Depression-like Mice Research Articles

High-performance fluorescence probe for fast and specific visualization of norepinephrine in vivo and depression-like mice

Norepinephrine (NE), as an important neurotransmitter, is closely associated with the pathogenesis of anxiety and depressive disorders. Effective monitoring of NE fluctuation aids in the diagnosis of depression and the therapeutic assessment of the antidepressant intervention. The construction of novel fluorescent probes with high specificity towards NE for imaging in depression models is still in demand urgently. In this work, a novel resorufin-based red-emitting fluorescent probe for real-time tracking NE was developed. NE can significantly increase the fluorescence of probe LNE by triggering deprotection of carbonothioate ligand via nucleophilic substitution. The probe LNE demonstrated significant NE selectivity and sensitivity over other analytes in vitro. In addition, probe LNE showed a fast response time (<10 min), and the change in fluorescence signal was positively linked with NE concentration, which could be utilized to track the dysregulation of NE in vivo. More importantly, this powerful probe was successfully employed for real-time visual and imaging of NE in living cells and depression-like behavior animals.

Viral metagenomics combined with metabolomics reveals the role of gut viruses in mouse model of depression

Depression is a heterogeneous mental disorder that has been linked to disturbances in the gut microbiome. As an essential part of the gut microbiome, gut virome may play critical roles in disease progression and development. However, the relationship between the effect of gut virome on neurotransmitter metabolism and depression is unknown. We evaluated the alterations of gut virome and neurotransmitters in chronic restraint stress (CRS)-induced mouse model of depression based on viral metagenomics and LC-MS/MS metabolomics analyses. The results reveal that the gut virome profile of CRS group differed significantly from CON group. Microviridae was the most abundant differential viral family in both groups, followed by Podoviridae, while Siphoviridae was only enriched in CRS group of the top 100 differential viruses. The differential viruses that predicted to Enterobacteriaceae phage, Gammaproteobacteria phage and Campylobacteraceae phage were enriched in CRS group. Furthermore, 12 differential neurotransmitters primarily involved in the tryptophan metabolism pathway were altered in depressive-like mice. Besides, tryptamine and 5-methoxytryptamine hydrochloride were strongly associated with differential viruses belonging to Podoviridae and Microviridae. Our findings provide new insight into understanding the potential role of the gut virome and metabolites in depression.

Deficiency of astrocyte CysLT1R ameliorates depression-like behaviors in mice by modulating glutamate synaptic transmission

Our previous study suggests that hippocampal cysteinyl leukotriene receptor 1 (CysLT1R) could be involved in depression. Herein we hypothesize that CysLT1R may regulate depression by affecting synaptic glutamate cycling based on existence of CysLT1R in the astrocytes that participate in occurrence of depression. We found that CysLT1R expression was significantly increased in the astrocyte of chronic unpredictable mild stress (CUMS)-induced depression-like mice, CysLT1R astrocyte-specific conditional knockout (AcKO) significantly improved depression-like behaviors, as indicated by decreased immobility time in the forced swimming test and tail suspension test and increased sucrose preference in the sucrose preference test, and knockdown of CysLT1R in the astrocyte of dentate gyrus (DG), the region with the most significant increase of CysLT1R in the astrocyte of depression-like mice, produced similar effects. Correspondingly, overexpression of CysLT1R in the astrocyte of DG induced depression-like behaviors in mice. The further study showed that CysLT1R AcKO ameliorated synaptic plasticity impairment, as reflected by increased synapse, LTP and PSD95, and promoted glutamate transporter 1 (GLT-1) expression by inhibiting NF-κB p65 nuclear translocation mediated by β-arestin2 and clatrhin, subsequently decreased glutamate in synaptic cleft and GluN2B on postsynaptic membrane in depression-like mice. The present study also showed that GLT-1 agonist or NF-κB inhibitor ameliorated depressive-like behaviors induced by overexpression of the astrocyte CysLT1R of DG. Our study demonstrated that astrocyte CysLT1R regulated depression by modulating glutamate synaptic transmission, suggesting that CysLT1R could be a potential target for developing novel drugs of anti-depression.

