Chronic Stress-induced Depression Research Articles

Effect of acupuncture on AMPK/ULK1 signaling pathway of hippocampus in chronic stress-induced depression rats

To observe the effect of manual acupuncture stimulation on changes of behavior and hippocampal signaling pathways of AMP-activated kinase (AMPK)/UNC-51-like kinase 1 (ULK1) in rats with chronic unpredictable mild stress (CUMS)-induced depression, so as to explore its molecular mechanism underlying improvement of depression. Thirty-two male SD rats were randomly divided into normal control, model, acupuncture and medication (fluoxetine) groups, with 8 rats in each group. The depression model was established by using CUMS (fasting, water depredation, restraint, swimming in cold water, crowding, stroboscope stimulation, and tail clipping, each of which was used once a week) for 6 weeks. Manual acupuncture stimulation was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for 10 min, once daily, 6 times a week for 6 weeks before every-day modeling. Rats of the medication group received gavage of fluoxetine (10 mg/kg) once a day for 6 weeks before every-day modeling. The percentage of sucrose preference, and the percentages of open arm times and open arm time in the elevated plus maze experiments were detected. The expression levels of AMPK, phosphorylated (p)-AMPK, ULK1, p-ULK1, mammalian target of rapamycin (mTOR) and p-mTOR proteins in the hippocampus tissue were detected by Western blot, and the expression of autophagy effecting protein (Beclin-1) and the selective autophagy receptors (p62) mRNA in the hippocampal tissue was detected using real-time fluorescence quantitative PCR, respectively. Compared with the normal group, the percentage of sucrose preference, percentage of times of entering the open arm and percentage of open arm time, the expression levels of p-AMPK /AMPK ratio, p-ULK1 /ULK1 ratio of proteins, and Beclin-1 mRNA were significantly decreased (P<0.01, P<0.05), and the expression levels of p-mTOR /mTOR ratio and p62 mRNA were significantly increased (P<0.01, P<0.05) in the model group. In comparison with the model group, the percentage of sucrose preference, percentage of open arm times and open arm time, the expression levels of p-AMPK /AMPK ratio, p-ULK1/ULK1 ratio of proteins, and Beclin-1 mRNA were significantly increased in both acupuncture and medication groups (P<0.01, P<0.05), while the expression levels of p-mTOR /mTOR ratio of proteins, and p62 mRNA were markedly decreased only in the medication group (P<0.05). Acupuncture treatment can alleviate depression-like behavior in CUMS rats, which may be related to its functions in up-regulating AMPK/ULK1 signaling pathway to induce cellular autophagy in the hippocampus.

QRFP and GPR103 in the paraventricular nucleus play a role in chronic stress-induced depressive-like symptomatology by enhancing the hypothalamic-pituitary-adrenal axis

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for depression neurobiology. As the latest member of the RFamide peptide family in mammals, pyroglutamylated RFamide peptide (QRFP) is closely implicated in neuroendocrine maintenance by activating G-protein-coupled receptor 103 (GPR103). We hypothesized that QRFP and GPR103 might contribute to chronic stress-induced depression by promoting corticotropin-releasing hormone (CRH) release from neurons in the paraventricular nucleus (PVN), and various methods were employed in this study, with male C57BL/6J mice adopted as the experimental subjects. Chronic stress induced not only depression-like behaviors but also significant enhancement in QRFP and GPR103 in the PVN. Genetic overexpression of QRFP/GPR103 and stereotactic infusion of QRFP-26/QRFP-43 peptide in the PVN all mimicked chronic stress that induced various depression-like phenotypes in naïve mice, and this was mediated by promoting CRH biosynthesis and HPA activity. In contrast, genetic knockdown of QRFP/GPR103 in the PVN produced notable antidepressant-like effects in mice exposed to chronic stress. Furthermore, genetic knockout of QRFP also protected against chronic stress in mice. In addition, both the C-terminal biological region of QRFP and the downstream PKA/PKC-CREB signaling coupled to GPR103 stimulation underlie the role of QRFP and GPR103 in depression. Collectively, QRFP and GPR103 in PVN neurons could be viable targets for novel antidepressants.

