Stress-induced Depressive-like Behavior Research Articles

Fluoxetine treatment reverses chronic stress-induced promotion on Fk506-binding protein 5 expression and multiple effects on glucocorticoid receptor phosphorylation in the paraventricular nucleus of mice

BackgroundFluoxetine is widely used as a first-line antidepressant. However, the molecular mechanisms for its antidepressant effects are still not fully understood. Hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is a core pathogenic mechanism contributing to depression, and fluoxetine treatment prevents this dysfunction. The glucocorticoid receptor (GR) is a major negative feedback regulator of the HPA axis, while Fk506-binding protein 5 (Fkbp5) is a negative regulator of the GR signaling. Therefore, we examined the effects of fluoxetine on Fkbp5 and the GR signaling in the hypothalamic paraventricular nucleus (PVN) of depressed mice. MethodsMice were exposed to chronic social defeat stress (CSDS), chronic unpredictable mild stress (CUMS), or chronic restraint stress (CRS) with or without fluoxetine treatment (intraperitoneally injected, 20 mg/kg) and examined for changes in depression-like behaviors and HPA axis activity as well as Fkbp5 expression and GR phosphorylation in the PVN. We then examined if adeno-associated virus (AAV)-mediated Fkbp5 overexpression in the PVN affected the antidepressant actions of fluoxetine in mice. ResultsFluoxetine treatment significantly mitigated CSDS-, CUMS-, and CRS-induced depression-like behaviors and HPA axis hyperactivity in mice. Subsequent western blotting analyses showed that fluoxetine treatment fully reversed not only chronic stress-induced upregulation of Fkbp5 and CRH but also chronic stress-induced increase in Ser203 phosphorylation and decrease in Ser211 and Ser234 phosphorylation in GR in the PVN. Moreover, quantitative real-time reverse transcription PCR (qRT-PCR) analyses revealed that the enhanced mRNA levels of Fkbp5 and CRH in PVN neurons of mice subjected to CSDS/CUMS/CRS were also notably reversed by fluoxetine administration. Conversely, Fkbp5 overexpression in the PVN significantly eliminated the antidepressant effects of fluoxetine in mice without affecting their locomotor activity. ConclusionThese results together suggest that fluoxetine treatment reverses chronic stress-induced promotion on Fkbp5 expression and multiple effects on GR phosphorylation in the PVN of mice. Significance statementThe selective serotonin reuptake inhibitor fluoxetine (sold as Prozac) is a widely used treatment for depression, but the full spectrum of therapeutic mechanisms is still debated. Recent evidence suggests that these therapeutic mechanisms include suppression of chronic stress-activated hypothalamus–pituitary–adrenal (HPA) axis. The current study presents the first in vivo evidence showing that suppression of HPA axis hyperactivity by fluoxetine treatment involves reversal of glucocorticoid receptor (GR) phosphorylation via modulation of the GR negative regulator Fk506-binding protein 5 (Fkbp5) in the hypothalamic paraventricular nucleus (PVN). Fluoxetine treatment not only inhibited chronic stress-induced depression-like behaviors and HPA axis hyperactivity but also reversed Fkbp5 upregulation and GR phosphorylation changes in the PVN, while adeno-associated virus (AAV)-based Fkbp5 overexpression in the PVN eliminated the antidepressant effects of fluoxetine. These findings may expand our understanding of the pharmacological effects of fluoxetine, and further identify Fkbp5 as a possible target for novel antidepressants.

Luteolin ameliorates chronic stress-induced depressive-like behaviors in mice by promoting the Arginase-1+ microglial phenotype via a PPARγ-dependent mechanism.