Resveratrol alleviates postpartum depression-like behavior by activating autophagy via SIRT1 and inhibiting AKT/mTOR pathway

BackgroundPostpartum depression (PPD) causes maternal mortality, and has a high disability rate. In recent years, studies have suggested the Sirt1 gene to be involved in the pathogenesis of depression. Resveratrol (RSV), an activator of Sirt1, has been investigated in depressive behavior. However, its effect on PPD remains to be thoroughly elucidated. MethodsWe employed a mice model with bilateral oophorectomy combined with hormone-simulated pregnancy to assess postpartum depression-like behavior. The behavioral tests were performed 2 days after the withdrawal of estradiol benzoate. RSV was administered subcutaneously to the PPD model mice. Several behavioral tests were executed, including the open field test, forced swimming test, and tail suspension test. Western blot analyses and immunofluorescence staining were used to evaluate protein expression levels of SIRT1, autophagy markers, and the AKT/mTOR. ResultsPostpartum depressive-like behavior was triggered following the withdrawal of estradiol benzoate after hormone-stimulated-pregnancy. RSV improved postpartum depressive-like behavior of mice via its upregulation of the SIRT1 and autophagy markers, such as Beclin1, ATG5 and LC3B. Also, the downregulation of the p62 protein expression was observed. More importantly, we also detected the inhibition of phosphorylated AKT and mTOR in the hippocampus of postpartum depressive-like mice. ConclusionRSV could alleviate postpartum depression-like behavior in mice by stimulating the SIRT1, induce autophagy and inhibit the AKT/ mTOR signaling pathway.

Microglial NLRP3 inflammasome activates neurotoxic astrocytes in depression-like mice

The function and regulation of different heterogeneous reactive states of astrocytes in depression remain unclear. Here, we demonstrate that neurotoxic reactive (A1-like) astrocytes are strongly induced, prior to behavioral impairments and dendritic atrophy, in depression-like mice. More interestingly, global or microglia-specific knockout of Nod-like receptor protein 3 (Nlrp3) markedly mitigates A1-like astrocyte induction, whereas astrocyte-specific Nlrp3 depletion is ineffective. Microglial Nlrp3 ablation also alleviates the neuronal dysfunction induced by A1-like astrocytes both invitro and invivo. We further show that in microglia the NF-κB pathway activates the NLRP3 inflammasome which in turn activates caspase-1 to induce the secretion of A1 inductors, leading to the production of A1-like astrocytes. Altogether, this study reveals the function of microglial NLRP3 inflammasome in the induction of neurotoxic astrocytes via activating neuroinflammatory caspase-1 pathway in response to chronic stress and suggests a potential therapeutic strategy for depression.

Chronic unpredictable mild stress-induced mouse ovarian insufficiency by interrupting lipid homeostasis in the ovary.

Ovarian insufficiency results from a number of disorders, and a certain causal relationship between psychological stress and ovarian insufficiency has been reported, but the underlying mechanism remains unclear. In our study, C57BL/6J female mice were subjected to chronic unpredictable mild stress (CUMS), and depression-like mice were selected and identified according to the behavioral tests. The defective ovarian follicle development, low 17 β-estradiol (E2), and anti-Mullerian hormone (AMH) levels, which were consistent with the clinical characteristics of ovarian insufficiency, indicated that depression-like mice may be used to assess the effects of psychological stress on female reproductive function. To investigate a possible mechanism, lipid homeostasis of the ovary was detected by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis, and the decreased abundance of cholesteryl ester (CE 24:4) was supported to be associated with the downregulated E2. Moreover, granulosa cells did undergo more apoptosis in response to psychological stress, which was caused by downregulated Bcl2 and Bcl2/Bax in granulosa cells. Additionally, the disorder of cell death and growth-related pathways in depression-like mouse ovaries was confirmed by RNA-seq analysis. Taken together, this study will provide a better understanding of the female reproductive problem under psychological stress.

SIRT1/FOXO1 Axis-Mediated Hippocampal Angiogenesis is Involved in the Antidepressant Effect of Chaihu Shugan San.