Dynamic quantitative monitoring of cerebrospinal fluid monoamine neurotransmitter markers during the modeling process of chronic stress-induced depression in monkeys (Macaca mulatta).

Depression is known as the "mental cold" and is also considered a major cause of disability worldwide. It is estimated that over 300 million people worldwide suffer from severe depression, equivalent to 4.4% of the world's population. The monoamine hypothesis of depression predicts the underlying pathophysiological mechanisms of depression, but in-depth research has failed to find convincing evidence. In this study, we will dynamically and strictly quantitatively monitor the concentration changes of monoamine transmitters in the cerebrospinal fluid (CSF) of macaques, based on our previous work. In the experiment, timed and quantitative collection of CSF samples from macaques was performed and the concentration of monoamine transmitters was determined. The results showed that after 2 months of chronic stress, the concentrations of high vanillin acid (HVA) and 3,4-dihydroxy-phenylacetic acid were significantly higher in the maternal separation (MS) group, whereas there was no significant difference in dopamine and 5-hydroxyindoleacetic acid. This study is the first to observe the long-term dynamic relationship between early adversity, chronic stress, adolescent depression, and CSF monoamine concentrations. The research suggests that MS and chronic stress play an undeniable role in the pathogenesis of depression and that concentrations of HVA and dihydroxyphenylacetic acid are likely to serve as early markers of depressive-like symptoms in macaques.

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.

Prevention of Neuronal Damage in Brains of Chronic Stress-induced Male Wistar Rats Administering Centella asiatica (L) Urban

Introduction: Physiological and psychological response of an organism to repetitive stimulus leads to chronic stress which results in depression. This affects the neuro-endocrine axis causing hypersecretion of glucocorticoids which damages the hippocampal neurons in brain through oxidative stress. The body responds by producing Catalase (CAT) an antioxidant found on peroxisomes, which splits the hydrogen peroxide produced by oxidative stress into water and oxygen which are nontoxic, thus offering a protective effect. The synaptic function of the hippocampal neurons is dependent on acetylcholinesterase (AChE) and oxidative stress affects the levels of AChE. The available anti-depressants have the late onset of action and increased toxicity. Centella asiatica (CA), an herb with neuroprotective properties, is known as neuro-tonic and has less toxicity and has been used in ancient traditional medicines. This study aims to examine the neuroprotective effects of crude extract of CA on hippocampal neurons using Nissls stain and levels of AChE and expression of mRNA CAT in the brain tissues of chronic unpredictable mild stress (CUMS)-induced male Wistar rats. Materials and Methods: Thirty-six Male Wistar rats aged 8–10 weeks were held in six groups. One group assigned as control, whereas the other groups were administered CUMS by various stressors, namely restrain, forced swimming in cold water, overnight food and water deprivation, wet bedding, cage tilt at 45°, tail pinching, overcrowding the cages, and change of cage mates randomly for a period of 64 days. One of the stress-induced groups was retained as model group and others were administered crude extracts of CA at the doses of 200, 400, 800, and fluoxetine (Flx) 10 mg/kg body weight. At the end of 64 days, the rats were euthanized and the brain tissue was collected for Nissls staining of the hippocampus, measure levels of AChE using ELISA and expression of mRNA CAT levels using RT-PCR. Results: The rats of the model group exhibited reduced number of viable neurons in the hippocampus as observed in Nissls stain, reduced levels of AChE, and reduced expression of mRNA CAT in the brain tissue while the rat groups receiving CA showed increase in the number of viable neurons, increase in level of AChE, and increase in the expression of mRNA CAT in the brain tissues. The results were comparable to that of Flx. Conclusion: CA effectively attenuates CUMS-induced neuronal loss in the hippocampus of the rat’s brain, normalizes AChE levels, and also the expression of mRNA CAT antioxidant levels. CA could be used in the long-term prevention of chronic stress-induced depression.