Accumulating evidence shows that neuroinflammation substantially contributes to the pathology of depression, a severe psychiatric disease with an increasing prevalence worldwide. Although modulating microglial phenotypes is recognized as a promising therapeutic strategy, effective treatments are still lacking. Previous studies have shown that luteolin (LUT) has anti-inflammatory effects and confers benefits on chronic stress-induced depression. In this study, we investigated the molecular mechanisms by which LUT regulates the functional phenotypes of microglia in mice with depressive-like behaviors. Mice were exposed to chronic restraint stress (CRS) for 7 weeks, and were administered LUT (10, 30, 40 mg· kg-1 ·day-1, i.g.) in the last 4 weeks. We showed that LUT administration significantly ameliorated depressive-like behaviors and decreased hippocampal inflammation. LUT administration induced pro-inflammatory microglia to undergo anti-inflammatory arginase (Arg)-1+ phenotypic polarization, which was associated with its antidepressant effects. Furthermore, we showed that LUT concentration-dependently increased the expression of PPARγ in LPS + ATP-treated microglia and the hippocampus of CRS-exposed mice, promoting the subsequent inhibition of the NLRP3 inflammasome. Molecular dynamics (MD) simulation and microscale thermophoresis (MST) analysis confirmed a direct interaction between LUT and peroxisome proliferator-activated receptor gamma (PPARγ). By using the PPARγ antagonist GW9662, we demonstrated that LUT-driven protection, both in vivo and in vitro, resulted from targeting PPARγ. First, LUT-induced Arg-1+ microglia were no longer detected when PPARγ was blocked. Next, LUT-mediated inhibition of the NLRP3 inflammasome and downregulation of pro-inflammatory cytokine production were reversed by the inhibition of PPARγ. Finally, the protective effects of LUT, which attenuated the microglial engulfment of synapses and prevented apparent synapse loss in the hippocampus of CRS-exposed mice, were eliminated by blocking PPARγ. In conclusion, this study showed that LUT ameliorates CRS-induced depressive-like behaviors by promoting the Arg-1+ microglial phenotype through a PPARγ-dependent mechanism, thereby alleviating microglial pro-inflammatory responses and reversing microglial phagocytosis-mediated synapse loss.

Xylopia parviflora (A. rich.) benth. Mitigates anxiety behavior and chronic mild stress-induced depression-like behavior in mice: The involvement of biogenic amine neurotransmitters, cyclooxygenase-2 and stress biomarkers in its antidepressant activity

BackgroundXylopia parviflora is a novel botanical in Modern Chinese Medicine that contains bioactive constituents including alkaloids, flavonoids, and terpenoids, which are the pharmacologically active components in various Chinese herbal formulations such as Coptis chinensis (alkaloid-rich herbs), Ginkgo biloba (flavonoid-rich herbs) and Artemisia annua (terpenoid-rich herbs). ObjectiveThis investigation sought to evaluate the anxiolytic and antidepressant-like effects of the hydroethanol leaf extract of Xylopia parviflora using mouse models. We elucidated the roles of noradrenaline, serotonin, cyclooxygenase-2, and reactive oxidative species in mediating its antidepressant effects, providing a fresh perspective on the pharmacological activity of Xylopia parviflora. MethodsThe acute toxicity of XPE was assessed following OECD guideline 420. Established behavioral tests were used to evaluate the anxiolytic (including the hole-board, open field, elevated plus maze, and light/dark exploration assessments) and antidepressant (encompassing the forced swim and tail suspension tests) effects of the extract. Mice received treatments of distilled water (10 mL/kg, serving as the negative control), fluoxetine (20 mg/kg, acting as the reference medication), and XPE (at doses of 50, 100, and 200 mg/kg). The concentrations of noradrenaline, serotonin, and COX-2 within the brain tissue were quantified using ELISA kits. The levels of antioxidant biomarkers were evaluated using standardized commercial assay kits. ResultsThe oral/intraperitoneal LD50 for the extract was established at 2000 mg/kg. In the behavioral assessments designed to measure anxiolytic effects, XPE significantly mitigated anxiety levels in mice, as evidenced by an increase in exploratory behaviors (including head dips, sectional crossings, general square crossings, rearing, and assisted rearing) and an increased time spent in the brightly illuminated compartments. Concerning the antidepressant evaluations, XPE significantly reduced depression-like behaviors in mice, which was indicated by an increased latency to immobility and a decrease in the duration of immobility. XPE was found to modulate noradrenaline and serotonin transmissions, attenuate oxidative species, and inhibit COX-2 activity. ConclusionThe findings above demonstrate that Xylopia parviflora possesses anxiolytic and antidepressant-like activities. The antidepressant property of XPE, as revealed in this study, may be attributable to the enhancement of biogenic amines (specifically noradrenaline and serotonin), the suppression of oxidative species, and the inhibition of COX-2 activity.

Hippocampal SENP3 mediates chronic stress-induced depression-like behaviors by impairing the CREB-BDNF signaling

Impaired signaling between cyclic adenosine monophosphate response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus is generally considered to be the cause of depression. The mechanisms underlying the impairment of CREB-BDNF signaling under stress conditions are largely unclear. Small ubiquitin-like modifier (SUMO) specific peptidase 3 (SENP3) is a molecule that can regulate SUMOylation of target proteins related to synaptic plasticity. Its dynamic changes have been reported to be associated with neuronal damage in various models of central nervous disorders such as cerebral ischemia and traumatic brain injury. However, its role in depression is completely unknown. This problem was addressed in the present study. Our results showed that chronic unpredictable stress (CUS) triggered a specific increase in SENP3 expression in the hippocampus of non-stressed mice. Overexpression of SENP3 in the hippocampus of non-stressed mice elicited depression-like behaviors in the tail suspension test, forced swimming test, and sucrose preference test, accompanied by impairment of the CREB-BDNF signaling cascade in the hippocampus. Conversely, genetic silencing of SENP3 in the hippocampus suppressed the development of depression-like behaviors. Furthermore, infusion of SENP3-shRNA into the hippocampus failed to suppress CUS-induced depression-like behaviors when mice received genetic silencing CREB or BDNF in the hippocampus or inhibition of the BDNF receptor by K252a. Taken together, these results suggest that abnormally elevated SENP3 in the hippocampus leads to the development of depression-like behavior by impairing the CREB-BDNF signaling cascade. SENP3 in the hippocampus could be a promising target for the development of new antidepressants.