ObjectiveChaihu Shugan San (CSS) has a long history for treating major depressive disorder (MDD), which has been verified effectively and safely in clinical studies. Deficient angiogenesis plays important roles in MDD. However, the underlying mechanisms of CSS on angiogenesis remain poorly understood.MethodsNetwork pharmacology analysis was applied to explore the potential angiogenic targets and pathways between CSS and MDD. These targets would be validated in chronic unpredictable mild stress (CUMS)-induced depressive-like mice by Western blots, immunofluorescence, and immunohistochemistry. Then, the underlying molecular mechanisms were further investigated in brain microvascular endothelial cells (BMVECs) with CSS-containing serum by Western blots and immunofluorescence.ResultsNetwork pharmacology analysis showed that the antidepressant role of CSS was closely associated with Silent information regulator protein 1 (SIRT1)/Forkhead box O1 (FOXO1) axis-mediated angiogenesis. This prediction was confirmed in the following experiments. CSS induced angiogenesis, increased SIRT1 expression, and decreased FOXO1 expression in the hippocampus of CUMS mice. Five percent CSS-containing serum produced a significant increase in BMVECs proliferation, migration, and tube formation, but these effects were reduced by SIRT1 silencing. CSS serum could also promote FOXO1 translocation to the cytoplasm through SIRT1 signaling, which triggered FOXO1 protein degradation. What is more, CSS upregulated VEGFA and BDNF expressions not only in the hippocampus of depressive mice but also in BMVECs supernatants. Of note, these trophic factors play important roles in promoting neurogenesis.ConclusionThe study showed that CSS could promote angiogenesis and neurogenesis in the hippocampus of CUMS-induced mice. The underlying molecular mechanism involves the SIRT1/FOXO1 axis and subsequent regulation of VEGFA and BDNF. These findings provide novel insight into CSS drug development, and targeting the SIRT1/FOXO1 axis might be a promising strategy to treat MDD.

Structural and functional characteristics of the hippocampus in depressive-like recipients after transplantation of in vitro caffeine-modulated immune cells

The hippocampus is a key anatomical brain region associated with depression. On the other hand, immune cells and their releasing cytokines play an essential role in stress and depression. Noteworthy that the most of psychoactive drugs produce unidirectional effects on the cells of both nervous and immune systems. This suggests the immunotherapy for behavioral disorders based on the treatment with autologous immune cells in which functional activity was modulated ex vivo by a psychoactive drug. Here, we treated the immune cells of depressive-like mice in vitro with caffeine (100 μg per 15 × 106 cells). The effects of caffeine-treated immune cells transplantation on neuronal density, production of brain-derived neurotrophic factor (BDNF) and a number of cytokines in the hippocampus of depressive-like syngeneic animals were studied. In depressive-like recipients, an increase in the density of pyramidal neurons in CA1 and CA3 hippocampal regions, accompanied with augmented level of BDNF, decreased levels of pro-inflammatory (IL-1β, IL-6, INF-γ, and TNF-α) and increased levels of anti-inflammatory (IL-10 and IL-4) cytokines was found. The mechanisms of the revealed structural and functional alterations in the hippocampus of depressive-like recipients after transplantation of caffeine-treated immune cells are discussed.

Ketamine triggers rapid antidepressant effects by modulating synaptic plasticity in a new depressive-like mouse model based on astrocyte glutamate transporter GLT-1 knockdown in infralimbic cortex