Effect of Cryptotanshinone on BDNF/TrkB Pathway in Hippocampus of Chronic Stress-induced Depression Rats

Background: Cryptotanshinone (CTS) is a monomer possessing a diverse array of pharmacological properties, primarily derived from Salvia miltiorrhiza. CTS was examined for its impact on rats with depression subjected to chronic unpredictable mild stress (CUMS) in this study. Materials and methods: Depression-like behavior of rats was established by isolated feeding combined with CUMS for 28 days, with CTS (7/14/21 mg/kg) or fluoxetine (5 mg/kg) administered once daily during this time. A comprehensive evaluation was performed, including body weight assessment, sucrose preference test, forced swimming test, and open field test. Hematoxylin-eosin staining was conducted to detect pathological changes in hippocampal CA1 neurons. Western blot analysis was employed to assess the brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB), Ras-related C3 botulinum toxin substrate 1 (Rac1), and Cofilin expression levels in the hippocampus. Results: The depression rat model was successfully constructed. CTS can significantly improve impaired neurons in the hippocampal CA1 area, depression-like behaviors, and weight loss in CUMS-induced rats. Moreover, CTS reversed the down-regulation of BDNF/TrkB and Rac1/Cofilin in the CUMS-induced rats’ hippocampus. Conclusion: CTS demonstrates the therapeutic potential for depression by improving depression-like behaviors and ameliorating impaired neurons in the hippocampal CA1 area, and the mechanisms may involve the up-regulation of BDNF/TrkB and related signaling proteins Rac1/Cofilin.

Co-decoction of Lilii bulbus and Radix Rehmannia Recens and its key bioactive ingredient verbascoside inhibit neuroinflammation and intestinal permeability associated with chronic stress-induced depression via the gut microbiota-brain axis

BackgroundGut microbiota plays a critical role in the pathogenesis of depression and are a therapeutic target via maintaining the homeostasis of the host through the gut microbiota–brain axis (GMBA). A co-decoction of Lilii bulbus and Radix Rehmannia Recens (LBRD), in which verbascoside is the key active ingredient, improves brain and gastrointestinal function in patients with depression. However, in depression treatment using verbascoside or LBRD, mechanisms underlying the bidirectional communication between the intestine and brain via the GMBA are still unclear. PurposeThis study aimed to examine the role of verbascoside in alleviating depression via gut-brain bidirectional communication and to study the possible pathways involved in the GMBA. MethodsKey molecules and compounds involved in antidepressant action were identified using HPLC and transcriptomic analyses. The antidepressant effects of LBRD and verbascoside were observed in chronic stress induced depression model by behavioural test, neuronal morphology, and synaptic dendrite ultrastructure, and their neuroprotective function was measured in corticosterone (CORT)-stimulated nerve cell injury model. The causal link between the gut microbiota and the LBRD and verbascoside antidepressant efficacy was evaluate via gut microbiota composition analysis and faecal microbiota transplantation (FMT). ResultsLBRD and Verbascoside administration ameliorated depression-like behaviours and synaptic damage by reversing gut microbiota disturbance and inhibiting inflammatory responses as the result of impaired intestinal permeability or blood-brain barrier leakiness. Furthermore, verbascoside exerted neuroprotective effects against CORT-induced cytotoxicity in an in vitro depression model. FMT therapy indicated that verbascoside treatment attenuated gut inflammation and central nervous system inflammatory responses, as well as eliminated neurotransmitter and brain–gut peptide deficiencies in the prefrontal cortex by modulating the composition of gut microbiota. Lactobacillus, Parabacteroides, Bifidobacterium, and Ruminococcus might play key roles in the antidepressant effects of LBRD via the GMBA. ConclusionThe current study elucidates the multi-component, multi-target, and multi-pathway therapeutic effects of LBRD on depression by remodeling GMBA homeostasis and further verifies the causality between gut microbiota and the antidepressant effects of verbascoside and LBRD.

Chronic Stress Exacerbates the Immunosuppressive Microenvironment and Progression of Gliomas by Reducing Secretion of CCL3.