Inhibition of Glycolysis Alleviates Chronic Unpredictable Mild Stress Induced Neuroinflammation and Depression-like Behavior.

Growing evidence suggests that glucose metabolism plays a crucial role in activated immune cells, significantly contributing to the occurrence and development of neuroinflammation and depression-like behaviors. Chronic stress has been reported to induce microglia activation and disturbances in glucose metabolism in the hippocampus. This study aims to investigate how chronic stress-mediated glycolysis promotes neuroinflammation and to assess the therapeutic potential of the glycolysis inhibitor, 2-deoxy-D-glucose (2-DG), in a model of chronic stress-induced neuroinflammation and depression-like behavior. In in vitro studies, we first explored the effects of 2-DG on the inflammatory response of microglia cells. The results showed that corticosterone (Cort) induced reactive oxygen species (ROS) production, increased glycolysis, and promoted the release of inflammatory mediators. However, these effects were reversed by intervention with 2-DG. Subsequently, we examined changes in depression-like behavior and hippocampal glycolysis in mice during chronic stress. The results indicated that chronic stress led to prolonged escape latency in the Morris water maze, increased platform-crossing frequency, reduced sucrose preference index, and extended immobility time in the forced swim test, all of which are indicative of depression-like behavior in mice. Additionally, we found that the expression of the key glycolytic enzyme hexokinase 2 (HK2) was upregulated in the hippocampus of stressed mice, along with an increased release of inflammatory factors. Further in vivo experiments investigated the effects of 2-DG on glycolysis and pro-inflammatory mediator production, as well as the therapeutic effects of 2-DG on chronic stress-induced depression-like behavior in mice. The results showed that 2-DG alleviated chronic stress-induced depression-like behaviors, such as improving escape latency and platform-crossing frequency in the Morris water maze, and increasing the time spent in the center of the open field. Additionally, 2-DG intervention reduced the level of glycolysis in the hippocampus and decreased the release of pro-inflammatory mediators. These findings suggest that 2-DG can mitigate neuroinflammation and depressive behaviors by inhibiting glycolysis and inflammatory responses. Overall, our results highlight the potential of 2-DG as a therapeutic agent for alleviating chronic stress-induced neuroinflammation through the regulation of glycolysis.

GluN2A: A Promising Target for Developing Novel Antidepressants.

Depression is a heterogeneous disorder with high morbidity and disability rates that poses serious problems regarding mental health care. It is now well established that N-methyl D-aspartate receptor (NMDAR) modulators are being increasingly explored as potential therapeutic options for treating depression, although relatively little is known about their mechanisms of action. NMDARs are glutamate-gated ion channels that are ubiquitously expressed in the central nervous system (CNS), and they have been shown to play key roles in excitatory synaptic transmission. GluN2A, the predominant Glu2N subunit of functional NMDARs in neurons, is involved in various physiological processes in the CNS and is associated with diseases such as anxiety, depression, and schizophrenia. However, the role of GluN2A in the pathophysiology of depression has not yet been elucidated. We reviewed several past studies to better understand the function of GluN2A in depression. Additionally, we also summarized the pathogenesis of depression based on the regulation of GluN2A expression, particularly its interaction with neuroinflammation and neurogenesis, which has received considerable critical attention and is highly implicated in the onset of depression. These evidence suggests that GluN2A overexpression impairs structural and functional synaptic plasticity, which contributes to the development of depression. Consequently, this knowledge is vital for the development of selective antagonists targeting GluN2A subunits using pharmacological and molecular methods. Specific inhibition of the GluN2A NMDAR subunit is resistant to chronic stress-induced depressive-like behaviors, making them promising targets for the development of novel antidepressants.

