Low-frequency Stimulation at the Subiculum Prevents Extensive Secondary Epileptogenesis in Temporal Lobe Epilepsy.

Secondary epileptogenesis is characterized by increased epileptic susceptibility and a tendency to generate epileptiform activities outside the primary focus. It is one of the major resultants of pharmacoresistance and failure of surgical outcomes in epilepsy, but still lacks effective treatments. Here, we aimed to test the effects of low-frequency stimulation (LFS) at the subiculum for secondary epileptogenesis in a mouse model. Here, secondary epileptogenesis was simulated at regions both contralateral and ipsilateral to the primary focus by applying successive kindling stimuli. Mice kindled at the right CA3 showed higher seizure susceptibilities at both the contralateral CA3 and the ipsilateral entorhinal cortex and had accelerated kindling processes compared with naive mice. LFS at the ipsilateral subiculum during the primary kindling progress at the right CA3 effectively prevented secondary epileptogenesis at both the contralateral CA3 and the ipsilateral entorhinal cortex, characterized by decreased seizure susceptibilities and a retarded kindling process at those secondary foci. Only application along with the primary epileptogenesis was effective. Notably, the effects of LFS on secondary epileptogenesis were associated with its inhibitory effect at the secondary focus through interfering with the enhancement of synaptic connections between the primary and secondary foci. These results imply that LFS at the subiculum is an effective preventive strategy for extensive secondary epileptogenesis in temporal lobe epilepsy and present the subiculum as a target with potential translational importance.

Satellite glial cells in sensory ganglia play a wider role in chronic pain via multiple mechanisms.

Satellite glial cells are unique glial cells that surround the cell body of primary sensory neurons. An increasing body of evidence suggests that in the presence of inflammation and nerve damage, a significant number of satellite glial cells become activated, thus triggering a series of functional changes. This suggests that satellite glial cells are closely related to the occurrence of chronic pain. In this review, we first summarize the morphological structure, molecular markers, and physiological functions of satellite glial cells. Then, we clarify the multiple key roles of satellite glial cells in chronic pain, including gap junction hemichannel Cx43, membrane channel Pannexin1, K channel subunit 4.1, ATP, purinergic P2 receptors, and a series of additional factors and their receptors, including tumor necrosis factor, glutamate, endothelin, and bradykinin. Finally, we propose that future research should focus on the specific sorting of satellite glial cells, and identify genomic differences between physiological and pathological conditions. This review provides an important perspective for clarifying mechanisms underlying the peripheral regulation of chronic pain and will facilitate the formulation of new treatment plans for chronic pain.

Xiaoyaosan ameliorates depressive-like behavior and susceptibility to glucose intolerance in rat: involvement of LepR-STAT3/PI3K pathway in hypothalamic arcuate nucleus.

BACKGROUND: Accumulating evidence has demonstrated that arcuate nucleus (ARC) of the hypothalamus is likely responsible for the close association between chronic stress, depression, and diabetes. Xiaoyaosan (XYS), a Chinese herbal formula, remarkably improves depressive-like behavior and glucose intolerance, but the mechanism remains unclear. Leptin receptor (LepR) regulates energy expenditure and depression by mediating the action of leptin on the ARC. Therefore, we hypothesized that XYS may regulate depressive-like behavior and glucose intolerance via the leptin and its cascade LepR-STAT3/PI3K pathway in the ARC. METHODS: A rat model of depressive-like behavior and susceptibility to glucose intolerance was induced by exposure to chronic unpredictable mild stress (CUMS) for six weeks. XYS (2.224 g/kg) was orally gavaged for six weeks, and fluoxetine (2.0 mg/kg) was administrated to the positive control group. Depressive-like behaviors were assessed using the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST). Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed to evaluate the effects of XYS on blood glucose. Peripheral leptin and blood lipids were detected using enzyme-linked immunosorbent assay and an automatic biochemical analyzer, respectively. The effects of XYS on the LepR-STAT3/PI3K pathway were detected by quantitative real-time PCR and western blotting. RESULTS: XYS ameliorated CUMS-induced depressive-like behaviors and elevated blood glucose. XYS improved the food intake but have no significant effects on the body weight. Peripheral leptin and its central receptor were also suppressed by XYS, accompanied by the downregulation of JAK2/STAT3 and PI3K/AKT pathway in the ARC. Additionally, XYS increased AGRP and NPY expression but inhibited POMC in the ARC. CONCLUSIONS: XYS improves depressive-like behaviors and susceptibility to glucose intolerance induced by CUMS, which may be achieved by the downregulation of the LepR-STAT3/PI3K signaling pathway in the ARC.

Xiaoyaosan inhibits neuronal apoptosis by regulating the miR-200/NR3C1 signaling in the prefrontal cortex of chronically stressed rats.

