Depression-like Behavior In Mice Research Articles

Ganoderic acid A ameliorates depressive-like behaviors in CSDS mice: Insights from proteomic profiling and molecular mechanisms

ObjectiveGanoderic Acid A (GAA), a primary bioactive component in Ganoderma, has demonstrated ameliorative effects on depressive-like behaviors in a Chronic Social Defeat Stress (CSDS) mouse model. This study aims to elucidate the underlying molecular mechanisms through proteomic analysis. MethodsC57BL/6 J mice were allocated into control (CON), chronic social defeat stress (CSDS), GAA, and imipramine (IMI) groups. Post-depression induction via CSDS, the GAA and IMI groups received respective treatments of GAA (2.5 mg/kg) and imipramine (10 mg/kg) for five days. Behavioral assessments utilized standardized tests. Proteins from the prefrontal cortex were analyzed using LC-MS, with further examination via bioinformatics and PRM for differential expression. Western blot analysis confirmed protein expression levels. ResultsChronic social defeat stress (CSDS) induced depressive-like behaviors in mice, which were significantly alleviated by GAA treatment, comparably to imipramine (IMI). Proteomic analysis identified distinct proteins in control (305), GAA-treated (949), and IMI-treated (289) groups. Enrichment in mitochondrial and synaptic proteins was evident from GO and PPI analyses. PRM analysis revealed significant expression changes in proteins crucial for mitochondrial and synaptic functions (namely, Naa30, Bnip1, Tubgcp4, Atxn3, Carmil1, Nup37, Apoh, Mrpl42, Tprkb, Acbd5, Dcx, Erbb4, Ppp1r2, Fam3c, Rnf112, and Cep41). Western blot validation in the prefrontal cortex showed increased levels of Mrpl42, Dcx, Fam3c, Ppp1r2, Rnf112, and Naa30 following GAA treatment. ConclusionGAA exhibits potential antidepressant properties, with its action potentially tied to the modulation of synaptic functions and mitochondrial activities.

TNF-α/TNFR1 activated astrocytes exacerbate depression-like behavior in CUMS mice

Neuroinflammation is considered to be a significant mechanism contributing to depression. Several studies have reported that A1 astrocytes were highly prevalent in human neuroinflammatory and neurodegenerative diseases. However, the precise mechanism by which A1 astrocytes contribute to depression remains unclear. Clinical studies have suggested a correlation between TNF-α, an activator of A1 astrocytes, and the severity of depression. Based on these findings, we hypothesized that TNF-α might worsen depression by activating A1 astrocytes. Our previous studies indicated that Rhodomyrtone (Rho) has the potential to improve depression-like behavior in mice. However, the exact mechanism for this effect has not been fully elucidated. Importantly, it was reported that Rho alleviated skin inflammation in a mouse model of psoriasis by inhibiting the expression of TNF-α. Based on this finding, we hypothesized that rhodomyrtone may exert antidepressant effects by modulating the TNF-α pathway. However, further research is required to investigate and validate these hypotheses, shedding light on the relationships between neuroinflammation, A1 astrocytes, TNF-α, and depression. By obtaining a deeper understanding of the underlying mechanisms, these findings could lead to the development of novel antidepressant strategies that target the TNF-α pathway in the context of neuroinflammation. In vivo, based on the established chronic unpredictable mild stress (CUMS) mouse depression model, we characterized the mechanism of TNF-α and Rho during depression by using several behavioral assays, adeno-associated virus(AAV) transfection, western blotting, immunofluorescence, and other experimental methods. In vitro, we characterized the effect of Rho on inflammation in TNF-α-treated primary astrocytes. TNFR1 expression was significantly increased in the hippocampus of depression-like mice, with increased astrocytes activation and neuronal apoptosis. These processes were further enhanced with increasing levels of TNF-α in the cerebrospinal fluid of mice. However, this process was attenuated by knockdown of TNFR1 and infliximab (Inf; a TNF-α antagonist). Injection of rhodomyrtone decreased the expressions of TNFR1 and TNF-α, resulting in significant improvements in mouse depression-like behaviors and reduction of astrocyte activation. TNF-α could be involved in the pathophysiological process of depression, through mediating astrocytes activation by binding to TNFR1. By blocking this pathway, Rho may be a novel antidepressant.

