Chronic Stress-Induced Elevation of Melanin-Concentrating Hormone in the Locus Coeruleus Inhibits Norepinephrine Production and Associated With Depression-Like Behaviors in Rats.

BACKGROUND: Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that projects throughout the central nervous system, including the noradrenergic locus coeruleus (LC). Our previous study suggested that MCH/MCH receptor 1 (MCHR1) in the LC may be involved in the regulation of depression. The present study investigated whether the role of MCH/MCHR1 in the LC in depression-like behaviors is associated with the regulation of norepinephrine. METHOD: Chronic unpredictable stress (CUS) and an acute intra-LC microinjection of MCH induced depression-like behaviors in rats. The MCHR1 antagonist SNAP-94847 was also microinjected in the LC in rats that were suffering CUS or treated with MCH. The sucrose preference, forced swim, and locomotor tests were used for behavioral evaluation. Immunofluorescence staining, enzyme-linked immunosorbent assay, western blot, and high-performance liquid chromatography with electrochemical detection were used to explore the mechanism of MCH/MCHR1 in the regulation of depression-like behaviors. RESULTS: CUS induced an abnormal elevation of MCH levels and downregulated MCHR1 in the LC, which was highly correlated with the formation of depression-like behaviors. SNAP-94847 exerted antidepressant effects in CUS-exposed rats by normalizing tyrosine hydroxylase, dopamine ß hydroxylase, and norepinephrine in the LC. An acute microinjection of MCH induced depression-like behaviors through its action on MCHR1. MCHR1 antagonism in the LC significantly reversed the MCH-induced downregulation of norepinephrine production by normalizing MCHR1-medicated cAMP-PKA signaling. CONCLUSIONS: Our study confirmed that the MCH/MCHR1 system in the LC may be involved in depression-like behaviors by downregulating norepinephrine production. These results improve our understanding of the pathogenesis of depression that is related to the MCH/MCHR1 system in the LC.

Chronic social comparison elicits depression- and anxiety-like behaviors and alterations in brain-derived neurotrophic factor expression in male rats.

Social comparison is a fundamental human characteristic; however, long-term social comparison may induce psychological stress and can lead to depression and anxiety. Recent studies have shown that nonhuman primates compare themselves with others; however, no studies have investigated whether social comparisons exist among rodents. In the present study, we established a rat model of social comparison. This model was subsequently used to examine the effects of the differential environment of a partner on depression- and anxiety-like behaviors in male rats, as well as to assess the changes in serum, medial prefrontal cortex (mPFC), and dorsal hippocampus brain-derived neurotrophic factor (BDNF) levels induced by long-term social comparison. Compared to rats whose partners were exposed to the same environment, rats whose partners were exposed to two combined enriched environmental stimuli for 14 days showed significantly decreased social novelty preference and sucrose consumption. No anxiety-like behaviors were observed. Rats whose partners were exposed to one enriched environment for 31 days showed significantly increased immobility time in the forced swimming test, and significantly decreased time spent in the center area in the open-field test. Further, rats whose partners were exposed to one enriched environment for 31 days showed lower BDNF levels in the mPFC and dorsal hippocampus, but not following partner exposure for 14 days. These results suggest that social comparisons exist in rats and can induce psychosocial stress and other negative affect. This model will not only provide the possibility to reveal the neurobiological basis of the emotional impact of social comparison, but could also be used to confirm the conservative evolutionary characteristics of social comparison as a behavioral attribute.

Chronic Pb Exposure Induces Anxiety and Depression-like Behaviors in Mice via Excitatory Neuronal Hyperexcitability in Ventral Hippocampal Dentate Gyrus.