The protective effect of S-adenosylmethionine on chronic adolescent stress-induced depression-like behaviors by regulating gut microbiota

The efficacy and tolerability of current antidepressants for adolescent depression are inadequate. S-adenosylmethionine (SAMe), known for its effectiveness and minimal side effects in adult depression, remains unstudied in adolescents. This study explored the potential of SAMe to address depression-like behaviors in juvenile rats induced by chronic unpredictable mild stress (CUMS), with a focus on gut microbiome interactions. Adolescent male Wistar rats were subjected to a 4-week CUMS regimen and received daily intraperitoneal injections of 300 mg/kg SAMe. Behavioral assessments included the sucrose preference test, elevated plus maze test, open field test, and Y-maze test. Histopathological changes of the hippocampus and colon were observed by Nissl staining and hematoxylin and eosin staining, respectively. Gut microbiome composition was analyzed using Accurate 16S absolute quantification sequencing. The results showed that SAMe significantly improved behavioral outcomes, reduced histopathological damages in hippocampal neurons and colon tissues, and modulated the gut microbiota of depressed rats. It favorably altered the ratio of Bacteroidetes to Firmicutes, decreased the absolute abundance of Deferribacteres, and adjusted levels of key microbial genera associated with depression-like behaviors. These results suggested that SAMe could effectively counter depression-like behaviors in CUMS-exposed adolescent rats by mitigating hippocampal neuronal and colon damage and modulating the gut microbiota. This supports SAMe as a viable and tolerable treatment option for adolescent depression, highlighting the importance of the gut-brain axis in therapeutic strategies.

Acute rimonabant treatment prevents anhedonia and memory loss in rats submitted to mild restraint stress

Stress-related disorders are becoming increasingly common and are often associated with cognitive impairments. Within this context, the endocannabinoid (ECB) system, particularly the type 1 cannabinoid (CB1) receptor, seems to play a decisive role in restoring body homeostasis. There is consistent evidence in the literature that disrupted CB1-mediated neurotransmission can ultimately contribute to stress-related diseases. Therefore, the present study aimed to evaluate the participation of CB1 receptors in the integrity of stress-induced peripheral and behavioral responses. For this purpose, male adult Wistar rats underwent physical restraint (1 h/day, for 7 days), followed by a single administration of rimonabant (CB1 receptor antagonist, 3 mg/Kg, intraperitonial) at the end of stress protocol. Animals were then subjected to evaluation of neuroendocrine responses, behavioral tests and quantification of Iba-1 (microglial) immunoreactivity in the parvocellular subdivisions of the paraventricular nucleus of the hypothalamus (PVN). No effects of restraint stress or rimonabant administration were detected on body mass variation. However, stress significantly increased adrenal relative mass and corticosterone secretion, and reduced thymus relative size. The stress effects on adrenal size and corticosterone plasma levels were absent in rimonabant-treated rats, but the thymus size was further reduced in the restraint-rimonabant group. Restraint stress also induced anhedonia, a depression-like behavior, and reduced object recognition index, indicating memory recovery impairment. Treatment with the CB1 antagonist significantly reversed stress-induced anhedonia and memory deficit. In the PVN, restraint stress reduced the number of Iba-1 positive cells in the medial parvocellular region of vehicle- but not rimonabant-treated animals. Taken together, these results indicate that the acute inhibition of the CB1-mediated endogenous pathway restores stress-induced depression-like behaviors and memory loss, suggesting a role for endocannabinoids in the neuro-immune-endocrine interplay at both peripheral and hypothalamic levels.

Hyperglycemia sensitizes female mice to stress-induced depressive-like behavior in an inflammation-independent manner

BackgroundDepression is a multifaceted disorder that represents one of the most common causes of disability. The risk for developing depression is increased in women and among individuals with chronic diseases. For example, individuals in the United States with diabetes mellitus (DM) are at a twofold increased risk of developing depression compared to the general population and approximately one-quarter of women with diabetes have comorbid depression. The neurobiological mechanisms underlying this association between diabetes and depression is not fully understood and is particularly under-investigated in female models. We sought to explore the role of neuroinflammation in diabetes-induced depression in a female mouse model of hyperglycemia. MethodsTo this end, we utilized female C57BL/6 J mice to (1) characterize the depressive-like symptoms in response to 75 mg/kg/day dose of streptozotocin (STZ) over 5 days, a dose reported to induce hyperglycemia in female mice (n=20), (2) determine if female hyperglycemic mice are sensitized to unpredictable chronic mild stress (UCMS)-induced depressive-like behavior and neuroinflammation (n=28), and (3) investigate if female hyperglycemic mice are primed to respond to a subthreshold dose of lipopolysaccharide (LPS), an acute inflammatory challenge (n=21). ResultsOur results demonstrate that female mice exhibit robust hyperglycemia but limited evidence of depressive-like behavior in response to 75 mg/kg STZ. Additionally, we observe that healthy female mice have limited response to our stress protocol; however, hyperglycemic mice display increased stress-sensitivity as indicated by increased immobility in the forced swim test. While STZ mice show evidence of mild neuroinflammation, this effect was blunted by stress. Further, STZ mice failed to display a sensitization to inflammation-induced depressive-like behavior. ConclusionWe interpret this data to indicate that while STZ-induced hyperglycemia does increase vulnerability to stress-induced depressive-like behavior, this effect is not a consequence of neuroinflammatory priming. Future studies will seek to better understand the mechanisms underlying this sensitization.