Prophylactic Effects of n-Acethylcysteine on Inflammation-induced Depression-like Behaviors in Mice

Depression, affecting individuals worldwide, is a prevalent mental disease, with an increasing incidence. Numerous studies have been conducted on depression, yet its pathogenesis remains elusive. Recent advancements in research indicate that disturbances in synaptic transmission, synaptic plasticity, and reduced neurotrophic factor expression significantly contribute to depression's pathogenesis. In our study, we utilized adult male C57BL/6J mice. Lipopolysaccharide (LPS) can induce both chronic and acute depression-like symptoms in mice, a widely used model for studying depression associated with inflammation. N-acetylcysteine (NAC) exhibits anti-inflammatory and ameliorative effects on depressive symptoms. This study sought to determine whether NAC use could mitigate inflammatory depressive behavior through the enhancement of synaptic transmission, synaptic plasticity, and increasing levels of brain-derived neurotrophic factor (BDNF). In this study, we discovered that in mice modeled with depression-like symptoms, the expression levels of dendrites, BDNF, and miniature excitatory postsynaptic potential (mEPSC) in glutamatergic neurons, as well as the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors (AMPARs) GluA1 and GluA2 subunits, were significantly decreased. These findings suggest an impairment in the synaptic transmission of glutamatergic neurons. Following treatment with NAC, the previously mentioned levels improved, indicating an enhancement in both synaptic transmission and synaptic plasticity. Our results suggest that NAC exerts a protective effect on mouse models of inflammatory depression, potentially through the enhancement of synaptic transmission and plasticity, as well as the restoration of neurotrophic factor expression. These findings offer vital animal experimental evidence supporting NAC's role in mitigating inflammatory depressive behaviors.

Targeting the postsynaptic scaffolding protein PSD-95 enhances BDNF signaling to mitigate depression-like behaviors in mice.

Signaling mediated by brain-derived neurotrophic factor (BDNF), which is supported by the postsynaptic scaffolding protein PSD-95, has antidepressant effects. Conversely, clinical depression is associated with reduced BDNF signaling. We found that peptidomimetic compounds that bind to PSD-95 promoted signaling by the BDNF receptor TrkB in the hippocampus and reduced depression-like behaviors in mice. The compounds CN2097 and Syn3 both bind to the PDZ3 domain of PSD-95, and Syn3 also binds to an α-helical region of the protein. Syn3 reduced depression-like behaviors in two mouse models of stress-induced depression; CN2097 had similar but less potent effects. In hippocampal neurons, application of Syn3 enhanced the formation of TrkB-Gαi1/3-PSD-95 complexes and potentiated downstream PI3K-Akt-mTOR signaling. In mice subjected to chronic mild stress (CMS), systemic administration of Syn3 reversed the CMS-induced, depression-associated changes in PI3K-Akt-mTOR signaling, dendrite complexity, spine density, and autophagy in the hippocampus and reduced depression-like behaviors. Knocking out Gαi1/3 in hippocampal neurons prevented the therapeutic effects of Syn3, indicating dependence of these effects on the TrkB pathway. The findings suggest that compounds that induce the formation of PSD-95-TrkB complexes have therapeutic potential to alleviate depression.

Catechin Protects against Lipopolysaccharide-induced Depressive-like Behaviour in Mice by Regulating Neuronal and Inflammatory Genes

