N-methyl-D-aspartate receptors (NMDARs) for the treatment of major depressive disorder (MDD). According to the literature, ifenprodil (a GluN2B-containing NMDAR antagonist) can potentiate the antidepressant-like effects of certain antidepressant drugs in mice. Here, we report that a single injection of ifenprodil (3 mg/kg, intraperitoneally (i.p.)) was sufficient to provoke rapid antidepressant-like effects in chronic unpredictable mild stress (CUMS) rats. Moreover, ifenprodil activated mTOR signaling and reversed the CUMS-induced elevation of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the hippocampus after acute administration. Unfortunately, in our study, ifenprodil had no influence on corticosterone levels in the plasma. Our data indicate that ifenprodil per se might exert antidepressant-like effects by modulating neuroplasticity and inflammatory processes rather than the typical hormonal factors affected by stressors. OBJECTIVES:To explore the potential rapid antidepressant-like effects and mechanisms of ifenprodil, a GluN2B subunit-selective NMDAR antagonist. METHODS:Male Sprague-Dawley rats were used in 3 separate experiments. In experiment 1, we used the forced swim test (FST) and sucrose preference test (SPT) to identify the rapid antidepressant-like effects of ifenprodil in chronic unpredictable mild stress (CUMS) rats after acute administration. In experiment 2, we assessed neurochemical changes involved in synaptic plasticity within the hippocampus of CUMS rats. In experiment 3, we assessed the levels of corticosterone in the plasma and proinflammatory cytokines in the hippocampus in CUMS rats after ifenprodil treatment. RESULTS:Ifenprodil rapidly ameliorated depressive-like behaviors in the FST and SPT, activated mTOR signaling, dephosphorylated eukaryotic elongation factor 2, enhanced BDNF expression, and promoted the synthesis of the synaptic protein GluA1 synthesis after acute administration. Moreover, ifenprodil reversed the CUMS-induced elevation of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the hippocampus after acute administration. Unfortunately, ifenprodil had no influence on corticosterone levels in the plasma in our study. CONCLUSIONS:Our data indicate that ifenprodil per se might exert antidepressant-like effects through its effects on neuroplasticity and inflammatory processes rather than the typical hormonal factors affected by stressors.
Cang-ai volatile oil improves depressive-like behaviors and regulates DA and 5-HT metabolism in the brains of CUMS-induced rats.
Chen Bojun,Li Jijun,Xie Yuhuan,Ming Xi,Li Gang,Wang Jinjin,Li Meng,Li Xiaohong,Xiong Lei
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Cang-ai volatile oil (CAVO) is a traditional Chinese medicine (TCM) inhalational preparation for the treatment of some depressive and emotive disorders. AIM OF THE STUDY:This research aimed to evaluate the efficiency and possible mechanism of intranasal CAVO administration on depression in chronic unpredictable mild stress (CUMS)-induced rats compared to lavender volatile oil (LVO) treatment after CUMS exposure and bilateral olfactory bulb impairment (OBI) in rats. MATERIALS AND METHODS:Forty depressive-like model rats induced by CUMS were evaluated by the forced swim test (FST), open field test (OFT), and sucrose preference test (SPT). The model rats were divided into five groups: CUMS (n = 8), CAVOh + CUMS (n = 8), CAVOl + CUMS (n = 8), LVO + CUMS (n = 8), and OBI + CAVO + CUMS (n = 8). The CUMS-induced rats were treated for a period of 4 weeks. The other healthy rats were regarded as the control (CTR, n = 8) subjects. The levels of serotonin (5-HT) and dopamine (DA) and their respective metabolites homovanillic acid (HVA) and 5-hydroxyindol acetic acid (5-HIAA) were measured in brain tissue homogenates of CUMS-induced rats using enzyme-linked immunosorbent assay (ELISA). RESULTS:CAVO ameliorated depressive-like behaviors (p < 0.05). The levels of DA in the CUMS group were lower than those in the CTR and CAVOh groups (**p < 0.01 and *p < 0.05). The levels of HVA were lower in the CUMS group than in the CTR, LVO, OBI + CAVOh and CAVOh groups (**p < 0.01 and *p < 0.05) and lower in the OBI + CAVOh group than in the CAVOh group (**p < 0.01). The levels of 5-HT in the CUMS group were lower than those in the CTR and CAVOh groups (**p < 0.01). The levels of 5-HIAA were lower in the CUMS and OBI + CAVOh groups than in the CTR, LVO and CAVOh groups (**p < 0.01). CONCLUSIONS:CAVO can improve depressive-like behaviors concomitant with the regulation of DA and 5-HT metabolism in the brains of CUMS-induced rats.
The protective effects of Ghrelin/GHSR on hippocampal neurogenesis in CUMS mice.
Huang Hui-Jie,Chen Xiao-Rong,Han Qiu-Qin,Wang Jing,Pilot Adam,Yu Rui,Liu Qiong,Li Bing,Wu Gen-Cheng,Wang Yan-Qing,Yu Jin
Ghrelin is an orexigenic hormone that also plays an important role in mood disorders. Our previous studies demonstrated that ghrelin administration could protect against depression-like behaviors of chronic unpredictable mild stress (CUMS) in rodents. However, the mechanism related to the effect of ghrelin on CUMS mice has yet to be revealed. This article shows that ghrelin (5 nmol/kg/day for 2 weeks, i.p.) decreased depression-like behaviors induced by CUMS and increased hippocampal integrity (neurogenesis and spine density) measured via Ki67, 5-bromo-2-deoxyuridine (BrdU), doublecortin (DCX) labeling and Golgi-cox staining, which were decreased under CUMS. The behavioral phenotypes of Growth hormone secretagogue receptor (Ghsr)-null and wild type (WT) mice were evaluated under no stress condition and after CUMS exposure to determine the effect of Ghsr knockout on the behavioral phenotypes and stress susceptibility of mice. Ghsr-null mice exhibited depression-like behaviors under no stress condition. CUMS induced similar depression- and anxiety-like behavioral manifestations in both Ghsr-null and WT mice. A similar pattern of behavioral changes was observed after hippocampal GHSR knockdown. Additionally, both Ghsr knockout as well as CUMS exhibited deleterious effects on neurogenesis and spine density in the dentate gyrus (DG). Besides, CCK8 assay and 5-Ethynyl-2'-deoxyuridine (EdU) incorporation assay showed that ghrelin has a proliferative effect on primary cultured hippocampal neural stem cells (NSCs) and this proliferation was blocked by D-Lys3-GHRP-6 (DLS, the antagonist of GHSR, 100 μM) pretreatment. Ghrelin-induced proliferation is associated with the inhibition of G1 arrest, and this inhibition was blocked by LY294002 (specific inhibitor of PI3K, 20 μM). Furthermore, the in vivo data displayed that LY294002 (50 nmol, i.c.v.) can significantly block the antidepressant-like action of exogenous ghrelin treatment. All these results suggest that ghrelin/GHSR signaling maintains the integrity of hippocampus and has an inherent neuroprotective effect whether facing stress or not.