A novel probiotic formula, BLLL, ameliorates chronic stress-induced depression-like behaviors in mice by reducing neuroinflammation and increasing neurotrophic factors.

Introduction: Probiotics have been recognized for their various biological activities, including antioxidant and anti-inflammatory properties. This study investigates the therapeutic effect of a novel probiotic formula, BLLL, consisting of Bifidobacterium breve, Lactobacillus plantarum, Lactobacillus paracasei, and Lactobacillus helveticus, on chronic stress-induced depression-like behaviors in mice. Methods: The BLLL formula or phosphate-buffered saline (PBS) was given orally at a dose of 2, 4, or 8 × 1010 CFU/kg once daily for 10days in mice treated with chronic unpredictable stress (CUS) treated or vehicle. Depression-like behaviors were assessed using the sucrose preference test (SPT), the forced swimming test (FST), and the tail suspension test (TST). The mRNA and/or protein expression of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), IL-4, IL-10, and chitinase-3-like protein 3 (CHI3L1, also known as Ym-1), as well as the concentration of nitrite, malondialdehyde (MDA), glutathione (GSH), and brain-derived neurotrophic factor (BDNF) in the hippocampus and medial prefrontal cortex were examined. Results: The BLLL formula treatment at a dose of 8 × 1010 CFU/kg, but not at a dose of 2 or 4 × 1010 CFU/kg, improved CUS-induced depression-like behaviors in mice, as shown by the decrease in immobility time in the TST and FST and the increase in sucrose intake in the SPT. Further analysis revealed that BLLL treatment suppressed the CUS-induced increase in IL-1β, IL-6, and TNF-α mRNA and protein levels, as well as the CUS-induced decrease in IL-4, IL-10, and Ym-1 mRNA and/or protein levels in the hippocampus and medial prefrontal cortex. In addition, treatment with the BLLL formula countered the CUS-induced increase in nitrite and MDA levels and the CUS-induced decrease in GSH content and BDNF concentration in the hippocampus and medial prefrontal cortex. Conclusion: These results demonstrate that the novel probiotic formula BLLL ameliorates chronic stress-induced depression-like behavior in mice by suppressing neuroinflammation and oxido-nitrosative stress in the brain.

The Regulation of Frontal Cortex Cholesterol Metabolism Abnormalities by NR3C1/NRIP1/NR1H2 Is Involved in the Occurrence of Stress-Induced Depression.

Stress-induced alterations in central neuron metabolism and function are crucial contributors to depression onset. However, the metabolic dysfunctions of the neurons associated with depression and specific molecular mechanisms remain unclear. This study initially analyzed the relationship between cholesterol and depression using the NHANES database. We then induced depressive-like behaviors in mice via restraint stress. Applying bioinformatics, pathology, and molecular biology, we observed the pathological characteristics of brain cholesterol homeostasis and investigated the regulatory mechanisms of brain cholesterol metabolism disorders. Through the NHANES database, we initially confirmed a significant correlation between cholesterol metabolism abnormalities and depression. Furthermore, based on successful stress mouse model establishment, we discovered the number of cholesterol-related DEGs significantly increased in the brain due to stress, and exhibited regional heterogeneity. Further investigation of the frontal cortex, a brain region closely related to depression, revealed stress caused significant disruption to key genes related to cholesterol metabolism, including HMGCR, CYP46A1, ACAT1, APOE, ABCA1, and LDLR, leading to an increase in total cholesterol content and a significant decrease in synaptic proteins PSD-95 and SYN. This indicates cholesterol metabolism affects neuronal synaptic plasticity and is associated with stress-induced depressive-like behavior in mice. Adeno-associated virus interference with NR3C1 in the prefrontal cortex of mice subjected to short-term stress resulted in reduced protein levels of NRIP1, NR1H2, ABCA1, and total cholesterol content. At the same time, it increased synaptic proteins PSD95 and SYN, effectively alleviating depressive-like behavior. Therefore, these results suggest that short-term stress may induce cholesterol metabolism disorders by activating the NR3C1/NRIP1/NR1H2 signaling pathway. This impairs neuronal synaptic plasticity and consequently participates in depressive-like behavior in mice. These findings suggest that abnormal cholesterol metabolism in the brain induced by stress is a significant contributor to depression onset.