Background: Many studies have suggested that tea has antidepressant effects; however, the underlying mechanism is not fully studied. As the main anti-inflammatory polyphenol in tea, catechin may contribute to the protective role of tea against depression. background: Many studies have suggested that tea has antidepressant effects; however, the underlying mechanism is not fully studied. As the main anti-inflammatory polyphenol in tea, catechin may contribute to the protective role of tea against depression. Objective: The objective of this study is to prove that catechin can protect against lipopolysaccharide (LPS)-induced depressive-like behaviours in mice, and then explore the underlying molecular mechanisms. objective: The objective of this study is to prove that catechin can protect against lipopolysaccharide (LPS)-induced depressive-like behaviours in mice, and then explore the underlying molecular mechanisms. Method: Thirty-one C57BL/6J mice were categorized into the normal saline (NS) group, LPS group, catechin group, and amitriptyline group according to their treatments. Elevated Plus Maze (EPM), Tail Suspension Test (TST), and Open Field Test (OFT) were employed to assess depressive- like behaviours in mice. RNA sequencing (RNA-seq) and subsequent Bioinformatics analyses, such as differential gene analysis and functional enrichment, were performed on the four mouse groups. method: Thirty-one C57BL/6J mice were categorized into normal saline (NS) group, LPS group, catechin group, and amitriptyline group according to their treatments. Elevated Plus Maze (EPM), Tail Suspension Test (TST), and Open Field Test (OFT) were employed to assess depressive-like behaviours in mice. RNA sequencing (RNA-seq) and subsequent Bioinformatics analyses, such as differential gene analysis and functional enrichment, were performed on the four mouse groups. Results: In TST, the mice in the LPS group exhibited significantly longer immobility time than those in the other three groups, while the immobility times for the other three groups were not significantly different. Similarly in EPM, LPS-treated mice exhibited a significantly lower percentage in the time/path of entering open arms than the mice in the other three groups, while the percentages of the mice in the other three groups were not significantly different. In OFT, LPS-treated mice exhibited significantly lower percentages in the time/path of entering the centre area than those in the other three groups. The results suggested that the LPS-induced depression models were established successfully and catechin can reverse (LPS)-induced depressive-like behaviours in mice. Finally, RNA-seq analyses revealed 57 differential expressed genes (DEGs) between LPS and NS with 19 up-regulated and 38 down-regulated. Among them, 13 genes were overlapped with the DEGs between LPS and cetechin (in opposite directions), with an overlapping p-value < 0.001. The 13 genes included Rnu7, Lcn2, C4b, Saa3, Pglyrp1, Gpx3, Lyz2, S100a8, S100a9, Tmem254b, Gm14288, Hbb-bt, and Tmem254c, which might play key roles in the protection of catechin against LPS-induced depressive-like behaviours in mice. The 13 genes were significantly enriched in defense response and inflammatory response, indicating that catechin might work through counteracting changes in the immune system induced by LPS. Conclusion: Catechin can protect mice from LPS-induced depressive-like behaviours through affecting inflammatory pathways and neuron-associated gene ontologies.

Tao-Hong-Si-Wu-Tang Improves the Depressive-like Behaviors in Mice Experiencing Perimenopausal Depression Through Modulating Activity of the Hypothalamic-Pituitary-Adrenal-Ovary Axis and Activating the BDNF-TrkB-CREB Signaling Pathway.

Tao-Hong-Si-Wu-Tang (THSWT), a traditional Chinese herbal remedy, is commonly utilized for the treatment of female perimenopausal depression through regulating menstruation, but the mechanism remains unknown. In this study, ICR mice were randomly divided into six groups: low, medium, and high dose of THSWT (0.5, 1.5, and 4.5 g/kg), soy isoflavone (250 mg/kg), ovariectomy group, and control group. All mice, except the control group, had ovaries removed and were exposed to hypoxic stimulation for 28 days to establish a perimenopausal depression mice model. The mice, having unrestricted access to food and water, were administered THSWT treatment for a duration of 14 days. The Western blotting and Enzyme linked immunosorbent assay kits were used to determine protein and hormone levels, respectively. Experimental results showed that THSWT reduced the immobility time of mice from 150.8 s to 104.9 s in the tail suspension test, and it decreased the immobility time of mice from 165.7 s to 119.0 s in the forced swimming test, outperforming the results obtained with soy isoflavones. In addition, THSWT upregulated the protein expression of follicle-stimulating hormone receptor and downregulated the protein expression of corticotropin-releasing hormone-receptor 1 in the hippocampus. Compared with the oophorectomized group, treatment with THSWT decreased the levels of corticosterone and adrenocorticotropic hormone in serum by 173.7 and 23.4 ng/mL, respectively. These findings showed that THSWT could stimulate the perimenopausal nerve tissue and regulate the level of serum hormones in mice. THSWT exhibited promising potential as a viable alternative drug for hormone treatment of perimenopause in clinical use.

GPR55 activation improves anxiety- and depression-like behaviors of mice during methamphetamine withdrawal

Methamphetamine is a potent and highly addictive neurotoxic psychostimulant that triggers a spectrum of adverse emotional responses during withdrawal. G-protein coupled receptor 55 (GPR55), a novel endocannabinoid receptor, is closely associated with mood regulation. Herein, we developed a murine model of methamphetamine-induced anxiety- and depressive-like behavior during abstinence which showed a decreased GPR55 expression in the hippocampus. Activation of GPR55 mitigated these behavioral symptoms, concomitantly ameliorating impairments in hippocampal neurogenesis and reducing neuroinflammation. These findings underscore the pivotal role of GPR55 in mediating the neuropsychological consequences of methamphetamine withdrawal, potentially via mechanisms involving the modulation of hippocampal neurogenesis and inflammation.

