Cuscutae semen alleviates CUS-induced depression-like behaviors in mice via the gut microbiota-neuroinflammation axis.

Introduction: Major depressive disorder is a mental disease with complex pathogenesis and treatment mechanisms involving changes in both the gut microbiota and neuroinflammation. Cuscutae Semen (CS), also known as Chinese Dodder seed, is a medicinal herb that exerts several pharmacological effects. These include neuroprotection, anti-neuroinflammation, the repair of synaptic damage, and the alleviation of oxidative stress. However, whether CuscutaeSemen exerts an antidepressant effect remains unknown. Methods: In this study, we evaluated the effect of CS on chronic unpredictable stress (CUS)-induced depression-like behaviors in mice by observing changes in several inflammatory markers, including proinflammatory cytokines, inflammatory proteins, and gliocyte activation. Meanwhile, changes in the gut microbiota were analyzed based on 16 S rRNA sequencing results. Moreover, the effect of CS on the synaptic ultrastructure was detected by transmission electron microscopy. Results: We found that the CS extract was rich in chlorogenic acid and hypericin. And CS relieved depression-like behaviors in mice exposed to CUS. Increased levels of cytokines (IL-1ß and TNF-α) and inflammatory proteins (NLRP3, NF-κB, and COX-2) induced by CUS were reversed after CS administration. The number of astrocytes and microglia increased after CUS exposure, whereas they decreased after CS treatment. Meanwhile, CS could change the structure of the gut microbiota and increase the relative abundance of Lactobacillus. Moreover, there was a significant relationship between several Lactobacilli and indicators of depression-like behaviors and inflammation. There was a decrease in postsynaptic density after exposure to CUS, and this change was alleviated after CS treatme. Conclusion: This study found that CS treatment ameliorated CUS-induced depression-like behaviors and synaptic structural defects in mice via the gut microbiota-neuroinflammation axis. And chlorogenic acid and hypericin may be the main active substances for CS to exert antidepressant effects.

Sirtuin Type 1 Mediates the Antidepressant Effect of S-Ketamine in a Chronic Unpredictable Stress Model.

Background: Major depressive disorder (MDD) refers to a mental disease with complex pathogenesis and treatment mechanism. S-ketamine exhibited high effectiveness in treating MDD. However, the pharmacological activity of S-ketamine has not been reported yet. Materials and Methods: In this study, depression-like characteristics were induced by chronic unpredictable stress (CUS). After S-ketamine (15 mg/kg) was intraperitoneally injected, the behaviors of mice were tested by conducting open-field test, elevated plus maze test, tail suspension test, and forced swimming test. Bilateral injection of sirtuin type 1 (SIRT1) inhibitor EX-527 was injected into the medial prefrontal cortex (mPFC) to upregulate the SIRT1 expression. The expression of SIRT1 and brain-derived neurotrophic factor (BDNF) was detected by conducting Western blot and immunofluorescence assays. Meanwhile, the synaptic ultrastructure was detected by transmission electron microscopy. Results: In this study, the mice showed depression-like behavior in a series of behavioral tests. After the treatment with S-ketamine, the depression-like behavior stopped. Further, the synaptic ultrastructure in mPFC, including the decreased curvature of the post synaptic density and thinning of the postsynaptic density, improved after the S-ketamine treatment. Moreover, we found that S-ketamine had the possibility of spontaneous binding with SIRT1 at the molecular level and reversed CUS-induced SIRT1 reduction. Meanwhile, a positive relationship between SIRT1 and BDNF expression in mPFC and SIRT1 inhibitor limited the role of S-ketamine in reducing the depression-like behavior and increasing the BDNF level. Conclusion: S-ketamine upregulated the SIRT1-mediated BDNF in mPFC and reversed the synaptic structural defects caused by CUS. SIRT1 is a mediator of S-ketamine in alleviating depression-like behavior.

Morphological and hemispheric and sex differences of the anterior ascending ramus and the horizontal ascending ramus of the lateral sulcus.