Hippocampal SorCS2 overexpression represses chronic stress-induced depressive-like behaviors by promoting the BDNF-TrkB system

BackgroundEmerging data has demonstrated that in mature neurons, SorCS2 localizes to the postsynaptic density of dendritic spines and facilitates plasma membrane sorting of TrkB by interacting with it, transmitting positive signaling from BDNF on neurons. Thus, it is possible that SorCS2 plays a role in the pathophysiology of depression by regulating the BDNF-TrkB system. MethodsIn the present study, SorCS2 expression in different brain regions [hippocampus, medial prefrontal cortex (mPFC), hypothalamus, amygdala, ventral tegmental area (VTA), and nucleus accumbens (NAc)] was thoroughly investigated in the chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression. The changes in depressive-like behaviors, the hippocampal BDNF signaling cascade, and amounts of hippocampal immature neurons were further investigated after SorCS2 overexpression by microinjection of the adenovirus associated virus vector containing the coding sequence of mouse SorCS2 (AAV-SorCS2) into the hippocampus of mice exposed to CSDS or CUMS. ResultsIt was found that both CSDS and CUMS significantly decreased the protein and mRNA expression of SorCS2 in the hippocampus but not in other brain regions. Chronic stress also notably downregulated the level of hippocampal SorCS2-TrkB binding in mice. In contrast, AAV-based genetic overexpression of hippocampal SorCS2 fully reversed the chronic stress-induced not only depressive-like behaviors but also decreased SorCS2-TrkB binding, BDNF signaling pathway, and amounts of immature neurons in the hippocampus of mice. ConclusionAll these results suggest that enhancing the hippocampal SorCS2 expression protects against chronic stress, producing antidepressant-like actions. Hippocampal SorCS2 may participate in depression neurobiology and be a potential antidepressant target. Significance statementTargeting of proteins to distinct subcellular compartments is essential for neuronal activity and modulated by VPS10P domain receptors which include SorCS2. In mature neurons, SorCS2 localizes to the postsynaptic density of dendritic spines and facilitates plasma membrane sorting of TrkB by interacting with it, transmitting positive signaling from BDNF on neurons. Our study is the first direct evidence preliminarily showing that SorCS2 plays a role in depression neurobiology. It was found that chronic stress induced not only depressive-like behaviors but also decreased SorCS2 expression in the hippocampus. Chronic stress did not affect SorCS2 expression in the mPFC, hypothalamus, amygdala, VTA, or NAc. In contrast, genetic overexpression of hippocampal SorCS2 prevented against chronic stress, producing antidepressant-like actions in mice. Thus, hippocampal SorCS2 is a potential participant underlying depression neurobiology and may be a novel antidepressant target. Our study may also extend the knowledge of the neurotrophic hypothesis of depression.

The improvement effect of exercise on rats with chronic stress-induced depression-like behavior: a discussion based on the kynurenine pathway.

To observe the effects of 4 weeks of voluntary wheel running on depressive-like behavior in a rat chronic stress-induced depression model to explore the anti-depressive mechanism of exercise. In this observational study, 36 Sprague-Dawley rats were randomly divided into control, stress model, and stress exercise groups (12 rats/group). The control group received no intervention, and the stress model and stress exercise group rats underwent chronic mild unpredictable stress and isolation. The stress exercise group rats also underwent 4 weeks of voluntary wheel running. Behavioral changes and hippocampal protein and mRNA expression levels were detected. Voluntary wheel running significantly increased horizontal and vertical movements, sucrose intake, and the sucrose preference percentage and reduced immobility time in the forced swimming test in depression model rats. The hippocampal tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and quinolinic acid levels were significantly decreased, while the IL-4, IL-10, and kynurenic acid levels were significantly increased. Kynurenine-3-monooxygenase and 3-hydroxyanthranilate-3, 4-dioxygenase mRNA levels were downregulated, and kynurenine aminotransferase mRNA was upregulated. Voluntary wheel running improved depressive-like behavior in depression model rats. The mechanism may be related to a kynurenine pathway metabolite level imbalance, which has neurotoxic and neuroprotective effects, caused by long-term voluntary wheel running.