Immunization with a low dose of zymosan A confers resistance to depression-like behavior and neuroinflammatory responses in chronically stressed mice.

Stimulation of the innate immune system prior to stress exposure is a possible strategy to prevent depression under stressful conditions. Based on the innate immune system stimulating activities of zymosan A, we hypothesize that zymosan A may prevent the development of chronic stress-induced depression-like behavior. Our results showed that a single injection of zymosan A 1 day before stress exposure at a dose of 2 or 4 mg/kg, but not at a dose of 1 mg/kg, prevented the development of depression-like behaviors in mice treated with chronic social defeat stress (CSDS). The prophylactic effect of a single zymosan A injection (2 mg/kg) on CSDS-induced depression-like behaviors disappeared when the time interval between zymosan A and stress exposure was extended from 1 day or 5 days to 10 days, which was rescued by a second zymosan A injection 10 days after the first zymosan A injection and 4 days (4×, once daily) of zymosan A injections 10 days before stress exposure. Further analysis showed that a single zymosan A injection (2 mg/kg) 1 day before stress exposure could prevent the CSDS-induced increase in pro-inflammatory cytokines in the hippocampus and prefrontal cortex. Inhibition of the innate immune system by pretreatment with minocycline (40 mg/kg) abolished the preventive effect of zymosan A on CSDS-induced depression-like behaviors and CSDS-induced increase in pro-inflammatory cytokines in the brain. These results suggest that activation of the innate immune system triggered by zymosan A prevents the depression-like behaviors and neuroinflammatory responses in the brain induced by chronic stress.

Atractylodin ameliorates lipopolysaccharide-induced depressive-like behaviors in mice through reducing neuroinflammation and neuronal damage

Depression is a psychiatric disorder associated with multiple factors including microglia-mediated neuroinflammation. Although atractylodin exerted a variety of biological activities, however the effect of atractylodin on neuroinflammation-related depression was still unclear. In this study, the lipopolysaccharide (LPS)-induced mouse model was used to explore the antidepressant effects and molecular mechanisms of atractylodin. The results showed that atractylodin increased sugar preference, also reduced immobility time in FST and TST. Further study showed atractylodin reduced the oxidative stress and the activation of microglia in mouse hippocampus, also inhibited the level of cytokine release, especially IL-1β. The results of western blotting showed that atractylodin significantly inhibited the expression of NLRP3 and pro-IL1β via inhibition of NF-κB pathway. Our studies showed that atractylodin upregulated BDNF/Akt pathway in mouse hippocampus. Therefore, this study firstly indicated that atractylodin can ameliorate lipopolysaccharide-induced depressive-like behaviors in mice through reducing neuroinflammation and neuronal damage, and its molecular mechanism may be associated with the decrease of the expression of NLRP3 inflammasome and upregulation of BDNF/Akt pathway.

Investigating the synergistic effects of amitriptyline and H. pylori eradication on depressive-like behaviors and inflammatory cytokines in mice

BackgroundRecent research has highlighted the potential role of Helicobacter pylori in the pathogenesis of psychiatric disorders. This study aimed to evaluate the potential synergistic effects of an antidepressant drug and H. pylori eradication therapy in a mouse model. MethodsMale C57BL/6 mice were divided into four groups: control, H. pylori infection, antidepressant treatment, and combined treatment. H. pylori infection was induced by oral gavage with a clinically relevant strain, and the antidepressant drug was administered via intraperitoneal injections. Behavioral tests including the forced swim test, sucrose preference test, and open field test were conducted to assess depressive-like behaviors and locomotor activity. ResultsThe study demonstrated that H. pylori infection induced depressive-like behaviors in mice, as evidenced by increased immobility time in the forced swim test and reduced sucrose preference. Antidepressant treatment alone partially ameliorated these behavioral changes. Strikingly, the combined treatment of the antidepressant drug and H. pylori eradication therapy led to a significantly greater reduction in depressive-like behaviors compared to either treatment alone. Furthermore, the combined treatment group exhibited increased locomotor activity in the open field test, suggesting a potential improvement in overall psychomotor functioning. ELISA assays revealed alterations in inflammatory cytokines in the H. pylori-infected mice, which were partially attenuated by the combined treatment. ConclusionThe study provides novel evidence for the potential synergistic effects of an antidepressant drug and H. pylori eradication therapy in alleviating depressive-like behaviors in a mouse model.