Lead (Pb) is a widespread neurotoxic pollutant. Pb exposure is associated with mood disorders, with no well-established neural mechanisms elucidated. In the present study, we aimed to investigate whether excitatory neurons in the dentate gyrus subregion of the ventral hippocampus (vDG) played a key role in Pb-induced anxiety and depression-like behaviors. C57BL/6 mice were exposed to 100 ppm Pb starting on day 1 of pregnancy until experiments were performed using the offspring. Behavioral studies suggested that chronic Pb exposure triggered anxiety and depression-like behaviors. A combination of electrophysiological, optogenetic, and immunohistochemistry experiments was conducted. Results showed that Pb exposure resulted in excitatory neuronal hyperexcitability in vDG and that the behavioral deficits caused by Pb exposure could be rescued by inhibition of excitatory neuronal activity. Moreover, it was found that the action potential (AP) threshold of excitatory neurons was decreased by electrophysiological recordings. Our study demonstrates a significant role for excitatory neurons in vDG in Pb-induced anxiety and depression-like behaviors in mice, which is likely a result of decreased AP threshold. These outcomes can serve as an important basis for understanding mechanisms of anxiety and depression under environmental Pb exposure and help in the design of therapeutic strategies.

lncRNA MIR155HG Alleviates Depression-Like Behaviors in Mice by Regulating the miR-155/BDNF Axis.

Depression is one of most common psychiatric disorders, and the detailed molecular mechanism remains to be fully elucidated. Brain-derived neurotrophic factor (BDNF) is a critical neurotrophic factor that is decreased and closely involved in the development of depression. Noncoding RNAs are central regulators of cellular activities that modulate target genes. However, the roles of long noncoding RNA (lncRNA) MIR155HG and miRNA-155 (miR-155) in the pathophysiology of depression are unclear. In the present study, we aimed to explore the effects of lncRNA MIR155HG and miR-155 on the development of depression and uncover the underlying molecular mechanism. Real-time quantitative polymerase chain reaction was used to examine the expression of MIR155HG and miR-155. Western blotting was applied to measure the expression of BDNF. A luciferase reporter assay was utilized to determine the regulatory relationship between MIR155HG and miR-155. Our current work found that lncRNA MIR155HG and BDNF levels decreased while miR-155 levels increased in the hippocampal region of CUMS (chronic unpredictable mild stress) mice, a well-accepted mouse model of depression. Moreover, MIR155HG rescued while miR-155 exacerbated the depression-like behaviors of CUMS mice. Through bioinformatics analysis and luciferase reporter assays, we found that MIR155HG directly bound to and negatively modulated the expression of miR-155. Moreover, increased miR-155 was found to repress the expression of BDNF, a critical neurotrophic factor that has been reported to alleviate the depression-like behaviors of CUMS mice. Our present study revealed that lncRNA MIR155HG protected CUMS mice by regulating the miR-155/BDNF axis. Our study aimed to understand the pathophysiology of depression and provided potential therapeutic targets to diagnose and treat depression.

An Adapted Chronic Constriction Injury of the Sciatic Nerve Produces Sensory, Affective, and Cognitive Impairments: A Peripheral Mononeuropathy Model for the Study of Comorbid Neuropsychiatric Disorders Associated with Neuropathic Pain in Rats.

BACKGROUND: Chronic constriction injury (CCI) is a model of neuropathic pain induced by four loose ligatures around the sciatic nerve. This work aimed to investigate the sensory, affective, cognitive, and motor changes induced by an adaptation of the CCI model by applying a single ligature around the sciatic nerve. METHODS: Mechanical allodynia was measured from day 1 to day 28 postsurgery by the von Frey test. The beam walking test (BWT) was conducted weekly until 28 days after surgery. Anxiety- and depression-like behaviors, and cognitive performance were assessed through the open field (OF), forced swimming (FS), and novel object recognition (NOR) tests, respectively, 21 days after surgery. RESULTS: The two CCI models, both Bennett and Xie's model (four ligatures of the sciatic nerve) and a modification of it (one ligature), induced mechanical allodynia, increased immobility in the FS, and reduced recognition index in the NOR. The exploratory behavior and time spent in the central part of the arena decreased, while the defensive behavior increased in the OF. The animals subjected to the two CCI models showed motor alterations in the BWT; however, autotomy was observed only in the group with four ligatures and not in the group with a single ligature. CONCLUSIONS: Overall these results demonstrate that our adapted CCI model, using a single ligature around the sciatic nerve, induces sensory, affective, cognitive, and motor alterations comparable to the CCI model with four ligatures without generating autotomy. This adaptation to the CCI model may therefore represent an appropriate and more easily performed model for inducing neuropathic pain and study underlying mechanisms and effective treatments.

