Hippocampal Inhibitory Synapsis Deficits Induced by α5-Containing GABAA Receptors Mediate Chronic Neuropathic Pain-Related Cognitive Impairment.

Chronic neuropathic pain often leads to cognitive impairment, but the exact mechanism remains unclear. Gamma-aminobutyric acid A receptors (GABAARs) are the major inhibitory receptors in the brain, of which the α5-containing GABAARs (GABAARs-α5) are implicated in a range of neuropsychiatric disorders with cognitive deficits. However, whether GABAARs-α5 are involved in chronic neuropathic pain-related cognitive impairment remains unknown. In this study, the rats with chronic neuropathic pain induced by right sciatic nerve ligation injury (SNI) exhibited cognitive impairment with declined spontaneous alternation in Y-maze test and discrimination index in novel object recognition test. The GABAARs-α5 expressing on parvalbumin and somatostatin interneurons increased remarkably in hippocampus, resulting in decreased mean frequency of spontaneous inhibitory postsynaptic currents in hippocampal pyramidal neurons. Significantly, antagonizing the GABAARs-α5 by L655708 rescued weakened inhibitory synaptic transmission and cognitive impairment induced by chronic neuropathic pain. Taken together, these data suggest that the GABAARs-α5 play a crucial role in chronic neuropathic pain-induced cognitive impairment by weakening inhibitory synaptic transmission, which may provide insights into the pharmacologic treatment of chronic neuropathic pain-related cognitive impairment.

Intestinal dysbacteriosis-propelled T helper 17 cells activation mediate the perioperative neurocognitive disorder induced by anesthesia/surgery in aged rats.

BACKGROUND: Perioperative neurocognitive disorders (PND) is a common postoperative disease in elderly patients, but its pathogenesis remains unclear. METHODS: Exploratory laparotomy was performed to establish PND model under sevoflurane anesthesia. 16S rRNA high-throughput sequencing was used to detect the changes of intestinal flora. Antibiotics were used to relatively eliminate intestinal flora before anesthesia/surgery, and behavior tests, such as open field, Y maze, and fear conditioning tests were applied to detect the changes of memory ability. The number of Th17 cells and Foxp3 cells was detected by flow cytometry in the Peyer's patches (PP), mesenteric lymph nodes (MLN), blood and brain. Western blot was used to detect the expression of IL17, IL17RA, IL6 and IL10 in the hippocampus. Immunofluorescence was used to detect the expression of IL17, IL17R and IBA1 (ionized calcium binding adaptor molecule1) in the hippocampus. RESULTS: Anesthesia/surgery caused intestinal flora imbalance and induced neurocognitive impairment, increased the number of Th17 cells in the PP, MLN, blood and brain, increased the level of IL17, IL17R and inflammatory factors production in the hippocampus. Antibiotics administration before anesthesia/surgery significantly decreased the number of Th17 cells and the level of IL17, IL17R and inflammatory factors production, and improved the memory function. In addition, we found that IL17R was co-labeled with IBA1 in a large amount in the hippocampus through immunofluorescence double-staining. CONCLUSION: Our study suggested that intestinal dysbacteriosis-propelled T helper 17 cells activation and IL17 secretion might play an important role in the pathogenesis of PND induced by anesthesia/surgery in aged rats.

Store-Operated Calcium Channels Contribute to Remifentanil-Induced Postoperative Hyperalgesia via Phosphorylation of CaMKIIα in Rats.

PURPOSE: The mechanisms of remifentanil-induced postoperative hyperalgesia (RIPH) remain unclear. Store-operated calcium channels (SOCCs) are mainly comprised of stromal interaction molecules 1 (STIM1) and pore-forming subunits (Orai1). They were found to take a pivotal part in Ca2+-dependent procedures and involved in the development of central sensitization and pain. Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα), regulated by Ca2+/calmodulin complex, has been shown to have a crucial role in RIPH. This study aims to determine whether SOCCs contribute to RIPH via activating CaMKIIα. MATERIALS AND METHODS: Intra-operative infusion of remifentanil (1.0 µg kg-1 min-1, 60 min) was used to establish a RIPH rat model. The SOCCs blocker (YM-58483) was applied intrathecally to confirm the results. Animal behavioral tests including paw withdrawal thermal latency (PWTL) and paw withdrawal mechanical threshold (PWMT) were performed at -24, 2, 6, 24, 48 h after incision and remifentanil treatments. The protein expression of STIM1, Orai1, CaMKIIα, and p-CaMKIIα was assayed with Western blot, and the number of STIM1 and Orai1 positive cells was shown by immunofluorescence. RESULTS: Remifentanil administration significantly induced postoperative mechanical and thermal hyperalgesia, as well as increased STIM1 and Orai1 protein expression in the spinal dorsal horn. Furthermore, the intrathecal administration of YM-58483 effectively alleviated remifentanil-induced postoperative mechanical and thermal hyperalgesia according to the behavioral tests. In addition, YM-58483 suppressed the phosphorylation of CaMKIIα but had no effect on the expression of STIM1 and Orai1. CONCLUSION: Our study demonstrated that SOCCs are involved in RIPH. The over-expressed STIM1 and Orai1 in the spinal cord contribute to RIPH via mediating the phosphorylation of CaMKIIα. Blockade of SOCCs may provide an effective therapeutic approach for RIPH.