Protective Effect of Hop Ethyl Acetate Extract on Corticosterone-Induced PC12 and Improvement of Depression-like Behavior in Mice.

Depression is a common mental disorder. In recent years, more and more attention has been paid to depression and its etiology and pathogenesis. This review aims to explore the neuroprotective and antidepressant effects of hop components. By establishing an in vitro cell damage model using PC12 cells induced by corticosterone (CORT) and an in vivo depression model through the intracranial injection of lipopolysaccharide (LPS) in mice, hop ethyl acetate extract (HEA) was used to study the protective effect and mechanism of HEA on neuronal cells in vitro and the antidepression effect and mechanism in vivo. The results showed that HEA increased the survival and decreased the rate of lactate dehydrogenase (LDH) release, apoptosis, and the ROS and NO content of CORT-induced PC12 cells. HEA alleviated depressive-like behavior, neuroinflammation, reduction of norepinephrine, and dendritic spines induced by intracerebroventricular injection of LPS in mice and increases the expression levels of BDNF, SNAP 25, and TrkB proteins without any significant side effects or toxicity. Hops demonstrated significant comprehensive utilization value, and this work provided an experimental basis for the role of hops in the treatment of depression and provided a basis for the development of HEA for antidepressant drugs or dietary therapy products.

Quercetin and Kaempferol inhibit HMC-1 activation via SOCE/NFATc2 signaling and suppress hippocampal mast cell activation in lipopolysaccharide-induced depressive mice.

Mast cells (MCs), as the fastest immune responders, play a critical role in the progression of neuroinflammation-related diseases, especially in depression. Quercetin (Que) and kaempferol (Kae), as two major diet-derived flavonoids, inhibit MC activation and exhibit significant antidepressant effect due to their anti-inflammatory capacity. The study aimed to explore the mechanisms of inhibitory effect of Que and Kae on MC activation, and whether Que and Kae suppress hippocampal mast cell activation in LPS-induced depressive mice. In vitro assays, human mast cells (HMC-1) were pretreated with Que or Kae for 1h, then stimulated by phorbol 12-myristate 13-acetate (PMA) and 2,5-di-t-butyl-1,4-benzohydroquinone (tBHQ) for 3h or 12h. In vivo assays, Que or Kae was administered by oral gavage once daily for 14days and then lipopolysaccharide (LPS) intraperitoneally injection to induce depressive behaviors. The secretion and expression of TNF-α were determined by ELISA and Western blotting. The nuclear factor of activated T cells (NFAT) transcriptional activity was measured in HMC-1 stably expressing NFAT luciferase reporter gene. Nuclear translocation of NFATc2 was detected by nuclear protein extraction and also was fluorescently detected in HMC-1 stably expressing eGFP-NFATc2. We used Ca2+ imaging to evaluate changes of store-operated calcium entry (SOCE) in HMC-1 stably expressing fluorescent Ca2+ indicator jGCamP7s. Molecular docking was used to assess interaction between the Que or Kae and calcium release-activated calcium modulator (ORAI). The hippocampal mast cell accumulation and activation were detected by toluidine blue staining and immunohistochemistry with β-tryptase. In vitro assays of HMC-1 activated by PtBHQ (PMA and tBHQ), Que and Kae significantly decreased expression and secretion of TNF-α. Moreover, NFAT transcriptional activity and nuclear translocation of NFATc2 were remarkably inhibited by Que and Kae. In addition, the Ca2+ influx mediated by SOCE was suppressed by Que, Kae and the YM58483 (ORAI inhibitor), respectively. Importantly, the combination of YM58483 with Que or Kae had no additive effect on the inhibition of SOCE. The molecular docking also showed that Que and Kae both exhibit high binding affinities with ORAI at the same binding site as YM58483. In vivo assays, Que and Kae significantly reversed LPS-induced depression-like behaviors in mice, and inhibited hippocampal mast cellactivation in LPS-induced depressive mice. Our results indicated that suppression of SOCE/NFATc2 pathway-mediated by ORAI channels may be the mechanism of inhibitory effect of Que and Kae on MC activation, and also suggested Que and Kae may exert the antidepressant effect through suppressing hippocampal mast cell activation.