Recently, we reported on a new MDD-like mouse model based on a regionally selective knockdown of astroglial glutamate transporters, GLAST/GLT-1, in infralimbic cortex (IL) which evokes widespread changes in mouse brain associated with the typical alterations found in MDD patients. To further characterize this new MDD-like mouse model, here we examine some transcriptional elements of glutamatergic/GABAergic neurotransmission and neuroplasticity in forebrain regions in the GLT-1 knockdown mice. Furthermore, we assess the acute ketamine effects on these transcriptional processes. We used a small interfering RNA (siRNA) pool targeting GLT-1 mRNA to disrupt the GLT-1 transcription in mouse IL. Histological assays were performed to examine postsynaptic density protein-95 (PSD95), neuritin (NRN), glutamine acid descarboxilase-65 (GAD65), and GLT-1 mRNA expression in IL and hippocampus. Knockdown of GLT-1 in mouse IL leads to decreased expression of PSD95 and NRN neuroplasticity mRNAs in IL and hippocampus, which was reversed by an acute dose of ketamine antidepressant. Likewise, a single dose of ketamine also increased the mRNA levels of GAD65 and GLT-1 in IL of GLT-1 knockdown mice, reaching the basal values of control mice. The glutamatergic neuronal hyperactivity and deficits in the GABA system resulting from siRNA-induced astroglial glutamate transporter knockdown in IL can compromise the integrity/plasticity of neurocircuits affected in MDD. Suitable depressive-like animal models to address the neurobiological changes in MDD are an unmet need and the development of the GLAST/GLT-1 knockdown mouse model may represent a better option to understand the rapid-acting antidepressant effects of ketamine. Recientemente, informamos sobre un nuevo modelo de ratón de depresión basado en una reducción parcial de la transcripción de los transportadores de glutamato, GLAST/GLT-1, en los astrocitos de la corteza infralímbica (IL), que conduce a cambios generalizados de la función cerebral del ratón, que refleja alteraciones típicas encontradas en pacientes con depresión. Para caracterizar más detalladamente este nuevo modelo de ratón de depresión, aquí examinamos algunos elementos transcripcionales relacionados con la neurotransmisión glutamatérgica/GABAérgica y la neuroplasticidad en regiones corticales y subcorticales de los ratones con niveles reducidos de GLT-1. Además, evaluamos los efectos agudos de la ketamina, antidepresivo de acción rápida, en estos procesos transcripcionales. Utilizamos ARN de interferencia (siRNA) dirigido al mRNA de GLT-1 para interrumpir su transcripción en la IL de ratón. Se realizaron ensayos histológicos para examinar la expresión de los mRNA de las siguientes proteínas: proteína de densidad postsináptica-95 (PSD95), neuritina (NRN), descarboxilasa de ácido glutámico-65 (GAD65) y GLT-1 en la IL e hipocampo. La reducción de la expresión de GLT-1 en IL de ratón conduce a una disminución de la expresión de los mRNA de neuroplasticidad PSD95 y NRN en la IL y el hipocampo, efecto que se revirtió con una única administración del antidepresivo ketamina. Asimismo, una sola dosis de ketamina también aumentó los niveles de los mRNA de GAD65 y GLT-1 en la IL de ratones silenciados para GLT-1, que alcanzaron los valores basales de los ratones control. La hiperactividad neuronal glutamatérgica y los déficits en el sistema GABAérgico resultantes de la reducción de los niveles del transportador de glutamato astroglial inducida por siRNA en IL pueden comprometer la integridad/plasticidad de aquellos neurocircuitos afectados en la depresión. Sin embargo, no disponemos de modelos animales de depresión adecuados para abordar los cambios neurobiológicos que se suceden en esta enfermedad y su tratamiento. El desarrollo del modelo de ratón con reducción parcial de GLAST/GLT-1 puede representar una mejor opción para comprender los efectos antidepresivos de acción rápida de la ketamina.

Ketamine triggers rapid antidepressant effects by modulating synaptic plasticity in a new depressive-like mouse model based on astrocyte glutamate transporter GLT-1 knockdown in infralimbic cortex

ObjectiveRecently, we reported on a new MDD-like mouse model based on a regionally selective knockdown of astroglial glutamate transporters, GLAST/GLT-1, in infralimbic cortex (IL) which evokes widespread changes in mouse brain associated with the typical alterations found in MDD patients. To further characterize this new MDD-like mouse model, here we examine some transcriptional elements of glutamatergic/GABAergic neurotransmission and neuroplasticity in forebrain regions in the GLT-1 knockdown mice. Furthermore, we assess the acute ketamine effects on these transcriptional processes. Material and methodsWe used a small interfering RNA (siRNA) pool targeting GLT-1 mRNA to disrupt the GLT-1 transcription in mouse IL. Histological assays were performed to examine postsynaptic density protein-95 (PSD95), neuritin (NRN), glutamine acid descarboxilase-65 (GAD65), and GLT-1 mRNA expression in IL and hippocampus. ResultsKnockdown of GLT-1 in mouse IL leads to decreased expression of PSD95 and NRN neuroplasticity mRNAs in IL and hippocampus, which was reversed by an acute dose of ketamine antidepressant. Likewise, a single dose of ketamine also increased the mRNA levels of GAD65 and GLT-1 in IL of GLT-1 knockdown mice, reaching the basal values of control mice. ConclusionsThe glutamatergic neuronal hyperactivity and deficits in the GABA system resulting from siRNA-induced astroglial glutamate transporter knockdown in IL can compromise the integrity/plasticity of neurocircuits affected in MDD. Suitable depressive-like animal models to address the neurobiological changes in MDD are an unmet need and the development of the GLAST/GLT-1 knockdown mouse model may represent a better option to understand the rapid-acting antidepressant effects of ketamine.