Broca's area is composed of the pars opercularis (PO) and the pars triangularis (PTR) of the inferior frontal gyrus; the anterior ascending ramus of the lateral sulcus (aals) separates the PO from the PTR, and the horizontal ascending ramus of the lateral sulcus (hals) separates the PTR from the pars orbitalis. The morphometry of these two sulci maybe has potential effects on the various functions of Broca's area. Exploring the morphological variations, hemispheric differences and sex differences of these two sulci contributed to a better localization of Broca's area. BrainVISA was used to reconstruct and parameterize these two sulci based on data from 3D MR images of 90 healthy right-handed subjects. The 3D anatomic morphologies of these two sulci were investigated using 4 sulcal parameters: average depth (AD), average width (AW), outer length (OL) and inner length (IL). The aals and hals could be identified in 98.89% and 98.33%, respectively, of the hemispheres evaluated. The morphological patterns of these two sulci were categorized into four typical types. There were no statistically significant interhemispheric or sex differences in the frequency of the morphological patterns. There was statistically significant interhemispheric difference in the IL of the aals. Significant sex differences were found in the AD and the IL of the aals and OL of the hals. Our results not only provide a structural basis for functional studies related to Broca's area but also are helpful in determining the precise position of Broca's area in neurosurgery.

Synaptic Ultrastructure Might Be Involved in HCN1-Related BDNF mRNA in Withdrawal-Anxiety After Ethanol Dependence.

Withdrawal from ethanol dependence has been associated with heightened anxiety and reduced expression of Brain-derived neurotropic factor which promotes the synaptic transmission and plasticity of synapses. Hyperpolarization-activated cyclic nucleotide-gated channel 1 regulates expression; however, whether Hyperpolarization-activated cyclic nucleotide-gated channel 1-related Brain-derived neurotropic factor is involved in the synaptic ultrastructure that generates withdrawal-anxiety has been poorly perceived. Sprague-Dawley rats were treated with ethanol 3-9% (v/v) for a period of 21 days. Conditioned place preference and body weight were investigated during ethanol administration. Rats were subjected to behavioral testing and biochemical assessments after ethanol withdrawal, which was induced by abrupt discontinuation of the treatment. The results showed that the ethanol administration induced severe ethanol dependence behaviors, with higher body weight and more time in the ethanol-paired compartment. After withdrawal, rats had a higher total ethanol withdrawal score and explored less. Additionally, increased Hyperpolarization-activated cyclic nucleotide-gated channel 1 protein and gene expression and decreased Brain-derived neurotropic factor protein and gene expression were detected in the Ethanol group. Eventually, there was a negative correlation between the level of Brain-derived neurotropic factor mRNA and Hyperpolarization-activated cyclic nucleotide-gated channel 1 protein. Importantly, the synaptic ultrastructure changed in the Ethanol group, including increased synaptic cleft width and reduction in postsynaptic density thickness or synaptic curvature. The synthesis of the Brain-derived neurotropic factor mRNA could be down-regulated by higher Hyperpolarization-activated cyclic nucleotide-gated channel 1 protein expression. Changes in synaptic ultrastructure may be induced by lower Brain-derived neurotropic factor protein, which could be associated with the withdrawal-anxiety that is experiences after ethanol dependence.

Applying ketamine to alleviate the PTSD-like effects by regulating the HCN1-related BDNF.

BACKGROUND: Post-traumatic stress disorder (PTSD) is commonly associated with concurrent anxiety and depression symptoms, and reduce the expression of the Brain-Derived Neurotrophic Factor (BDNF) which promotes the proliferation and survival of neurons. The hyperpolarization-activated cyclic nucleotide-gated channel 1(HCN1) could be inhibited by the ketamine, a drug to alleviate depression and anxiety, and regulated the BDNF expression, however, the effects of ketamine in alleviating PTSD symptoms by regulating the HCN1-related BDNF have been poorly perceived. METHODS: In the present study, the effects of ketamine were examined on the PTSD-like effects in a rat model of PTSD induced by SPS&S procedure. After the SPS&S procedure and model testing, PTSD rats were subjected to behavioral testing and biochemical assessments, followed by single treatment with certain doses of ketamine (5, 10, 15 and 20 mg/kg IP). RESULTS: The results showed that the SPS&S procedure induced severe PTSD-like behaviors, with lower levels of BDNF protein levels and higher level of the HCN1 protein in the prefrontal cortex (PFC). These were reversed by a single administration of ketamine. The ketamine with dose of 15 mg/kg significantly increased locomotor behavior in the open field test, aggrandized exploratory behavior in the elevated plus maze test, and decreased immobility time spent in the forced swim test. Meanwhile, ketamine with dose of 15 mg/kg could increase the BDNF protein level, while down-regulate the expression of the HCN1. Eventually, there was a negative correlation between the level of BDNF and HCN1 in the PFC. CONCLUSION: Ketamine affects the HCN1-related BDNF signaling pathways to alleviate PTSD-like effects in rat.