Effects of autotaxin and lysophosphatidic acid deficiencies on depression-like behaviors in mice exposed to chronic unpredictable mild stress

The involvement of lipids in the mechanism of depression has triggered extensive discussions. Earlier studies have identified diminished levels of lysophosphatidic acid (LPA) and autotaxin (ATX) in individuals experiencing depression. However, the exact significance of this phenomenon in relation to depression remains inconclusive. This study seeks to explore the deeper implications of these observations. We assessed alterations in ATX and LPA in both the control group and the chronic unpredictable mild stress (CUMS) model group. Additionally, the impact of ATX adeno-associated virus (AAV-ATX) injection into the hippocampus was validated through behavioral tests in CUMS-exposed mice. Furthermore, we probed the effects of LPA on synapse-associated proteins both in HT22 cells and within the mouse hippocampus. The mechanisms underpinning the LPA-triggered shifts in protein expression were further scrutinized. Hippocampal tissues were augmented with ATX to assess its potential to alleviate depression-like behavior by modulating synaptic-related proteins. Our findings suggest that the decrement in ATX and LPA levels alters the expression of proteins associated with synaptic plasticity in vitro and in vivo, such as synapsin-I (SYN), synaptophysin (SYP), and brain-derived neurotrophic factor (BDNF). Moreover, we discerned a role for the ERK/CREB signaling pathway in mediating the effects of ATX and LPA. Importantly, strategic supplementation of ATX effectively mitigated depression-like behaviors. This study indicates that the ATX-LPA pathway may influence depression-like behaviors by modulating synaptic plasticity in the brains of CUMS-exposed mice. These insights augment our understanding of depression's potential pathogenic mechanism in the context of lipid metabolism and propose promising therapeutic strategies for ameliorating the disease.

SorCS2 is involved in promoting periodontitis-induced depression-like behaviour in mice.

Emerging evidence supports the association between periodontitis and depression, although the mechanisms are unclear. This study investigated the role of SorCS2 in the pathogenesis of periodontitis-induced depression. An experimental periodontitis model was established using SorCS2 knockout mice and their wild-type littermates, and depression-like behaviour was evaluated. The expression of proBDNF signalling, neuronal activity, and glutamate-associated signalling pathways were further measured by western blotting and immunofluorescence. In addition, neuroinflammatory status, astrocytic and microglial markers, and the expression of corticosterone-related factors were measured by immunofluorescence, western blotting, and enzyme-linked immunosorbent assays. SorCS2 deficiency alleviated periodontitis-induced depression-like behaviour in mice. Further results suggested that SorCS2 deficiency downregulated the expression of pro-BDNF and glutamate signalling and restored neuronal activities in mice with periodontitis. Neuroinflammation in the mouse hippocampus was triggered by experimental periodontitis but was not affected by SorCS2 deficiency. The levels of corticosterone and the expression of glucocorticoid receptors were also not altered. Our study, for the first time, reveals the critical role of SorCS2 in the pathogenesis of periodontitis-induced depression. The underlying mechanism involves proBDNF and glutamate signalling in the hippocampus, providing a novel therapeutic target for periodontitis-associated depression.

Antidepressant effect of teriflunomide via oligodendrocyte protection in a mouse model

Addressing the treatment of depression is crucial; nevertheless, the etiology and pathogenesis remain unelucidated. Therefore, this study investigated the effects of teriflunomide (TF) on corticosterone (CORT)-induced depression-like behaviors in mice. Notably, TF administration resulted in a substantial amelioration of anxiety and depression-like behaviors observed in CORT-treated mice. This was evidenced by behavioral assessments conducted via the sucrose preference test (SPT), open-field test (OFT), novelty-suppressed feeding test (NSFT), forced swimming test (FST), and tail suspension test (TST). The administration of CORT inflicts damage upon oligodendrocytes and neurons within the hippocampus. Our findings indicate that TF offers significant protective effects on oligodendrocytes, mitigating apoptosis both in vivo and in vitro. Additionally, TF was found to counteract the CORT-induced neuronal loss and synaptic damage, as demonstrated by an increase in Nissl-positive cells across hippocampal regions CA1, CA3, and the dentate gyrus (DG) alongside elevated levels of synapse-related proteins including PSD-95 and synaptophysin. Additionally, TF treatment facilitated a reduction in the levels of apoptosis-related proteins while simultaneously augmenting the levels of Bcl2. Our findings indicate that TF administration effectively mitigates CORT-induced depression-like behaviors and reverses damage to oligodendrocytes and neurons in the hippocampus, suggesting TF as a promising candidate for depression.