Beneficial effects of Lactococcus lactis subsp. cremoris LL95 treatment in an LPS-induced depression-like model in mice

Clinical evidence suggests that neuroinflammation, activation of the immune system, and the composition of the intestinal microbiota are involved in the pathology of depression. This study evaluated the effectiveness of a probiotic intervention using Lactococcus lactis subsp. cremoris LL95 in ameliorating mood disorders in a lipopolysaccharide (LPS)-induced depression-like mouse model. C57BL/6 mice were randomly divided into four groups and treated with 5 mg/kg LPS via intraperitoneal injection to induce depression-like symptoms, followed by oral administration of LL95 for one week (1 × 109 CFU/mouse). The animals were then subjected to a series of behavioral assessments, including open field, sucrose preference, and forced swimming tests. In addition, we evaluated the levels of reactive oxygen species, tumor necrosis factor-α, and interleukin-1β in the hippocampal tissues of these animals, and also determined their fecal lactic acid bacteria (LAB) content. LL95 intervention improved LPS-induced depression-like behaviors in mice, including decreased sucrose preference and increased immobility time in the forced swim test. LL95 treatment reversed the LPS-induced increase in hippocampal levels of reactive oxygen species and tumor necrosis factor-α, and of interleukin-1β to a lesser extent. Furthermore, LL95 intervention increased the fecal LAB content in these animals, suggesting changes in the gut microbiota. These findings suggest that LL95 exerts antidepressant-like effects in LPS-induced depression, which may be attributed to modulation of the oxidative status and pro-inflammatory cytokine expression in the hippocampus and alteration in the LAB content of the gut microbiota.

Inhibition of Microglial NLRP3 with MCC950 Attenuates Microglial Morphology and NLRP3/Caspase-1/IL-1β Signaling In Stress-induced Mice.

Major depressive disorder is characterized by the deficiencies of monoamine neurotransmitters, neurotrophic factors and persistent neuroinflammation. Microglial activation has been associated with neuroinflammation-related mental diseases, accompanied by NLR family pyrin domain containing 3 (NLRP3) inflammasome. Here, we investigated the effect of NLRP3 inhibition by its small molecular inhibitor MCC950 on inflammatory activity and depressive-like mice induced by chronic unpredictable mild stress (CUMS), followed by the behavioral tests including sucrose preference test and forced swimming test. NLRP3/caspase-1/IL-1β signaling and microglial morphology in the prefrontal cortex were measured. The results showed that CUMS caused a decrease in sucrose preference and an increase in immobility time, which were reversed by NLRP3 inhibitor MCC950. In addition, NLRP3 inhibition decreased the number of microglia and changed the activated state of microglia to a resting state by morphology 3D reconstruction. Moreover, NLRP3 inhibition inactivated NLRP3/caspase-1/IL-1β signaling in the prefrontal cortex. The results from immunofluorescence demonstrated that NLRP3 and IL-1β expression was decreased in microglia in response to MCC950 treatment. Accordingly, proinflammatory cytokines were also decreased by NLRP3 inhibition. In conclusion, this study demonstrates that microglial NLRP3 inhibition prevents stress-induced neuroinflammation in the prefrontal cortex and suggests that microglial NLRP3 could be one of the potential therapeutic targets for depression treatment.

Effect of M2 Macrophage-Derived Soluble Factors on Behavioral Patterns and Cytokine Production in Various Brain Structures in Depression-Like Mice.

