Lateral hypothalamus orexinergic projection to the medial prefrontal cortex modulates chronic stress-induced anhedonia but not anxiety and despair.

Chronic stress-induced anxiodepression is a common health problem, however its potential neurocircuitry mechanism remains unclear. We used behavioral, patch-clamp electrophysiology, chemogenetic, and optogenetic approaches to clarify the response of the lateral hypothalamus (LH) and the medial prefrontal cortex (mPFC) to stress, confirmed the structural connections between the LH and mPFC, and investigated the role of the LH-mPFC pathway in chronic stress-induced anxiodepression symptoms. Unpredictable chronic mild stress (UCMS) caused anxiodepression-like behaviors, including anxiety, anhedonia, and despair behaviors. We discovered that the activity of the LH and mPFC was both increased after restraint stress (RS), a stressor of UCMS. Then we found that the orexinergic neurons in the LH predominantly project to the glutamatergic neurons in the mPFC, and the excitability of these neurons were increased after UCMS. In addition, overactivated LH orexinergic terminals in the mPFC induced anhedonia but not anxiety and despair behaviors in naive mice. Moreover, chemogenetically inhibited LH-mPFC orexinergic projection neurons and blocked the orexin receptors in the mPFC alleviated anhedonia but not anxiety and despair behaviors in UCMS-treated mice. Our study identified a new neurocircuit from LH orexinergic neurons to mPFC and revealed its role in regulating anhedonia in response to stress. Overactivation of LHOrx-mPFC pathway selectively mediated chronic stress-induced anhedonia. In normal mice, the LHOrx-mPFC pathway exhibits relatively low activity. However, after chronic stress, the activity of orexinergic neuron in LH is overactivated, leading to an increased release of orexin into the mPFC. This heightened orexin concentration results in increased excitability of the mPFC through OX1R and OX2R, consequently triggering anhedonia.

Mediodorsal thalamus projection to medial prefrontal cortical mediates social defeat stress-induced depression-like behaviors.

Clinical studies have shown that the mediodorsal thalamus (MD) may play an important role in the development of depression. However, the molecular and circuit mechanisms by which the mediodorsal thalamus (MD) participates in the pathological processes of depression remain unclear. Here, we show that in male chronic social defeat stress (CSDS) mice, the calcium signaling activity of glutamatergic neurons in MD is reduced. By combining conventional neurotracer and transneuronal virus tracing techniques, we identify a synaptic circuit connecting MD and medial prefrontal cortex (mPFC) in the mouse. Brain slice electrophysiology and fiber optic recordings reveal that the reduced activity of MD glutamatergic neurons leads to an excitatory-inhibitory imbalance of pyramidal neurons in mPFC. Furthermore, activation of MD glutamatergic neurons restores the electrophysiological properties abnormal in mPFC. Optogenetic activation of the MD-mPFC circuit ameliorates anxiety and depression-like behaviors in CSDS mice. Taken together, these data support the critical role of MD-mPFC circuit on CSDS-induced depression-like behavior and provide a potential mechanistic explanation for depression.

Corrigendum: Risk factors for gastric cancer: A comprehensive analysis of observational studies.

[This corrects the article DOI: 10.3389/fpubh.2022.892468.].

Overexpressing lnc240 Rescues Learning and Memory Dysfunction in Hepatic Encephalopathy Through miR-1264-5p/MEF2C Axis.

Hepatic encephalopathy (HE) is a nervous system disease caused by severe liver diseases and different degrees of learning and memory dysfunction. Long non-coding RNA (lncRNA) is highly expressed in the brain and plays important roles in central nervous system diseases like Alzheimer's disease. In the present work, we found that the expression of lnc240 in the hippocampus of HE mice was significantly downregulated, but its pathogenesis in HE has not been clarified. This study aimed to explore the effects of lnc240 on the cognitive function of HE. The expression of lnc240, miR-1264-5p, and MEF2C was analyzed with RNA-seq and further determined by qRT-PCR in HE mouse. Double luciferase reporter gene testing confirmed the relationship between lnc240, MEF2C, and miR-1264-5p. The functional role of lnc240 and MEF2C in vitro and in vivo was evaluated by qRT-PCR, western blot analysis, immunofluorescence staining, Golgi staining, electrophysiology, and Morris water maze. The expression of lnc240 was decreased in HE mice. The overexpression of lnc240 could significantly downregulate miR-1264-5p and upregulate MEF2C, also increasing the amplitude and frequency of mEPSC in primary cultured hippocampal neurons. The overexpression of miR-1264-5p reversed the effect of lnc240 on MEF2C. Moreover, in vivo experiments have shown that the overexpression of lnc240 could improve HE mice's spatial learning and memory functions. Golgi staining suggested that overexpression of lnc240 could increase the density and maturity of dendritic spines in hippocampal neurons of HE mice. Lnc240 can regulate the expression of MEF2C through miR-1264-5p and regulate the synaptic plasticity of hippocampal neurons, thereby saving the learning and memory dysfunction in HE mice, suggesting that lnc240 might be a potential therapeutic target for the treatment of HE.