As understanding of cancer has deepened, increasing attention has been turned to the roles of psychological factors, especially chronic stress-induced depression, in the occurrence and development of tumors. However, whether and how depression affects the progression of gliomas are still unclear. In this study, we have revealed that chronic stress inhibited the recruitment of tumor-associated macrophages (TAM) and other immune cells, especially M1-type TAMs and CD8+ T cells, and decreased the level of proinflammatory cytokines in gliomas, leading to an immunosuppressive microenvironment and glioma progression. Mechanistically, by promoting the secretion of stress hormones, chronic stress inhibited the secretion of the chemokine CCL3 and the recruitment of M1-type TAMs in gliomas. Intratumoral administration of CCL3 reprogrammed the immune microenvironment of gliomas and abolished the progression of gliomas induced by chronic stress. Moreover, levels of CCL3 and M1-type TAMs were decreased in the tumor tissues of glioma patients with depression, and CCL3 administration enhanced the antitumor effect of anti-PD-1 therapy in orthotopic models of gliomas undergoing chronic stress. In conclusion, our study has revealed that chronic stress exacerbates the immunosuppressive microenvironment and progression of gliomas by reducing the secretion of CCL3. CCL3 alone or in combination with an anti-PD-1 may be an effective immunotherapy for the treatment of gliomas with depression. See related Spotlight by Cui and Kang, p. 514.

Discovery of a novel class of reversible monoacylglycerol lipase inhibitors for potential treatment of depression

Biological studies on the endocannabinoid system (ECS) have suggested that monoacylglycerol lipase (MAGL), an essential enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), is a novel target for developing antidepressants. A decrease of 2-AG levels in the hippocampus of the brain has been observed in depressive-like models induced by chronic stress. Herein, employing a structure-based approach, we designed and synthesized a new class of (piperazine-1-carbonyl) quinolin-2(1H)-one derivatives as potent, reversible and selective MAGL inhibitors. And detailed structure-activity relationships (SAR) studies were discussed. Compound 27 (IC50 = 10.3 nM) exhibited high bioavailability (92.7%) and 2-AG elevation effect in vivo. Additionally, compound 27 exerted rapid antidepressant effects caused by chronic restraint stress (CRS) and didn't show signs of addictive properties in the conditioned place preference (CPP) assays. Our study is the first to report that reversible MAGL inhibitors can treat chronic stress-induced depression effectively, which may provide a new potential therapeutic strategy for the discovery of an original class of safe, rapid antidepressant drugs.

Differences in psychiatric comorbidity patterns in patients diagnosed with chronic stress-induced exhaustion disorder and depression – A cohort study in the total population of Region Stockholm

The high prevalence of stress-related disorders and depression underscores the urgent need to unravel their impact on individual well-being. This study aim to investigate common psychiatric and stress-related diagnoses, along with postviral fatigue, in individuals with prior stress-induced exhaustion disorder (SED) and prior depression compared to those without prior SED or depression, and to study whether the psychiatric comorbidity patterns differ.The study includes individuals in Region Stockholm who, in 2011, did not have a diagnosis of SED or depression. ICD-10 diagnosis of SED, depression, or both, recorded in 2012–2013, were compared to individuals without prior SED or depression in a cohort (n = 1,362,886), aged 18 to 65. Odds ratios (OR) with 99 % confidence intervals, adjusted for age and neighborhood socioeconomic status, were calculated for psychiatric disorders and post-viral fatigue in 2014–2022.Patients with prior SED showed associations primarily with stress related diagnoses, including acute stress reaction, reaction to severe stress, as well as post-COVID-19 and post-viral fatigue syndrome. These ORs were all larger for SED than depression. Depression was primarily associated with post-traumatic stress disorder (PTSD), alcohol related and substance use disorders, schizophrenia, schizotypal disorders, delusional disorders, manic episode, bipolar affective disorder, persistent mood disorder, neurotic disorder, borderline personality disorder, autistic disorder, Asperger's syndrome, attention -deficit hyperactivity disorder, attention-deficit disorders ADHD/ADD), and suicide attempt. These ORs were all higher for depression, although autistic disorders, ADHD/ADD and PTSD were also highly associated with prior SED (OR > 3.5).The divergent psychiatric comorbidity patterns suggest different underlying mechanisms and clinical prognosis.