We studied the effect of soluble factors derived from human macrophages polarized to M2 phenotype under conditions of serum deprivation (M2-SF) on behavioral pattern and cytokine production in various brain structures in mice with modeled stress-induced depression. Intranasal administration of M2-SF for 7 days led to stimulation of locomotor and exploratory activities and a decrease in emotional reactivity in the open-field test as well as reduction in depression-like behavior in Porsolt forced swimming test and a decrease in anxiety and anhedonia. Correction of depression-like behavior was accompanied by down-regulation of proinflammatory cytokines (IL-1β, IL-6, TNFα, and IFNγ) in pathogenetically important brain structures (striatum, hippocampus, and frontal cortex). These data indicate that the antidepressant potential of M2 type macrophages can be mediated by the anti-inflammatory effects of M2-SF.

Preventive effect of a Kampo medicine, kososan, on recurrent depression in a mouse model of repeated social defeat stress.

Depression is deemed a mood disorder characterized by a high rate of relapse. Therefore, overcoming of the recurrent depression is globally expecting. Kososan, a traditional Japanese herbal medicine, has been clinically used for mild depressive mood, and our previous studies have shown some evidence for its antidepressive-like efficacy in experimental animal models of depression. However, it remains unclear whether kososan has beneficial effects on recurrent depression. Here, we examined its effect using a mouse model of modified repeated social defeat stress (SDS) paradigm. Male BALB/c mice were exposed to a 5-min SDS from unfamiliar aggressive CD-1 mice for 5days. Kososan extract (1.0kg/kg/day) or an antidepressant milnacipran (60mg/kg/day) was administered orally for 26days (days 7-32) to depression-like mice with social avoidant behaviors on day 6. Single 5min of SDS was subjected to mice recovered from the social avoidance on day 31, and then the recurrence of depression-like behaviors was evaluated on day 32. Hippocampal gene expression patterns were also assayed by DNA microarray analysis. Water- or milnacipran-administered mice resulted in a recurrence of depression-like behaviors by re-exposure of single SDS, whereas kososan-administered mice did not recur depression-like behaviors. Distinct gene expression patterns were also found for treating kososan and milnacipran. Collectively, this finding suggests that kososan exerts a preventive effect on recurrent depression-like behaviors in mice. Pretreatment of kososan is more useful for recurrent depression than that of milnacipran.

Ketamine ameliorates depressive-like behaviors in mice through increasing glucose uptake regulated by the ERK/GLUT3 signaling pathway

To investigate the effects of ketamine on glucose uptake and glucose transporter (GLUT) expression in depressive-like mice. After HA1800 cells were treated with ketamine, 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) was added to the cells to test the effects of ketamine on glucose uptake, production of lactate, and expression levels of GLUT, ERK1/2, AKT, and AMPK. Adult female C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS), 27 CUMS mice were randomly divided into the depression, ketamine (i.p.10 mg/kg), and FR180204 (ERK1/2 inhibitor, i.p.100 mg/kg) + ketamine group. Three mice randomly selected from each group were injected with 18F-FDG at 6 h after treatment. The brain tissue was collected at 6 h after treatment for p-ERK1/2 and GLUTs. Treatment with ketamine significantly increased glucose uptake, extracellular lactic-acid content, expression levels of GLUT3 and p-ERK in astrocytes and glucose uptake in the prefrontal cortex (P < 0.05), and the immobility time was significantly shortened in depressive-like mice (P < 0.01). An ERK1/2 inhibitor significantly inhibited ketamine-induced increases in the glucose uptake in depressive-like mice (P < 0.05), as well as prolonged the immobility time (P < 0.01). The expression levels of p-ERK1/2 and GLUT3 in depressive-like mice were significantly lower than those in normal control mice (P < 0.01). Ketamine treatment in depressive-like mice significantly increased the expression levels of p-ERK1/2 and GLUT3 in the prefrontal cortex (P < 0.01), whereas an ERK1/2 inhibitor significantly inhibited ketamine-induced increases (P < 0.01).Our present findings demonstrate that ketamine mitigated depressive-like behaviors in female mice by activating the ERK/GLUT3 signal pathway, which further increased glucose uptake in the prefrontal cortex.