Social defeat drives hyperexcitation of the piriform cortex to induce learning and memory impairment but not mood-related disorders in mice.

Clinical studies have shown that social defeat is an important cause of mood-related disorders, accompanied by learning and memory impairment in humans. The mechanism of mood-related disorders has been widely studied. However, the specific neural network involved in learning and memory impairment caused by social defeat remains unclear. In this study, behavioral test results showed that the mice induced both learning and memory impairments and mood-related disorders after exposure to chronic social defeat stress (CSDS). c-Fos immunofluorescence and fiber photometry recording confirmed that CaMKIIα expressing neurons of the piriform cortex (PC) were selectively activated by exposure to CSDS. Next, chemogenetics and optogenetics were performed to activate PC CaMKIIα expressing neurons, which showed learning and memory impairment but not mood-related disorders. Furthermore, chemogenetic inhibition of PC CaMKIIα expressing neurons significantly alleviated learning and memory impairment induced by exposure to CSDS but did not relieve mood-related disorders. Therefore, our data suggest that the overactivation of PC CaMKIIα expressing neurons mediates CSDS-induced learning and memory impairment, but not mood-related disorders, and provides a potential therapeutic target for learning and memory impairment induced by social defeat.

Strategies for Targeting Neural Circuits: How to Manipulate Neurons Using Virus Vehicles.

Viral strategies are the leading methods for mapping neural circuits. Viral vehicles combined with genetic tools provide the possibility to visualize entire functional neural networks and monitor and manipulate neural circuit functions by high-resolution cell type- and projection-specific targeting. Optogenetics and chemogenetics drive brain research forward by exploring causal relationships among different brain regions. Viral strategies offer a fresh perspective for the analysis of the structure-function relationship of the neural circuitry. In this review, we summarize current and emerging viral strategies for targeting neural circuits and focus on adeno-associated virus (AAV) vectors.

Comprehensive Analysis of lncRNAs, miRNAs and mRNAs in Mouse Hippocampus With Hepatic Encephalopathy.

Hepatic encephalopathy (HE) often presents with varying degrees of cognitive impairment. However, the molecular mechanism of its cognitive impairment has not been fully elucidated. Whole transcriptome analysis of hippocampus between normal and HE mice was performed by using RNA sequencing. 229 lncRNAs, 49 miRNAs and 363 mRNAs were differentially expressed in HE mice. The lncRNA-miRNA-mRNA interaction networks were established, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Dysregulated RNAs in interaction networks were mainly involved in synaptic plasticity and the regulation of learning and memory. In NH4Cl-treated hippocampal neurons, the dendritic spine density and maturity decreased significantly, the amplitude and frequency of mIPSC increased, while the amplitude and frequency of mEPSC decreased. These manifestations can be reversed by silencing SIX3OS1. Further research on these no-coding RNAs may lead to new therapies for the treatment and management of brain dysfunction caused by HE.

Risk factors for gastric cancer: A comprehensive analysis of observational studies.

Background: Multifarious factors have a causal relationship with gastric cancer (GC) development. We conducted a comprehensive analysis to evaluate the strength of the evidence examining non-genetic risk factors for gastric cancer. Methods: PubMed, Web of Science, and the Cochrane Library were searched from inception to November 10, 2021 to identify meta-analyses of observational studies examining the association between environmental factors and GC risk. For each meta-analysis, the random effect size, 95% confidence interval, heterogeneity among studies, and evidence of publication bias were assessed; moreover, the evidence was graded using predefined criteria, and the methodological quality was evaluated using AMSTAR 2. Results: A total of 137 associations were examined in 76 articles. Among these meta-analyses, 93 associations yielded significant estimates (p < 0.05). Only 10 associations had strong epidemiologic evidence, including 2 risk factors (waist circumference and bacon), and 8 protective factors (dietary total antioxidant capacity, vegetable fat, cruciferous vegetable, cabbage, total vitamin, vitamin A, vitamin C, and years of fertility); 26 associations had moderate quality of evidence; and the remaining 57 associations were rated as weak. Ninety-four (68.61%) associations showed significant heterogeneity. Twenty-five (18.25%) associations demonstrated publication bias. Conclusions: In this comprehensive analysis, multiple associations were found between environmental factors and GC with varying levels of evidence. Healthy dietary habits and lifestyle patterns could reduce the risk for GC. However, further high-quality prospective studies are still necessary to draw more definitive conclusions.