The role of pituitary adenylyl cyclase activating polypeptide in affective signs of nicotine withdrawal.

Recent evidence implicates endogenous pituitary adenylyl cyclase activating polypeptide (PACAP) in the aversive effect of nicotine. In the present study, we assessed if nicotine-induced conditioned place preference (CPP) or affective signs of nicotine withdrawal would be altered in the absence of PACAP and if there were any sex-related differences in these responses. Male and female mice lacking PACAP and their wild-type controls were tested for baseline place preference on day 1, received conditioning with saline or nicotine (1 mg/kg) on alternate days for 6 days and were then tested for CPP the next day. Mice were then exposed to four additional conditioning and were tested again for nicotine-induced CPP 24 hr later. Controls were conditioned with saline in both chambers and tested similarly. All mice were then, 96 hr later, challenged with mecamylamine (3 mg/kg), and tested for anxiety-like behaviors 30 min later. Mice were then, 2 hr later, forced to swim for 15 min and then tested for depression-like behaviors 24 hr later. Our results showed that male but not female mice lacking PACAP expressed a significant CPP that was comparable to their wild-type controls. In contrast, male but not female mice lacking PACAP exhibited reduced anxiety- and depression-like behaviors compared to their wild-type controls following the mecamylamine challenge. These results suggest that endogenous PACAP is involved in affective signs of nicotine withdrawal, but there is a sex-related difference in this response.

Downregulation of hippocampal SIRT6 activates AKT/CRMP2 signaling and ameliorates chronic stress-induced depression-like behavior in mice.

Sirtuin 6 (SIRT6) has been reported to play a key role in cognitive function and mood regulation, yet its role in mood disorders is not completely understood. Here, we confirmed that knockdown of hippocampal SIRT6 alleviated depression-like behaviors induced by chronic unpredictable stress (CUS) in mice. Our in vitro data showed that SIRT6 negatively regulated protein kinase B (AKT) signaling by deacetylating histone 3 at Lys9 and Lys56. Knockdown of SIRT6 significantly increased AKT phosphorylation activity, while decreased collapsin response mediator protein 2 (CRMP2) phosphorylation activity. Furthermore, pharmacologic inhibition of SIRT6 by ferulic acid (FA) (40 or 80 mg· kg-1 per day, i.g.) could activate AKT/CRMP2 pathway in vitro, which has been proved to exert an antidepressant-like effect on CUS-induced depressive models. In conclusion, our study suggested that hippocampal SIRT6 contributes to the performance of depression-like behaviors by suppressing AKT/CRMP2 signaling, and FA ameliorates CUS-induced depression-like behaviors in mice as a potential pharmacologic inhibitor of SIRT6.

The Requirement of L-Type Voltage-Dependent Calcium Channel (L-VDCC) in the Rapid-Acting Antidepressant-Like Effects of Scopolamine in Mice.

Background: Previous studies have shown that a low dose of scopolamine produces rapid-acting antidepressant-like actions in rodents. Understanding the mechanisms underlying this effect and the dose-dependent variations of drug responses remains an important task. L-type voltage-dependent calcium channels were found to mediate rapid-acting antidepressant effects of certain medications (e.g., ketamine). Therefore, it is of great interest to determine the involvement of L-type voltage-dependent calcium channels in the action of scopolamine. Methods: Herein, we investigated the mechanisms underlying behavioral responses to various doses of scopolamine in mice to clarify the involvement of L-type voltage-dependent calcium channels in its modes of action. Open field test, novel object recognition test, and forced swimming test were performed on mice administered varied doses of scopolamine (0.025, 0.05, 0.1, 1, and 3 mg/kg, i.p.) alone or combined with L-type voltage-dependent calcium channel blocker verapamil (5 mg/kg, i.p.). Then, the changes in brain-derived neurotrophic factor and neuropeptide VGF (nonacronymic) levels in the hippocampus and prefrontal cortex of these mice were analyzed. Results: Low doses of scopolamine (0.025 and 0.05 mg/kg) produced significant antidepressant-like effects in the forced swimming test, while higher doses (1 and 3 mg/kg) resulted in significant memory deficits and depressive-like behaviors. Moreover, the behavioral changes in responses to various doses may be related to the upregulation (0.025 and 0.05 mg/kg) and downregulation (1 and 3 mg/kg) of brain-derived neurotrophic factor and VGF in the hippocampus and prefrontal cortex in mice. We further found that the rapid-acting antidepressant-like effects and the upregulation on brain-derived neurotrophic factor and VGF produced by a low dose of scopolamine (0.025 mg/kg) were completely blocked by verapamil. Conclusions: These results indicate that L-type voltage-dependent calcium channels are likely involved in the behavioral changes in response to various doses of scopolamine through the regulation of brain-derived neurotrophic factor and VGF levels.