Dorsal dentate gyrus mediated enriched environment-induced anxiolytic and antidepressant effects in cortical infarcted mice

Anxiety and depression are the most common mental health disorders worldwide, each affecting around 30% stroke survivors. These complications not only affect the functional recovery and quality of life in stroke patients, but also are distressing for caregivers. However, effective treatments are still lacking. Enriched environment (EE), characterized with novel and multi-dimensional stimulation, has been reported to exert therapeutic effects on physical and cognitive function. In addition, EE also had potential positive effects on emotional disorders after ischemic stroke; however, the underling mechanisms have not been well elucidated. This study aimed to explore the effectiveness of EE on emotional disorders after cerebral ischemia and its underling mechanism. In this study, sensorimotor cortical infarction was induced by photothrombosis with stable infarct location and volume, resulting in motor dysfunction, anxiety and depression-like behaviors in mice, with decreased ALFF and ReHo values and decreased c-fos expression in the infarction area and adjacent regions. Seven days' EE treatment significantly improved motor function of contralateral forelimb and exhibited anxiolytic and antidepressant effects in infarcted mice. Compared to the mice housing in a standard environment, those subjected to acute EE stimulation had significantly increased ALFF and ReHo values in the bilateral somatosensory cortex (S1, S2), dorsal dentate gyrus (dDG), dorsal CA1 of hippocampus (dCA1), lateral habenular nucleus (LHb), periaqueductal gray (PAG), ipsilateral primary motor cortex (M1), retrosplenial cortex (RSC), parietal association cortex (PtA), dorsal CA3 of hippocampus (dCA3), claustrum (Cl), ventral pallidum (VP), amygdala (Amy), and contralateral auditory cortex (Au). Some of, but not all, the ipsilateral brain regions mentioned above showed accompanying increases in c-fos expression with the most significant changes in the dDG. The number of FosB positive cells in the dDG, decreased in infarcted mice, was significantly increased after chronic EE treatment. Chemogenetic activation of dDG neurons reduced anxiety and depressive-like behaviors in infarcted mice, while neuronal inhibition resulted in void of the anxiolytic and antidepressant effects of EE. Altogether, these findings indicated that dDG neurons may mediate EE-triggered anxiolytic and antidepressant effects in cortical infarcted mice.

Effects of sleep deprivation on anxiety-depressive-like behavior and neuroinflammation

BackgroundDepression is defined by a persistent low mood and disruptions in sleep patterns, with the WHO forecasting that major depression will rank as the third most prevalent contributor to the global burden of disease by the year 2030. Sleep deprivation serves as a stressor that triggers inflammation within the central nervous system, a process known as neuroinflammation. This inflammatory response plays a crucial role in the development of depression by upregulating the expression of inflammatory mediators that contribute to symptoms such as anxiety, hopelessness, and loss of pleasure. MethodsIn this study, sleep deprivation was utilized as a method to induce anxiety and depressive-like behaviors in mice. The behavioral changes in the mice were then evaluated using the EZM, EPM, TST, FST, and SPT. H&E staining and Nissl staining was used to detect morphological changes in the medial prefrontal cortical (mPFC) regions. Elisa to assess serum CORT levels. Detection of mRNA levels and protein expression of clock genes, high mobility genome box-1 (Hmgb1), silent message regulator 6 (Sirt6), and pro-inflammatory factors by RT-qPCR, Western blotting, and immunofluorescence techniques. ResultsSleep deprivation resulted in decreased exploration of unfamiliar territory, increased time spent in a state of despair, and lower sucrose water intake in mice. Additionally, sleep deprivation led to increased secretion of serum CORT and upregulation of clock genes, IL6, IL1β, TNFα, Cox-2, iNOS, Sirt6, and Hmgb1. Sleep. ConclusionsSleep deprivation induces anxiety-depressive-like behaviors and neuroinflammation in the brain. Transcription of clock genes and activation of the Sirt6/Hmgb1 pathway may contribute to inflammatory responses in the mPFC.