Etanercept ameliorates chronic mild stress-induced depressive-like behavior in rats: Crosstalk between MAPK and STAT3 pathways and norepinephrine and serotonin transporters

Depression is a serious medical illness characterized by persistent feelings of sadness, hopelessness, and lack of interest in daily activities. It can interfere with daily functioning and quality of life. Despite decades of research, the pathophysiology of depression remains incompletely understood. The correlation between depression and inflammation has recently attracted considerable attention. This study investigated the potential antidepressant effect of etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor, utilizing a chronic mild stress (CMS) model in rats. Male Wistar rats were divided into two groups; one following a non-stressed protocol and the other a stressed protocol for 5 weeks. From the beginning of the third week, rats were treated either with saline daily or with etanercept twice a week (0.3 mg/kg, i.p.) or with fluoxetine daily (10 mg/kg, i.p) as a reference. Etanercept exhibited comparable effects to those of fluoxetine in counteracting CMS-induced behavioral manifestation in the forced swimming and splash tests. Etanercept also restored serotonin and norepinephrine levels to control values in the prefrontal cortex (PFC). Moreover, the current study verified the antioxidant and anti-inflammatory effects of etanercept. Interestingly, etanercept halted the expression of both norepinephrine and serotonin transporters in stressed rats. This could be attributed to abrogation of the p38 mitogen-activated protein kinase (p38 MAPK) and signal transducer and activator of transcription 3 (STAT-3) pathways in the PFC. The findings of the present study contribute to the understanding of the potential of etanercept as an antidepressant and provide insights into the neurobiological mechanisms underlying its therapeutic effects.

Targeting Phactr4 to rescue chronic stress-induced depression-like behavior in rats via regulating neuroinflammation and neuroplasticity

Depression is a neuropsychiatric disorder characterized by persistent pleasure loss and behavioral despair. However, the potential mechanisms and therapeutic targets for depression treatment remain unclear. Therefore, identifying the underlying pathogenesis of depression would promote the development of novel treatment and provide effective targets for antidepressant drugs. In this study, proteomics analysis showed that the expression level of phosphatase and actin regulator 4 (Phactr4) was significantly increased in the CA1 hippocampus of depressed rats. The upregulated Phactr4 might induce dysfunction of the synaptic structure via suppressing the p-LIMK/p-Cofilin signaling pathway, and promote neuroinflammation via activating the NF-κB/NLRP3 pathway, which ultimately contributes to the pathogenesis of depression. In contrast, the downregulation of Phactr4 in hippocampal CA1 of depressed rats alleviated depression-like behaviors, along with reducing neuroinflammation and improving synaptic plasticity. In conclusion, these findings provide evidence that Phactr4 plays an important role in regulating neuroinflammatory response and impairment of synaptic plasticity, effects seem to involve in the pathogenesis of depression, and Phactr4 may serve as a potential target for antidepressant treatment.

Anti-Depressant Like Effects of Aethoscytus Foveolus Oil by Improving Stress-mediated Alterations of Monoamine Oxidase, Oxidative Stress, and Neuroinflammation In-vivo.

Depression is a neuropsychological disorder with a complex pathophysiology and its pharmacotherapy is compromised by adverse side effects. Addressing the need for effective treatment for depression, the current study aims to characterize the antidepressant activity of oil extract derived from Aethoscytus foveolus, bugs that are widely available in India, in a mice model of stress-induced depression. Chemical moieties characterized by GC-MS of A. foveolus oil extract have shown good affinity for monoamine oxidase A (MAO-A) in-silico. In-vitro MAO-inhibitory assay using mouse brain homogenates also showed similar results at IC50 1.363 nM (R2 = 0.981, SD ± 0.05, n = 3) of it. These results encouraged us to investigate the antidepressant potential of this oil extract in vivo. Stress-exposed mice (Swiss Albino, either sex, 25-30 gm) were administered 5 and 10 mg/kg doses of oil extract and classified as separate groups (N = 6 per group). Behavioral tests like the forced-swim test, tail-suspension test, and open-field test demonstrated significant attenuation of stress-induced depressive-like behavior of mice by both doses (p < 0.0001 with positive control group i.e., stress group), while biochemical tests on mice brain tissues showed amelioration of stress-induced hyperactivation of MAO (p < 0.0001) and oxidative stress (by increasing Superoxide dismutase and catalase, while reducing lipid peroxidase and nitric oxide) (p < 0.0001). The altered mRNA expression of proinflammatory cytokines (NF-κB, IL-6, IL-12, and TNF-α) (p < 0.015) was also improved by this oil extract. In addition, histopathology of hippocampus tissues of mice supports that this oil recovers stress-mediated structural changes of the brain. In conclusion our findings suggest that oil derived from A. foveolus could be beneficial in the alleviation of stress-mediated depressive-like behavior of mice, and in our knowledge, this is the first report identifying anti-neurodegenerative potential of A. foveolus.