BACKGROUND: Depression is a prevalent emotion disorder which is thought to be due to neuronal structural alterations and/or functional impairment within specific brain regions. Several studies have shown that microRNAs are involved in the pathogenesis of depression. As a Chinese herbal formula, Xiaoyaosan (XYS) could have antidepressive effects, although the mechanisms associated with microRNAs are poorly understood. PURPOSE: In this study, we investigated whether inhibition of the miR-200a/b-3p/NR3C1 pathway in the prefrontal cortex is involved in the anti-neuronal apoptosis and anti-stress effects of XYS and then further delineated the underlying mechanism. METHODS: To evaluate the efficacy of XYS in relieving stress behaviors and altering the expression of miRNAs involved in the regulation of these behaviors in vivo, a chronic unpredictable mild stress (CUMS) rodent model and RNA-seq were performed. Primary cortical neurons were used to evaluate the molecular function of miR-200a/b-3p and detect the in vitro neuroprotective function of paeoniflorin, which is one of the main components of XYS. To investigate the function of miR-200a/b-3p in stress behaviors, stereotactic microinjection of AAV2/9-Syn-miR-200a/b-3p was performed to deliver the treatment to the rat mPFC. RESULTS: XYS reduced the anxiety and depression-like behaviors associated with chronic stress and reduced the expression of miR-200a/b-3p and neuronal apoptosis in the prefrontal cortex (PFC). The overexpression of miR-200a/b-3p in primary cortical neurons reduced the expression of the target gene NR3C1, increased the protein expression of cleaved caspase-3 and Bax, and decreased the anti-apoptotic protein Bcl-2. One of the active ingredients of XYS, paeoniflorin, can inhibit miR-200a/b-3p-mediated apoptosis of primary neurons and abnormal expression of apoptosis-related proteins. After overexpressing miR-200a/b-3p in vivo (vmPFC), the rats eventually showed significant anxiety-like behaviors similar to those caused by chronic stress. CONCLUSION: Our findings indicate that XYS can inhibit the CUMS-induced expression of miR-200a/b-3p, regulate miR-200a/b-3p/NR3C1 signaling in the PFC caused by chronic stress, and reduce neuronal apoptosis and stress-related behaviors.

Potential therapeutic effect and methods of traditional Chinese medicine on COVID-19-induced depression: A review.

COVID-19 (coronavirus) has spread all over the world with a high infection rate. Currently, there are no targeted therapeutic drugs for COVID-19 as well as for stress induced by COVID-19. The unpredictable events of COVID-19 can trigger feelings of fear, worry, or unease in people, leading to stress-related disorders such as depression and anxiety. It has been reported that individuals, including COVID-19 patients, medical staff, and ordinary people, are under both physical and psychological pressure, and many of them have developed depression or anxiety during this pandemic. Traditional Chinese medicine (TCM) has been widely used in treating depression with relatively better safety and efficacy and may have an important role in treating stress-related disorders induced by COVID-19. In this review, we collected the common TCM treatment methods including Qigong, Acupuncture, Five Elements Musical Therapy, Five Elements Emotional Therapy, and Chinese herbal medicine from the databases of PubMed and the China National Knowledge Internet to illustrate the effect of TCM on depression. The better knowledge of TCM and implementation of TCM in COVID-19 clinics may help to effectively improve depression induced by COVID-19, may assist people to maintain a healthy physical and mental quality, and may alleviate the current shortage of medical resources.

Xiaoyaosan Improves Antibiotic-Induced Depressive-Like and Anxiety-Like Behavior in Mice Through Modulating the Gut Microbiota and Regulating the NLRP3 Inflammasome in the Colon.

Disturbance of the gut microbiota plays an essential role in mental disorders such as depression and anxiety. Xiaoyaosan, a traditional Chinese medicine formula, has a wide therapeutic spectrum and is used especially in the management of depression and anxiety. In this study, we used an antibiotic-induced microbiome-depleted (AIMD) mouse model to determine the possible relationship between imbalance of the intestinal flora and behavioral abnormalities in rodents. We explored the regulatory effect of Xiaoyaosan on the intestinal flora and attempted to elucidate the potential mechanism of behavioral improvement. We screened NLRP3, ASC, and CASPASE-1 as target genes based on the changes in gut microbiota and explored the effect of Xiaoyaosan on the colonic NLRP3 pathway. After Xiaoyaosan intervention, AIMD mice showed a change in body weight and an improvement in depressive and anxious behaviors. Moreover, the gut flora diversity was significantly improved. Xiaoyaosan increased the abundance of Lachnospiraceae in AIMD mice and decreased that of Bacteroidaceae, the main lipopolysaccharide (LPS)-producing bacteria, resulting in decreased levels of LPS in feces, blood, and colon tissue. Moreover, serum levels of the inflammatory factor, IL-1ß, and the levels of NLRP3, ASC, and CASPASE-1 mRNA and DNA in the colon were significantly reduced. Therefore, Xiaoyaosan may alleviate anxiety and depression by modulating the gut microbiota, correcting excessive LPS release, and inhibiting the immoderate activation of the NLRP3 inflammasome in the colon.