A TrkB cleavage fragment in hippocampus promotes Depressive-Like behavior in mice

Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1β-C/EBPβ-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1–486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1–486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1–486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer’s disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.

The anti-depression effect and potential mechanism of the petroleum ether fraction of CDB: Integrated network pharmacology and metabolomics

The combination of Chaidangbo (CDB) is an antidepressant traditional Chinese medicine (TCM) prescription simplified by Xiaoyaosan (a classic antidepressant TCM prescription) through dismantling research, which has the effect of dispersing stagnated liver qi and nourishing blood in TCM theory. Although the antidepressant effect of CBD has been confirmed in animal studies, the material basis and possible molecular mechanism for antidepressant activity in CBD have not been clearly elucidated. Herein, we investigated the effects and potential mechanisms of CDB antidepressant fraction (petroleum ether fraction of CDB, PEFC) on chronic unpredictable mild stress (CUMS)-induced depression-like behavior in mice using network pharmacology and metabolomics. First, a UPLC-QE/MS was employed to identify the components of PEFC. To extract active ingredients, SwissADME screening was used to the real PEFC components that were found. Potential PEFC antidepressant targets were predicted based on a network pharmacology approach, and a pathway enrichment analysis was performed for the predicted targets. Afterward, a CUMS mouse depression model was established and LC-MS-based untargeted hippocampal metabolomics was performed to identify differential metabolites, and related metabolic pathways. Finally, the protein expressions in mouse hippocampi were determined by Western blot to validate the network pharmacology and metabolomics deduction. A total of 16 active compounds were screened in SwissADME that acted on 73 core targets of depression, including STAT3, MAPKs, and NR3C1; KEGG enrichment analysis showed that PEFC modulated signaling pathways such as PI3K-Akt signaling pathway, endocrine resistance, and MAPK to exert antidepressant effects. PEFC significantly reversed abnormalities of hippocampus metabolites in CUMS mice, mainly affecting the synthesis and metabolism of glycine, serine, and threonine, impacting catecholamine transfer and cholinergic synapses and regulating the activity of the mTOR signaling pathway. Furthermore, Western blot analysis confirmed that PEFC significantly influenced the main protein levels of the PI3K/Akt/mTOR signaling pathways in the hippocampus of mice subjected to CUMS. This study integrated metabolomics, network pharmacology and biological verification to explore the potential mechanism of PEFC in treating depression, which is related to the regulation of amino acid metabolism dysfunction and the activation of PI3K/Akt/mTOR signaling pathways in the hippocampus. The comprehensive strategy also provided a reasonable way for unveiling the pharmacodynamic mechanisms of multi-components, multi-targets, and multi-pathways in TCM with antidepressant effect.

Gastrodin ameliorates depressive-like behaviors via modulating gut microbiota in CUMS-induced mice

PurposeDepression is a psychiatric disorder and the treatment of depression is an urgent problem that need to be solved. Gastrodin (GAS) is a Traditional Chinese Medicine from an orchid and is used for neurological diseases, including depressive disorders. MethodsTo assess the effect of GAS on gut microbiota of depressive mice, we established a chronic unpredictable mild stress (CUMS)-induced mouse model, and GAS was administered to one group of the mice. Animal behavior experiments were used to detect depressive-like behaviors, and 16 S rRNA gene analysis was applied to detect the gut microbiota of each group. All raw sequences were deposited in the NCBI Sequence Read Archive under accession number SRP491061. ResultsGAS treatment significantly improved depressive-like behaviors as well as the diversity and abundance of the gut microbiota. The depressive-like behaviors of the CUMS-GAS group were improved in different degrees compared with the CUMS group. The linear discriminant analysis (LDA) of the gut microbiota showed that the makeup of the gut microbiota in mice changed dramatically in the CUMS-GAS group, compared with the CUMS group, Bacteroides (LDA = 3.94, P < 0.05) were enriched in the CUMS-GAS group at the genus level. In comparison to the CUMS group, the CUMS-GAS group had a greater concentration numbers of Lactobacillus, Corynebacterium, Staphylococcus, Bacteroides, Psychrobacter, and Alistipes. ConclusionOur results suggested that GAS improved depressive-like behaviors in mice and impacted the microbial composition of the gut. Our research indicated that dysbiosis of the gut microbiota may be affected by GAS treatment, which improved depressive-like behaviors in the CUMS-induced mouse model of depression.