Decreased Prostaglandin D2 Levels in Major Depressive Disorder Are Associated with Depression-Like Behaviors.

Background: Prostaglandin (PG) D2 is the most abundant prostaglandin in the mammalian brain. The physiological and pharmacological actions of PGD2 in the central nervous system seem to be associated with some of the symptoms exhibited by patients with major depressive disorder. Previous studies have found that PGD2 synthase was decreased in the cerebrospinal fluid of major depressive disorder patients. We speculated that there may be a dysregulation of PGD2 levels in major depressive disorder. Methods: Ultra-performance liquid chromatography-tandem mass spectrometry coupled with a stable isotopic-labeled internal standard was used to determine PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice. A total of 32 drug-free major depressive disorder patients and 30 healthy controls were recruited. An animal model of depression was constructed by exposing mice to 5 weeks of chronic unpredictable mild stress. To explore the role of PGD2 in major depressive disorder, selenium tetrachloride was administered to simulate the change in PGD2 levels in mice. Results: Mice exposed to chronic unpredictable mild stress exhibited depression-like behaviors, as indicated by reduced sucrose preference and increased immobility time in the forced swimming test. PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice were both decreased compared with their corresponding controls. Further inhibiting PGD2 production in mice resulted in an increased immobility time in the forced swimming test that could be reversed by imipramine. Conclusion: Decreased PGD2 levels in major depressive disorder are associated with depression-like behaviors.

Radioprotective effect of Ginkgolide B on brain: the mediating role of DCC/MST1 signaling.

PURPOSE: The risk of brain exposure to ionizing radiation increases gradually due to the extensive application of nuclear technology in medical, industrial, and aerospace fields. Radiation-induced brain injury (RBI) is highly likely to cause a wide range of neurological complications, including schizophrenia, Alzheimer's disease (AD), depression. Ginkgolide B (GB) is one of the effective active components extracted from ginkgo biloba leaves, exerts protective effects on CNS, which is involved in the regulation of the Hippo signaling pathway. MST1, as one of the core kinases of the Hippo pathway, participated in regulating cell proliferation, differentiation, and apoptosis. However, it remains unclear whether GB attenuates radiation brain injury (RBI) and whether the radioprotective effect of GB refers to MST1 signaling. Hence, our study aimed to explore the radiation protection effect and the potential mechanism of GB. MATERIALS AND METHODS: C57BL/6 mice were stimulated with an X-ray (20 Gy) to establish an RBI model. Then, morris water maze test (MWM) and step-down passive avoidance test (SDPAT) were used to assess the learning and memory function of mice. The open field test (OFT), tail suspension test (TST), and forced swimming test (FST) were used to assess changes in locomotor activity and hopelessness. Besides, X-ray-stimulated SH-SY5Y cells were used to verify the radioprotective effect of GB. Immunofluorescence double staining, Dihydroethidium (DHE), western blot, and flow cytometry were used to explore the role of DCC/MST1 signaling in RBI. RESULTS: In this study, X-ray-treated mice exhibited cognitive impairment and depression-like behavior, which was ameliorated by GB treatment. GB also reduced the ROS production and the number of TUNEL-positive cells in the hippocampus. Moreover, GB increased the protein levels of p-AKT and Bcl2, while decreased the protein levels of MST1, p-p38, p-JNK, cleaved-caspase-3 and Bax both in vivo and in vitro. Additionally, exogenous Netrin-1 alleviated X-ray-induced ROS production and apoptosis, whereas knockout of Netrin-1 receptor DCC abolished the protective effect of GB. CONCLUSION: Oxidative stress and MST1-mediated neuronal apoptosis participated in radiation-induced cognitive impairment and depression-like behaviors, and modulation of DCC by GB was an effective intervention against RBI.