Chronic stress dysregulates the Hippo/YAP/14-3-3η pathway and induces mitochondrial damage in basolateral amygdala in a mouse model of depression.

Rationale: Recent evidence highlights the pivotal role of mitochondrial dysfunction in mood disorders, but the mechanism involved remains unclear. We studied whether the Hippo/YAP/14-3-3η signaling pathway mediates mitochondrial abnormalities that result in the onset of major depressive disorder (MDD) in a mouse model. Methods: The ROC algorithm was used to identify a subpopulation of mice that were exposed to chronic unpredictable mild stress (CUMS) and exhibited the most prominent depressive phenotype (Dep). Electron microscopy, biochemical assays, quantitative PCR, and immunoblotting were used to evaluate synaptic and mitochondrial changes in the basolateral amygdala (BLA). RNA sequencing was used to explore changes in the Hippo pathway and downstream target genes. In vitro pharmacological inhibition and immunoprecipitation was used to confirm YAP/14-3-3η interaction and its role in neuronal mitochondrial dysfunction. We used virus-mediated gene overexpression and knockout in YAP transgenic mice to verify the regulatory effect of the Hippo/YAP/14-3-3η pathway on depressive-like behavior. Results: Transcriptomic data identified a large number of genes and signaling pathways that were specifically altered from the BLA of Dep mice. Dep mice showed notable synaptic impairment in BLA neurons, as well as mitochondrial damage characterized by abnormal mitochondrial morphology, compromised function, impaired biogenesis, and alterations in mitochondrial marker proteins. The Hippo signaling pathway was activated in Dep mice during CUMS, and the transcriptional regulatory activity of YAP was suppressed by phosphorylation of its Ser127 site. 14-3-3η was identified as an important co-regulatory factor of the Hippo/YAP pathway, as it can respond to chronic stress and regulate cytoplasmic retention of YAP. Importantly, the integrated Hippo/YAP/14-3-3η pathway mediated neuronal mitochondrial dysfunction and depressive behavior in Dep mice. Conclusion: The integrated Hippo/YAP/14-3-3η pathway in the BLA neuron is critical in mediating depressive-like behaviors in mice, suggesting a causal role for this pathway in susceptibility to chronic stress-induced depression. This pathway therefore may present a therapeutic target against mitochondrial dysfunction and synaptic impairment in MDD.

Corydalis yanhusuo Polysaccharides Ameliorate Chronic Stress-Induced Depression in Mice through Gut Microbiota-Derived Short-Chain Fatty Acid Activation of 5-Hydroxytryptamine Signaling.

Depression, a prevalent psychiatric disorder, presents a serious health risk to humans. Increasing evidence suggested that the gut microbiota and the 5-hydroxytryptamine (5-HT) pathway both contribute significantly to depression. This research aimed to investigate how Corydalis yanhusuo polysaccharides (CYP) could potentially alleviate depression induced by chronic unpredictable mild stress in mice, as well as its underlying mechanism. The sucrose preference test, tail suspension test, and forced swimming test were employed to evaluate the behavior of mice. Enzyme-linked immunosorbent assay and PCR techniques were utilized to measure depression-related factors (dopamine [DA], 5-HT, norepinephrine [NE], brain-derived neurotrophic factor [BDNF], tryptophan hydroxylase 2 [TPH-2], 5-hydroxytryptophan [5-HTP], and tryptophan hydroxylase [TPH-1] levels). Hematoxylin and eosin staining and Nissl staining were conducted to observe histopathological changes in the hippocampus, the differences in the diversity of gut flora between groups were analyzed using 16S rRNA sequencing, and gas chromatography-mass spectrometry metabolomics was utilized to evaluate short-chain fatty acid (SCFA) concentrations. The findings indicated that CYP treatment increased the sucrose preference index, decreased the immobility time, and improved neuropathological injury. In depressed mice, CYP improved the dysregulation of the gut microbiota, and increased the SCFA levels. In addition, CYP enhanced the DA, 5-HT, NE, BDNF, and TPH-2 levels in the brain and the expression of 5-HTP and TPH-1 in the colon, while SCFAs were positively correlated with these levels. In summary, our study suggested that CYP may mitigate depression by ameliorating gut microbiota dysregulation, promoting the generation of SCFAs, and activation of 5-HT signaling expression.