Xiaoyaosan Exerts Antidepressant Effect by Downregulating RAGE Expression in Cingulate Gyrus of Depressive-Like Mice.

Xiaoyaosan (XYS), as a classic Chinese medicine compound, has been proven to have antidepressant effect in many studies, but its mechanism has not been clarified. In our previous studies, we found that chronic stress can induce depressive-like behavior and lead to emotion-related cingulate gyrus (Cg) dysfunction, as well as the decrease of neurotrophic factors and the increase of inflammatory-related proteins. Therefore, we speculated that XYS may play an antidepressant role by regulating the inflammation-related receptor of advanced glycation protein end product (RAGE) to affect the functional connectivity (FC) signal of the Cg and improve the depressive-like behavior. In order to verify this hypothesis, we analyzed the FC and RAGE expression in the Cg of depressive-like mice induced by chronic unpredictable mild stress (CUMS) and verified it with RAGE knockout mice. At the same time, we detected the effect of XYS on the depressive-like behavior, expression of RAGE, and the FC of the Cg of mice. The results showed that the FC of the Cg of depressive-like mice induced by CUMS was weakened, and the expression of RAGE was upregulated. The antidepressant effect of XYS is similar to that of fluoxetine hydrochloride, which can significantly reduce the depressive-like behavior of mice and inhibit the expression of the RAGE protein and mRNA in the Cg, and increase the FC of the Cg in mice. In conclusion, XYS may play an antidepressant role by downregulating the expression of RAGE in the Cg of depressive-like mice induced by CUMS, thereby affecting the functional signal and improving the depressive-like behavior.

Prospects for immunotherapy of depression based on cell technologies

IntroductionCell technologies actively used in the treatment of many diseases. These technologies are based on manipulating the patient’s cells outside the body, as a result of which cells acquire a higher therapeutic potential.ObjectivesNo doubt the essential role of immune cells and their biologically active products in the pathogenesis of depression, which allows to view the modulated immune cells as model objects for developing new approaches to immunotherapy for depression.Methods(CBAxC57Bl/6) F1 depressive-like male mice, developed under the long-term social stress, were undergoing the transplantation of syngeneic immune cells with in vitro caffeine-modulated functional activity. Recipient’s behavior, immune and nervous systems functional activity were studied.ResultsIt was found that immune cells isolated from depressive-like mice and treated in vitro with caffeine change their properties and after intravenous administration to syngeneic depressive-like recipients have a significant positive psycho- and neuroimmunomodulatory effects, affecting the main depression pathogenetic mechanisms: behavioral editing (reduction of anhedonia, stimulation of exploratory behavior and activity in the forced swimming test); hippocampal neurogenesis stimulation against the background of increased BDNF; modulation of cytokine production by brain cells, indicating a decrease in neuroinflammation; modulation of the immune system functional activity (stimulation of the immune response, splenocytes proliferation, reducing systemic inflammation, decrease spleen tryptophan catabolism).ConclusionsThe results serve as an experimental substantiation of a fundamentally new approach to immunotherapy of depression based on the introduction of immune cells with functional activity modulated outside the body and open up the possibility of developing new methods of immunotherapy of depressive states in humans.DisclosureNo significant relationships.

Chinese Medicine Formula Kai-Xin-San Ameliorates Neuronal Inflammation of CUMS-Induced Depression-like Mice and Reduces the Expressions of Inflammatory Factors via Inhibiting TLR4/IKK/NF-κB Pathways on BV2 Cells.

Kai-Xin-San (KXS) is a traditional Chinese medicinal formula composed of Ginseng Radix et Rhizoma, Polygalae Radix, Acori Tatarinowii Rhizoma, and Poria for relieving major depressive disorder and Alzheimer’s disease in traditional Chinese medicine (TCM) clinics. Previous studies on the antidepressant mechanism of KXS mainly focused on neurotransmitter and neurotrophic factor regulation, but few reports exist on neuronal inflammation regulation. In the current study, we found that KXS exerted antidepressant effects in chronic unpredictable mild stress-induced depression-like mice according to the results of behavioral tests. Meanwhile, KXS also inhibited the activation of microglia and significantly reduced the expression of pro-inflammatory cytokines such as IL-1β, IL−2, and TNF-α in the hippocampus of mice. In mice BV2 microglia cell lines, KXS extract reduced the expression of inflammatory factors in BV2 cells induced by lipopolysaccharide via inhibiting TLR4/IKK/NF-κB pathways, which was also validated by the treatment of signaling pathway inhibitors such as TAK-242 and JSH-23. T0hese data implied that the regulation of pro-inflammatory cytokines in microglia might account for the antidepressant effect of KXS, thereby providing more scientific information for the development of KXS as an alternative therapy for major depressive disorder.