DAPK1 mediates cognitive dysfunction and neuronal apoptosis in PSD rats through the ERK/CREB/BDNF signaling pathway.

Post-stroke depression (PSD) is one of the most common mental sequelae after a stroke and can damage the brain. Although PSD has garnered increasing attention in recent years, the precise mechanism remains unclear. Studies have indicated that the expression of DAPK1 is elevated in various neurodegenerative conditions, including depression, ischemic stroke, and Alzheimer's disease. However, the specific molecular mechanism of DAPK1-mediated cognitive dysfunction and neuronal apoptosis in PSD rats is unclear. In this study, we established a rat model of PSD, and then assessed depression-like behaviors and cognitive dysfunction in rats using behavioral tests. In addition, we detected neuronal apoptosis and analyzed the expression of DAPK1 protein and proteins related to the ERK/CREB/BDNF signaling pathway. The findings revealed that MCAO combined with CUMS can induce more severe depression-like behaviors and cognitive dysfunction in rats, while overexpression of DAPK1 may hinder the downstream ERK/CREB/BDNF signaling pathways, resulting in neuronal loss and exacerbation of brain tissue damage. In this study, we will focus on DAPK1 and explore its role in PSD.

Effects of chronic intermittent cold stress on anxiety-depression-like behaviors in adolescent rats.

Stress, which triggers numerous physiological and behavioral responses in the organism, is a significant risk factor that contributes to the development of psychiatric disorders such as depression and anxiety. This study aimed to investigate the inflammation, oxidative stress status, anxiety, and depression-like behaviors of adolescent rodents exposed to chronic intermittent cold stress. Adolescent male rats were subjected to a modified chronic intermittent cold stress model (21 days, 1 hour/day, 4 °C). Depression-like behaviors were evaluated using the sucrose preference and forced swimming tests, while anxiety-like behaviors were assessed using the open field, elevated plus maze, and light-dark box tests. We measured levels of cortisol, tumor necrosis factor-α, interleukin-1ß, brain-derived natriuretic factor, reactive oxygen species, malondialdehyde, total oxidants and antioxidants, and other chemicals in the prefrontal cortex, thalamus, striatum, and hippocampus brain regions of rats using ELISA and colorimetric methods. Data were analyzed using Student's t-test and Pearson correlation analysis. After the cold stress treatment, both anxiety and depression-like behaviors increased remarkably in the subjects. Our study revealed significant changes in various brain regions among the stress-exposed subjects. Cold stress resulted in decreased BDNF levels in the prefrontal cortex and striatum (p < 0.05), increased cortisol levels in the prefrontal cortex (p < 0.05), increased IL-1ß levels in the hippocampus and thalamus (p < 0.05), increased protein carbonyl levels in the striatum (p < 0.05), and decreased TAS in the prefrontal cortex and thalamus (p < 0.05). Adolescent rats exposed to cold exhibit both anxiety- and depression-like behaviors. This study observed an increase in inflammation in various brain regions, yet the responses to stress varied. Our findings suggest that adolescence is a period of heightened sensitivity to stress, which can lead to dramatic consequences.

Amelioration of nonylphenol-induced anxiety/depression-like behaviors in male rats using green tea and Zn-Se tea interventions.