Cell type-specific NRBF2 orchestrates autophagic flux and adult hippocampal neurogenesis in chronic stress-induced depression

Dysfunctional autophagy and impairment of adult hippocampal neurogenesis (AHN) each contribute to the pathogenesis of major depressive disorder (MDD). However, whether dysfunctional autophagy is linked to aberrant AHN underlying MDD remains unclear. Here we demonstrate that the expression of nuclear receptor binding factor 2 (NRBF2), a component of autophagy-associated PIK3C3/VPS34-containing phosphatidylinositol 3-kinase complex, is attenuated in the dentate gyrus (DG) under chronic stress. NRBF2 deficiency inhibits the activity of the VPS34 complex and impairs autophagic flux in adult neural stem cells (aNSCs). Moreover, loss of NRBF2 disrupts the neurogenesis-related protein network and causes exhaustion of aNSC pool, leading to the depression-like phenotype. Strikingly, overexpressing NRBF2 in aNSCs of the DG is sufficient to rescue impaired AHN and depression-like phenotype of mice. Our findings reveal a significant role of NRBF2-dependent autophagy in preventing chronic stress-induced AHN impairment and suggest the therapeutic potential of targeting NRBF2 in MDD treatment.

Preclinical Validation of Electrodes for Single Anodal Transcranial Direct Current Stimulation on Rat Model With Chronic Stress-Induced Depression

Transcranial direct current stimulation (tDCS) is an effective and safe non-invasive brain stimulation (NIBS) procedures to modulate neuronal excitability. The present preclinical study was carried out to validate the impact of the innovative high definition fabricated spiking Au/AgCI electrodes via non-invasive tDCS procedure on rat model with depression-like behaviour. In present study, chronic stress induced depression like behaviour rat model was developed over a period of 14-days. Further, the after-effects of NIBS procedures were investigated by providing a tDCS dose (2.00mA × 5.00minutes) by placing the electrodes on the interested region of the rat brain. The current study was performed in healthy rats, control rats with depression-like behaviour, and tDCS treated rats, which were used to examine the differential after-effects of tDCS dose. After single tDCS dose, a significant increase in average band power of electroencephalogram (EEG) has been observed (F(2, 15) = 8.376; P = 0.0036) alongside a significant increase in the glutamate level of hippocampus (F(2, 15) = 8.919; P = 0.0028), a significant reduction in immobility time (F(2, 15) = 7.552; P = 0.0054), and a significant increase in the percentage sucrose intake has been observed (F(2,15) = 5.941; P = 0.0126). Additionally, immunohistochemistry (IHC) showed a significant increase in theIba1 protein expression in microglia cell in the both cortex and hippocampus region (P < 0.05). Hence, the fabricated electrodes can deliver a tDCS dose that can penetrate up to the cortex and hippocampus regions from the surface of brain non-invasively within tolerable and safety limits.

Microglial Responses to Stress-Induced Depression: Causes and Consequences.

Chronic stress is a major risk factor for various psychiatric diseases, including depression; it triggers various cellular and structural changes, resulting in the alteration of neurocircuitry and subsequent development of depression. Accumulating evidence suggests that microglial cells orchestrate stress-induced depression. Preclinical studies of stress-induced depression revealed microglial inflammatory activation in regions of the brain that regulate mood. Although studies have identified several molecules that trigger inflammatory responses in microglia, the pathways that regulate stress-induced microglial activation remain unclear. Understanding the exact triggers that induce microglial inflammatory activation can help find therapeutic targets in order to treat depression. In the current review, we summarize the recent literature on possible sources of microglial inflammatory activation in animal models of chronic stress-induced depression. In addition, we describe how microglial inflammatory signaling affects neuronal health and causes depressive-like behavior in animal models. Finally, we propose ways to target the microglial inflammatory cascade to treat depressive disorders.

Decreased phase information transfer from the mPFC to the BLA: During exploratory behavior in CUMS rats.