Chronic ethanol exposure induced depressive-like behavior in male C57BL/6 N mice by downregulating GluA1

Chronic ethanol exposure can increase the risk of depression. The α-amino-3‑hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor is a key factor in depression and its treatment. The study was conducted to investigate the depressive-like behavior induced by chronic ethanol exposure in mice and to explore the mechanism in cells. To establish the chronic ethanol exposure mouse model, male C57BL/6 N mice were administered 10% (m/V) and 20% (m/V) ethanol as the only choice for drinking for 60 days, 90 days and 180 days. Depressive-like behavior in mice was confirmed by the forced swimming test (FST). Ethanol-induced changes in the mouse hippocampus were indicated by Western blotting, qPCR and Fluoro-Jade C (FJC) staining. We confirmed that 90- and 180-day ethanol exposure can lead to depressive-like mouse behavior, cell apoptosis, neuronal degeneration, a reduction in GluA1 and brain-derived neurotrophic factor (BDNF) expression, and an increase in IL-6 and IL-1β in the mouse hippocampus. GluA1 silencing and overexpression models of SH-SY5Y cells were established for further investigation. The cells were treated with 100 mM and 200 mM ethanol for 24 h. Ethanol exposure decreased cell viability and the expression of BDNF and increased the cell apoptosis rate and the expression of BAX, cleaved caspase-3, IL-1β and IL-6. GluA1 silencing aggravated ethanol-induced changes in cell viability and apoptosis and the expression of BDNF, BAX and cleaved caspase-3, and GluA1 overexpression attenuated these changes. Neither the silencing nor overexpression of GluA1 had an effect on ethanol-induced increases in IL-1β and IL-6. Our results indicated that chronic ethanol exposure induced depressive-like behavior in male C57BL/6 N mice by downregulating GluA1 expression.

Opioid System Contributes to the Trifluoromethyl-Substituted Diselenide Effectiveness in a Lifestyle-Induced Depression Mouse Model.

Energy-dense foods and ethanol consumption are associated with mood disorders. m-Trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] has been a prominent pharmacological target due to its antidepressant-like effects. This study investigated if the modulation of opioid and glucocorticoid receptors and its well-known antioxidant property contribute to the (m-CF3-PhSe)2 antidepressant-like effect in young mice subjected to an energy-dense diet and ethanol intake. Swiss male mice [postnatal day (PND) 25] were exposed to an energy-dense diet (containing 20% fat and 20% carbohydrate) or standard chow until the PND 67. Mice received ethanol (2g/kg) or water administration (3 times a week, intragastrically [i.g.]) from PND 45 to PND 60. After that, mice received (m-CF3-PhSe)2 (5mg/kg/day; i.g) or vegetal oil administration from PND 60 to 66. Mice performed the behavioral tests to evaluate the depressive-like phenotype. The results showed that individually neither an energy-dense diet nor ethanol group induced a depressive-like phenotype, but the association of both induced this phenotype in young mice. Oxidative stress was characterized by the increase of malondialdehyde, the decrease in the superoxide dismutase activity, and non-protein sulfhydryl levels in the cerebral cortex of depressive-like mice. Depressive-like mice showed an increase in the protein levels of opioid receptors and depletion in those of glucocorticoid. (m-CF3-PhSe)2 abolished depressive-like phenotype and oxidative stress as well as modulated the levels of glucocorticoid and opioid receptors. In conclusion, the modulation of opioid and glucocorticoid receptors and the antioxidant property contributed to the (m-CF3-PhSe)2 antidepressant-like effect in young mice exposed to an energy-dense diet and ethanol intake.