Susceptibility to Hyperglycemia in Rats With Stress-Induced Depressive-Like Behavior: Involvement of IL-6 Mediated Glucose Homeostasis Signaling.

Depression is a common psychiatric disorder comorbid with diabetes and may lead to high morbidity, disability, and mortality. However, the underlying mechanism behind their association remains unknown. Cytokine-mediated inflammation in brain may play important roles in the pathogenesis of depression and insulin resistance. In the present study, we subjected the rats to chronic unpredictable mild stress (CUMS) for 3 to 8 weeks. The tests to ascertain depression-like behaviors including open field test (OFT) and forced swimming test (FST) were performed, and levels of morning fasting blood glucose, triglyceride (TG), total cholesterol (CHOL), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C), body weight, food intake, histopathological examinations of liver, adipose tissues and hypothalamus, hypothalamic GLUT4 as well as the IL-6-mediated glucose homeostasis signaling pathway were measured. The results showed that CUMS exposure resulted in the depression-like behavior at various time points in rats. Moreover, the rats exhibited increased peripheral glucose levels, impaired hepatocytes and hippocampal neurons, and decreased hypothalamic GLUT4 levels after 6 weeks of CUMS exposure. Meanwhile, activated IL-6 but suppressed IL-6-mediated glucose homeostasis signaling was observed in the hypothalamus. Markers of lipid metabolism including TG, CHOL, HDL-C and LDL-C were dysregulated, and body weight and food intake were decreased in the CUMS-exposed rats. Our results show that depressed rats induced by 6-week CUMS stimulation display susceptibility to hyperglycemia, which is associated with IL-6-mediated inhibition of glucose homeostasis signaling in the hypothalamus.

A combination of depression and liver Qi stagnation and spleen deficiency syndrome using a rat model.

A syndrome (Zheng in Chinese) plays a critical role in disease identification, diagnosis, and treatment in traditional Chinese medicine (TCM). Clinically, the liver Qi stagnation and spleen deficiency syndrome (LQSSDS) is one of the most common syndrome patterns. Over the past few decades, several animal models have been developed to understand the potential mechanisms of LQSSDS, but until now, simulation of the syndrome is still unclear. Recently, several studies have confirmed that an animal model combining a disease and a syndrome is appropriate for simulating TCM syndromes. Overlapping previous studies have reported that depression is highly associated with LQSSDS; hence, we attempted to develop a rat model combining depression and LQSSDS. We exposed the rats to different durations of chronic unpredictable mild stress (CUMS). Subsequently, the evaluation indicators at macrolevel consisted of behavioral tests including open field test, sucrose preference test, and forced swim test, food intake, body weight, white adipose tissue, fecal water content, visceral hypersensitivity, and small bowel transit, and the evaluation indicators at microlevel included changes of hypothalamic-pituitary-adrenal axis. Serum D-xylose absorption was used to comprehensively confirm and assess whether the model was successful during the CUMS-induced process. The results showed that rats exposed to 6-week CUMS procedure exhibited significantly similar traits to the phenotypes of LQSSDS and depression. This study provided a new rat model for the LQSSDS and could potentially lead to a better understanding of the pathophysiology of LQSSDS and the development of new drugs for this syndrome.

Integrating Clinical and Genomic Analyses of Hippocampal-Prefrontal Circuit Disorder in Depression.

Major depressive disorder (MDD) is a prevalent, devastating and recurrent mental disease. Hippocampus (HIP)-prefrontal cortex (PFC) neural circuit abnormalities have been confirmed to exist in MDD; however, the gene-related molecular features of this circuit in the context of depression remain unclear. To clarify this issue, we performed gene set enrichment analysis (GSEA) to comprehensively analyze the genetic characteristics of the two brain regions and used weighted gene correlation network analysis (WGCNA) to determine the main depression-related gene modules in the HIP-PFC network. To clarify the regional differences and consistency for MDD, we also compared the expression patterns and molecular functions of the key modules from the two brain regions. The results showed that candidate modules related to clinical MDD of HIP and PFC, which contained with 363 genes and 225 genes, respectively. Ninety-five differentially expressed genes (DEGs) were identified in the HIP candidate module, and 51 DEGs were identified in the PFC candidate module, with only 11 overlapping DEGs in these two regional modules. Combined with the enrichment results, although there is heterogeneity in the molecular functions in the HIP-PFC network of depression, the regulation of the MAPK cascade, Ras protein signal transduction and Ephrin signaling were significantly enriched in both brain regions, indicating that these biological pathways play important roles in MDD pathogenesis. Additionally, the high coefficient protein-protein interaction (PPI) network was constructed via STRING, and the top-10 coefficient genes were identified as hub genes via the cytoHubba algorithm. In summary, the present study reveals the gene expression characteristics of MDD and identifies common and unique molecular features and patterns in the HIP-PFC network. Our results may provide novel clues from the gene function perspective to explain the pathogenic mechanism of depression and to aid drug development. Further research is needed to confirm these findings and to investigate the genetic regulation mechanisms of different neural networks in depression.