Depression is a mental disorder characterized by aberrant exploratory behavior. Environmental factors, such as chronic stress, are commonly used to induce depression-like behavior in rodent models. The medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) are crucial sites in subjects with chronic stress-induced depression. The transmission of amplitude information from the mPFC to the BLA was abated during exploratory behavior in depressive rats; however, the nature of the phase interaction between these two sites remains unknown. We used chronic unpredictable mild stress (CUMS) to model depression in rats and acquired local field potentials (LFPs) via multiple electrodes implanted in the mPFC and the BLA while rats (both the control and CUMS groups, respectively) were allowed to explore freely in an open field. The weighted phase lag index (WPLI) within the mPFC and the BLA and phase transfer entropy (PTE) from the mPFC to BLA were computed for two groups of rats (control and CUMS rats) to quantify the phase information transmission. Rats subjected to CUMS showed a decrease in exploratory behavior. The WPLI within the mPFC and the BLA showed strikingly higher phase synchrony at theta frequencies (4-12 Hz) than other frequency bands during exploratory behavior in both the control and CUMS groups. The results of theta PTE from the mPFC to BLA showed that PTE was significantly decreased in the CUMS group compared with the control group. These findings demonstrated that attenuated phase information transfer might restrain exploratory behavior in CUMS rats.

A thalamic circuit facilitates stress susceptibility via melanocortin 4 receptor‐mediated activation of nucleus accumbens shell

Central melanocortin 4 receptor (MC4R) has been reported to induce anhedonia via eliciting dysfunction of excitatory synapses. It is evident that metabolic signals are closely related to chronic stress-induced depression. Here, we investigated that a neural circuit is involved in melanocortin signaling contributing to susceptibility to stress. Chronic social defeat stress (CSDS) was used to develop depressive-like behavior. Electrophysiologic and chemogenetic approaches were performed to evaluate the role of paraventricular thalamus (PVT) glutamatergic to nucleus accumbens shell (NAcsh) circuit in stress susceptibility. Pharmacological and genetic manipulations were applied to investigate the molecular mechanisms of melanocortin signaling in the circuit. CSDS increases the excitatory neurotransmission in NAcsh through MC4R signaling. The enhanced excitatory synaptic input in NAcsh is projected from PVT glutamatergic neurons. Moreover, chemogenetic manipulation of PVTGlu -NAcsh projection mediates the susceptibility to stress, which is dependent on MC4R signaling. Overall, these results reveal that the strengthened excitatory neurotransmission in NAcsh originates from PVT glutamatergic neurons, facilitating the susceptibility to stress through melanocortin signaling. Our results make a strong case for harnessing a thalamic circuit to reorganize excitatory synaptic transmission in relieving stress susceptibility and provide insights gained on metabolic underpinnings of protection against stress-induced depressive-like behavior.

Innate immune tolerance against adolescent intermittent alcohol exposure-induced behavioral abnormalities in adult mice

It has been reported that pre-stimulation of the innate immune system in animals can prevent chronic stress-induced depression- and anxiety-like behaviors in animals, suggesting the possibility that innate immune stimulants may prevent the pathogenesis of neuropsychiatric disorders. Alcohol use, especially when it begins in adolescence, is a risk factor for the development of neuropsychiatric disorders in adulthood. Preventing the pathological changes induced by alcohol exposure in adolescence could be of great importance for improving human mental health. Here, we investigated whether pre-stimulation of the innate immune system can prevent the behavioral abnormalities in a disease model induced by adolescent intermittent alcohol exposure (AIE). The results showed that a single injection of lipopolysaccharide (LPS) injection (100 μg/kg) one day before alcohol exposure prevented the AIE-induced depression- and anxiety-like behaviors in the tail suspension test, forced swimming test, sucrose preference test, elevated pluz maze test, light–dark test, and open field test in adult mice. Single LPS injection (100 μg/kg) before alcohol exposure also transformed the AIE-induced neuroinflammatory responses in the hippocampus and prefrontal cortex in adult mice to an anti-inflammatory phenotype. Suppression of the innate immune response by minocycline pretreatment abolished the preventive effect of LPS on AIE-induced abnormalities and neuroinflammatory responses in the hippocampus and prefrontal cortex in adult mice. These results indicate that pre-stimulation of the innate immune system may prevent the AIE-induced depression- and anxiety-like behaviors in adult mice by preventing neuroinflammation. This may help to develop new strategies to prevent neuropsychiatric disorders induced by adolescent alcohol exposure.