Objective: This study aimed to investigate the effects of exposure to nonylphenol (NP) on anxiety/depression-like behaviors in rats and alleviation of those effects via green tea and zinc selenium (Zn-Se) tea interventions. Material and Methods: Totally, 40 male specific-pathogen free (SPF) Sprague-Dawley (SD) male rats were randomly divided into four groups (n = 10 rats per group): control group (5 ml/kg corn oil), NP group (40 mg/kg NP), NP + GT group (40 mg/kg NP + 1 g/kg/day green tea), and NP + Zn-Se tea group (40 mg/kg NP + 1 g/kg/day ZST). All dose-based groups received oral gavage of either corn oil or drugs over a 6-month period: NP at a dosage of 40 mg/kg/day was administered to rats for the initial 3 months, followed by a combination of NP with green tea and NP with Zn-Se tea for the subsequent 3 months. Results: Tea intervention resulted in weight loss in rats. The hippocampal tissue NP level in the tea group was slightly lower than that in the NP group. Following tea intervention, compared with the NP group, the residence time in the light-dark box test was shortened PGT = 0.048, P < 0.001), and the number of entries into the closed arm in the elevated plus maze test in the tea-treated group was significantly reduced. In addition, the immobility time in the central square in the open field test decreased. The sucrose preference index score in the sucrose preference test increased, and the immobility time in the forced swimming test was reduced (PGT = 0.049, PZST < 0.001). The effects of Zn-S e tea were superior to green tea. The damage to the hippocampal tissues in the group treated with tea was less than that in the NP group. The cellular arrangement was tighter with degeneration, deepstaining, and pyknotic nerve cells were visible. The nuclei in the NP group were atrophied, and the cells were sparsely arranged. Compared with the control group, serum brain-derived neurotrophic factor (BDNF) level was lower in the NP group. The serum corticosterone level in the NP group was elevated. Compared with the NP group, serum corticosterone level was reduced in the NP + Zn-Se tea group. Conclusion: Chronic NP exposure induced anxiety/depression-like behaviors in rats. Green tea effectively reduced the damage to the hippocampus and prefrontal cortex induced by NP. The effects of Zn-Se tea were slightly more noticeable than those of conventional green tea. Highlights: 1) Chronic NP exposure induced anxiety/depression-like behaviors in rats.2) Zn-Se tea reduced the damage of hippocampal and prefrontal cortex induced by NP.3) NP-induced depression accompanied by the changes of BDNF, CORT and neuropathology.

Gut microbiota from sigma-1 receptor knockout mice induces depression-like behaviors and modulates the cAMP/CREB/BDNF signaling pathway.

Introduction: Depression is a common mental disorder that affects approximately 350 million people worldwide. Much remains unknown about the molecular mechanisms underlying this complex disorder. Sigma-1 receptor (Sig-1R) is expressed at high levels in the central nervous system. Increasing evidence has demonstrated a close association between the Sig-1R and depression. Recently, research has suggested that the gut microbiota may play a crucial role in the development of depression. Methods: Male Sig-1R knockout (Sig-1R KO) and wild-type (WT) mice were used for this study. All transgenic mice were of a pure C57BL/6J background. Mice received a daily gavage of vancomycin (100 mg/kg), neomycin sulfate (200 mg/kg), metronidazole (200 mg/kg), and ampicillin (200 mg/kg) for one week to deplete gut microbiota. Fecal microbiota transplantation (FMT) was conducted to assess the effects of gut microbiota. Depression-like behaviors was evaluated by tail suspension test (TST), forced swimming test (FST) and sucrose preference test (SPT). Gut microbiota was analyzed by 16s rRNA and hippocampal transcriptome changes were assessed by RNA-seq. Results: We found that Sig-1R knockout induced depression-like behaviors in mice, including a significant reduction in immobility time and an increase in latency to immobility in the FST and TST, which was reversed upon clearance of gut microbiota with antibiotic treatment. Sig-1R knockout significantly altered the composition of the gut microbiota. At the genus level, the abundance of Alistipes, Alloprevotella, and Lleibacterium decreased significantly. Gut microbiota dysfunction and depression-like phenotypes in Sig-1R knockout mice could be reproduced through FMT experiments. Additionally, hippocampal RNA sequencing identified multiple KEGG pathways that are associated with depression. We also discovered that the cAMP/CREB/BDNF signaling pathway is inhibited in the Sig-1R KO group along with lower expression of neurotrophic factors including CTNF, TGF-α and NGF. Fecal bacteria transplantation from Sig-1R KO mice also inhibited cAMP/CREB/BDNF signaling pathway. Discussion: In our study, we found that the gut-brain axis may be a potential mechanism through which Sig-1R regulates depression-like behaviors. Our study provides new insights into the mechanisms by which Sig-1R regulates depression and further supports the concept of the gut-brain axis.