Evaluating the Antidepressant-like Properties of Melatonin and Vitamin D3 Combination in Mice Subjected to Restraint Stress: Investigating the Involvement of Oxidative Stress

Background: Increased levels of oxidative stress are connected with depression. Due to the melatonin's antioxidant effects and Vitamin D3 (Vit D3)'s regulatory effect on the biosynthesis of neurotransmitters and neurotrophic factors, the present study investigated the possible protective effect of melatonin and Vit D3 combination on restraint stress-induced depression-like behaviors in mice. Methods: After being subjected to restraint stress, mice were divided into six groups using a randomization process. These groups included non-stressed and stressed vehicle-treated groups, as well as groups treated with Vit D3 (25 μg/kg/day), melatonin (10 mg/kg) or fluoxetine. A group also received a combination of both melatonin and Vit D3. The Forced Swimming Test (FST), and Open Field Test (OFT) were conducted to evaluate behavioural changes. The Malondialdehyde (MDA) level and Catalase (CAT), Superoxide Dismutase (SOD) activity, and ADP/ATP ratio were evaluated in the hippocampus of mice. Results: Restraint stress lengthened the immobility period in FST, while melatonin, Vit D3, and their combination all significantly reversed this impact. Co-administration of melatonin and Vit D3 was more effective than melatonin or Vit D3 administration alone at reducing immobility time. The exposure of mice to restraint stress has been linked to an elevation in the ADP/ATP ratio and oxidative stress in their hippocampus; however, these effects are reversed by the administration of melatonin and Vit D3 (10 mg/kg) alone or in combination. Melatonin and Vit D3 combination increased the hippocampus CAT activity compared with melatonin and Vit D3 alone. Conclusion: The current study's findings suggested that Vit D3 may enhance melatonin's potential as an antidepressant in FST.

Antidepressant effect and mechanism of TMP269 on stress-induced depressive-like behavior in mice

TMP269, a class IIA histone deacetylase inhibitor with selectivity, that has a protective effect on the central nervous system, yet its specific mechanism of action remains ambiguous. Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that histone deacetylase 5 plays a key role in the pathological process of depression and the fact that preclinical studies have shown HDAC5 to be a potential antidepressant target, the search for natural drugs or small molecule compounds that can target HDAC5 may be a potential therapeutic strategy for the treatment of depression. In addition, we examined the role of the Brain-derived neurotrophic factor (BDNF), an important neurotrophic factor for neuronal survival and growth, as a potential downstream target of HDAC5. We found downward revision of HDAC5 levels in the hippocampus ameliorated depressive-like behavior in LH (Learned helplessness) mice. Furthermore, injection of HDAC5 overexpressing adenoviral vectors in the hippocampal dentate gyrus of wild-type mice produced a somewhat depressive-like phenotype. Pharmacological, immunofluorescence and biochemical experiments showed that TMP269 could produce antidepressant effects by inhibiting mouse hippocampal HDAC5 and thus modulating its downstream BDNF. Over all, TMP269 mitigated LH-induced depressive-like behaviors and abnormalities in synapse formation and neurogenesis within the hippocampus. These findings suggest potential beneficial effects of TMP269 on depression.

Oral microbiota dysbiosis alters chronic restraint stress-induced depression-like behaviors by modulating host metabolism

Studies have shown that the microbiota-gut-brain axis is highly correlated with the pathogenesis of depression in humans. However, whether independent oral microbiome that do not depend on gut microbes could affect the progression of depression in human beings remains unclear, neither does the presence and underlying mechanisms of the microbiota-oral-brain axis in the development of the condition. Hence this study that encompasses clinical and animal experiments aims at investigating the correlation between oral microbiota and the onset of depression via mediating the microbiota-oral-brain axis. We compared the oral microbial compositions and metabolomes of 87 patients with depressive symptoms versus 70 healthy controls. We found that the oral microbial and metabolic signatures were significantly different between the two groups. Significantly, germ-free (GF) mice transplanted with saliva from mice exposing to chronic restraint stress (CRS) displayed depression-like behavior and oral microbial dysbiosis. This was characterized by a significant differential abundance of bacterial species, including the enrichment of Pseudomonas, Pasteurellaceae, and Muribacter, as well as the depletion of Streptococcus. Metabolomic analysis showed the alternation of metabolites in the plasma of CRS-exposed GF mice, especially Eicosapentaenoic Acid. Furthermore, oral and gut barrier dysfunction caused by CRS-induced oral microbiota dysbiosis may be associated with increased blood-brain barrier permeability. Pseudomonas aeruginosa supplementation exacerbated depression-like behavior, while Eicosapentaenoic Acid treatment conferred protection against depression-like states in mice. These results suggest that oral microbiome and metabolic function dysbiosis may be relevant to the pathogenesis and pathophysiology of depression. The proposed microbiota-oral-brain axis provides a new way and targets for us to study the pathogenesis of depression.

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.