Neferine alleviates chronic stress-induced depression by regulating monoamine neurotransmitter secretion and gut microbiota structure.

Neferine (Nef) might possess anti-depressive properties; however, its therapeutic effects are yet to be elucidated. Therefore, in this study, we aimed to explore the anti-depressant property of Nef using a mouse model of chronic stress-induced depression. Fifteen depression-prone mice were randomly selected and divided into three groups, namely, the model, Nef, and fluoxetine (Flu) groups. We observed that in tail suspension and forced swimming tests, the Nef and Flu treatments significantly decreased the immobility time of the depressed mice, and increased their sucrose preference indices. Moreover, both Nef and Flu treatments induced significant increases in the levels of anti-depressant neurotransmitters, including dopamine (DA), serotonin (5-HT), and norepinephrine (NE), and also reduced pathological damage to the hippocampus of the depressed mice. Incidentally, Illumina MiSeq sequencing analysis demonstrated that the relative abundance of Lactobacillus in the intestinal microbiota of depressed mice was restored after Nef/Flu treatment. Moreover, colonic Lactobacillus abundance was positively correlated with the levels of DA, 5-HT, and NE in the hippocampus of the mice. In conclusion, Nef improved monoamine neurotransmitter secretion and modulated the intestinal flora structure, particularly the abundance of Lactobacillus. Hence, it showed considerable anti-depressant potential, and might be a prospective anti-depressant therapeutic agent.

Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain

BackgroundDepression is a recurrent and devastating mental disease that is highly prevalent worldwide. Prolonged exposure to stressful events or a stressful environment is detrimental to mental health. In recent years, an inflammatory hypothesis has been implicated in the pathogenesis of stress-induced depression. However, less attention has been given to the initial phases, when a series of stress reactions and immune responses are initiated. Peripheral CD4+ T cells have been reported as the major contributors to the occurrence of mental disorders. Chronic stress exposure-evoked release of cytokines can promote the differentiation of peripheral CD4+ cells into various phenotypes. Among them, Th17 cells have attracted much attention due to their high pathogenic potential in central nervous system (CNS) diseases. Thus, we intended to determine the crucial role of CD4+ Th17 cells in the development of specific subtypes of depression and unravel the underpinnings of their pathogenetic effect.MethodsIn the present research, a daily 6-h restraint stress paradigm was employed in rats for 28 successive days to mimic the repeated mild and predictable, but inevitable environmental stress in our daily lives. Then, depressive-like symptoms, brain–blood barrier (BBB) permeability, neuroinflammation, and the differentiation and functional changes of CD4+ cells were investigated.ResultsWe noticed that restrained rats showed significant depressive-like symptoms, concomitant BBB disruption and neuroinflammation in the dorsal striatum (DS). We further observed a time-dependent increase in thymus- and spleen-derived naïve CD4+ T cells, as well as the aggregation of inflammatory Th17 cells in the DS during the period of chronic restraint stress (CRS) exposure. Moreover, increased Th17-derived cytokines in the brain can further impair the BBB integrity, thus allowing more immune cells and cytokines to gain easy access to the CNS. Our findings suggested that, through a complex cascade of events, peripheral immune responses were propagated to the CNS, and gradually exacerbated depressive-like symptoms. Furthermore, inhibiting the differentiation and function of CD4+ T cells with SR1001 in the early stages of CRS exposure ameliorated CRS-induced depressive-like behaviour and the inflammatory response.ConclusionsOur data demonstrated that inflammatory Th17 cells were pivotal in accelerating the onset and exacerbation of depressive symptoms in CRS-exposed rats. This subtype of CD4+ T cells may be a promising therapeutic target for the early treatment of stress-induced depression.