Stress relief as a natural resilience mechanism against depression-like behaviors.

Relief, the appetitive state after the termination of aversive stimuli, is evolutionarily conserved. Understanding the behavioral role of this well-conserved phenomenon and its underlying neurobiological mechanisms are open and important questions. Here, we discover that the magnitude of relief from physical stress strongly correlates with individual resilience to depression-like behaviors in chronic stressed mice. Notably, blocking stress relief causes vulnerability to depression-like behaviors, whereas natural rewards supplied shortly after stress promotes resilience. Stress relief is mediated by reward-related mesolimbic dopamine neurons, which show minute-long, persistent activation after stress termination. Circuitry-wise, activation or inhibition of circuits downstream of the ventral tegmental area during the transient relief period bi-directionally regulates depression resilience. These results reveal an evolutionary function of stress relief in depression resilience and identify the neural substrate mediating this effect. Importantly, our data suggest a behavioral strategy of augmenting positive valence of stress relief with natural rewards to prevent depression.

Neurotoxicity of melittin: Role of mitochondrial oxidative phosphorylation system in synaptic plasticity dysfunction.

Melittin (Mel), a main active peptide component of bee venom, has been proven to possess strong antitumor activity. Previous studies have shown that Mel caused severe cell membrane lysis and acted on the central nervous system (CNS). Here, this study was designed to investigate the effects of Mel on CNS and explore the potential mechanism. We confirmed the neurotoxic effect of melittin by in vivo and in vitro experiments. After subcutaneous administration of Mel (4 mg/kg, 8 mg/kg) for 14 days, the mice exhibited obvious depression-like behavior in a dose dependent manner. Besides, RNA-sequencing analysis revealed that oxidative phosphorylation (OXPHOS) signaling pathway was mostly enriched in hippocampus. Consistently, we found that Mel distinctly inhibited the activity of OXPHOS complex I and induced oxidative stress injury. Moreover, Mel significantly induced synaptic plasticity dysfunction in hippocampus via BDNF/TrkB/CREB signaling pathway. Taken together, the neurotoxic effect of Mel was involved in impairing OXPHOS system and hippocampal synaptic plasticity. These novel findings provide new insights into fully understanding the health risks of Mel and are conducive to the development of Mel related drugs.

Investigating the antidepressant effect of Ziyan green tea on chronic unpredictable mild stress mice through fecal metabolomics.

Introduction: Some studies have shown the effectiveness of tea in reducing depression. Gut flora dysfunction is strongly associated with depression. The mechanism by which Ziyan green tea ameliorates depression is not clear. Methods: In this study, we examined the impact of Ziyan green tea on mice exhibiting symptoms similar to depression. We specifically focused on the role of intestinal flora and its metabolites. We first established a chronic unpredictable mild stress (CUMS) mouse model to induce depressive symptoms and conducted behavioural tests, biochemical tests, and pathological tissue analysis. We also investigated gut microbiota changes by 16S rRNA sequencing and measured faecal metabolites in mice using UHPLC-MS/MS. Results: The results showed that Ziyan green tea intervention improved depression-like behaviour, neurobiochemical factors, and reduced levels of pro-inflammatory factors in CUMS mice. Spearman's correlation analysis showed that different microbial communities (Corynebacterium, Faecalibaculum, Enterorhabdus, Desulfovibrio) correlation with differential metabolites (Cholic acid, Deoxycholic acid, etc.) and depression-related biochemical indicators (5-HT, DA, BDNF, IL-6, and TNF-α). Discussion: In conclusion, our findings suggest that both low and high-dose interventions of Ziyan green tea have positive preventive effects on CUMS mice without dose dependence, partly because they mainly affect intestinal Purine Metabolism, Bile Acid Biosynthesis and Cysteine Metabolism in CUMS mice, thus stimulating brain 5-HT, DA and BDNF, and decreasing the inflammatory factors IL-6, TNF-α, activate the composition of intestinal flora, improve the intestinal flora environment and thus promote the production of intestinal metabolites, which can be used for depression treatment. It is suggested that Ziyan green tea may achieve an antidepressant effect through the gut-microbiota-brain axis.

Acid-Sensing Ion Channel 1a Contributes to the Prefrontal Cortex Ischemia-Enhanced Neuronal Activities in the Amygdala.

Following a stroke, the emergence of amygdala-related disorders poses a significant challenge, with severe implications for post-stroke mental health, including conditions such as anxiety and depression. These disorders not only hinder post-stroke recovery but also elevate mortality rates. Despite their profound impact, the precise origins of aberrant amygdala function after a stroke remain elusive. As a target of reduced brain pH in ischemia, acid-sensing ion channels (ASICs) have been implicated in synaptic transmission after ischemia, hinting at their potential role in reshaping neural circuits following a stroke. This study delves into the intriguing relationship between post-stroke alterations and ASICs, specifically focusing on postsynaptic ASIC1a enhancement in the amygdala following prefrontal cortex (PFC) ischemia induced by endothelin-1 (ET-1) injection. Our findings intriguingly illustrate that mPFC ischemia not only accentuates the PFC to the amygdala circuit but also implicates ASIC1a in fostering augmented synaptic plasticity after ischemia. In contrast, the absence of ASIC1a impairs the heightened induction of long-term potentiation (LTP) in the amygdala induced by ischemia. This pivotal research introduces a novel concept with the potential to inaugurate an entirely new avenue of inquiry, thereby significantly enhancing our comprehension of the intricate mechanisms underlying post-stroke neural circuit reconfiguration. Importantly, these revelations hold the promise of paving the way for groundbreaking therapeutic interventions.

Exposure to X-rays Causes Depression-like Behaviors in Mice via HMGB1-mediated Pyroptosis.

The widespread application of ionizing radiation in industrial and medical fields leads to the increased brain exposure to X-rays. Radiation brain injury (RBI) seriously affects health of patients by causing cognitive dysfunction and neuroinflammation. However, the link between X-ray exposure and depressive symptoms and their detailed underlying mechanisms have not been well studied. Herein, we investigated the potential depression-like behaviors in mice exposed to X-rays and then explored the role of HMGB1 in this injury. We found that X-ray stimulation induced the generation of reactive oxygen species (ROS) in the prefrontal cortex in a dose-dependent manner, leading to the occurrence of depression-like behaviors of the mice. Moreover, X-ray exposure increased the expression of HMGB1, activated NLRP3 inflammasome signaling pathway and microglial cells, and then facilitated the release of pro-inflammatory cytokines, resulting in the pyroptosis and neuron loss both in vivo and in vitro. Additionally, glycyrrhizin (Gly), which is a HMGB1 inhibitor, reversed X-ray-induced behavioral changes and neuronal damage. Our findings indicated that HMGB1-mediated pyroptosis was involved in radiation-induced depression.

Sex-dependent effects of postweaning exposure to an enriched environment on visceral pain and anxiety- and depression-like behaviors induced by neonatal maternal separation.

Background: Neonatal maternal separation (NMS) can lead to visceral pain and anxiety- and depression-like behaviors. An enriched environment (EE) can alleviate NMS-induced pain and mental disorders, but previous studies have mostly been performed in male animals. Therefore, the aim of this study was to investigate whether the effects of EE were sex dependent at different stages of development. Methods: Female and Male C57BL/6 J mice that had been subjected to NMS alone and those subjected to both NMS and exposed to EE were used in this study. The visceral pain threshold test (PTT), open field test (OFT), sucrose preference test (SPT), and forced swimming test (FST) were conducted to evaluate visceral pain, anxiety-like behavior, and depression-like behavior in mice, respectively. Results: Compared with the male mice in the NMS group without EE exposure, those exposed to EE from postnatal day (P)21 to 41 showed an increase of the visceral pain threshold in the PTT, an increase of the central time and central distance in the OFT, an increase of the sucrose preference rate in the SPT, and a decrease of the time of immobility in the FST. Compared with both female and male mice in the NMS group without EE exposure, those exposed to EE from P21 to P61 had an increase of the visceral pain threshold in the PTT, an increase of the central time and central distance in the OFT, an increase in the sucrose preference rate in the SPT, and a decrease of the time of immobility in the FST. Conclusions: EE is more effective in male NMS mice, while longer EE is required in female NMS mice for positive effects.