Virtual Reality-Assisted Cognitive Behavioral Therapy for Anxiety Disorders: A Systematic Review and Meta-Analysis.

Objective: We aim to explore the effectiveness of virtual reality-assisted cognitive behavioral therapy (VRCBT) in the treatment of anxiety and depression in patients with anxiety disorders. We further compare the therapeutic effect of VRCBT with that of standard cognitive behavioral therapy (CBT), as well as investigate the long-term efficacy of VRCBT. Methods: As of March 3, 2020, a total of four databases (Web of Science, PubMed, PsycINFO, and Scopus) were retrieved, and two researchers independently conducted literature retrieval and research selection and performed data extraction. Methodological quality assessment was performed using the Cochrane risk of bias tool and Grading of Recommendation, Assessment, Development, and Evaluation tool (GRADE). Results: A total of 11 studies were included (n = 626; range, 25.3-43.8), and six randomized controlled trials were quantitatively analyzed. The main outcome was anxiety and depression, and the secondary outcome was the withdrawal rate and long-term effects. Meta-analysis showed that the therapeutic effect of VRCBT on anxiety was better than that of the waiting list group (WLG) (SMD = -0.92; 95% CI: -1.34, -0.50; p = 0.005, I 2 = 66%, n = 276), while the therapeutic effect of VRCBT on anxiety was similar to that of standard CBT treatment (SMD = -0.26; 95% CI: -0.50, -0.01; p = 0.77, I 2 = 0%, n = 150). We further found that the therapeutic effect of VRCBT on depression was better than that of the WLG (SMD = -1.29; 95% CI: -2.26, -0.32; p = 0.09, I 2 = 58%, n = 74), while the effect of VRCBT was similar to that of standard CBT (SMD = -0.30; 95% CI: -0.67, -0.07; p = 0.39, I 2 = 1%, n = 116). Of the five studies that reported withdrawal rates of patients during the VRCBT and CBT treatment process, the withdrawal rates of the VRCBT group and CBT group did not reach statistical significance (OR = 0.70, 1.48, p > 0.05); only two studies reported the long-term effectiveness of VRCBT in anxiety and depression on patients with anxiety disorders. Conclusion: VRCBT treatment has a specific positive effect on patients with anxiety disorders (anxiety and depression). Compared with standard CBT, similar therapeutic effects can be achieved in the treatment of anxiety disorders. However, limited randomized controlled trials were included, requiring that these results be treated with caution.

The dysfunction of parvalbumin interneurons mediated by microglia contributes to cognitive impairment induced by lipopolysaccharide challenge.

BACKGROUND: The mechanisms underlying cognitive impairments induced by systemic inflammation remain unclear. Increasing evidence has suggested that parvalbumin (PV) interneurons play an important role in regulating cognitive behaviors and its dysfunction is implicated in many neurological disorders. Thus, the present study was aimed to detect whether the destruction of PV interneurons mediates cognitive impairment associated with systemic inflammation. METHODS: Male wild-type C57BL/6J mice (12-14 weeks old) received lipopolysaccharide (LPS 2 mg/kg i.p.) injection to establish the systemic inflammation model. For the suppression of microglial activation, minocycline (50 mg/kg i.p.) was applied. Animal behavior tests were conducted on day 3 post-LPS injection including the open field test, fear conditioning test and Y maze test. The PV expression in hippocampus was detected by Western blot and immunofluorescence. The number of perisomatic boutons around the NeuN-positive cells and microglia in hippocampus was detected by immunofluorescence. RESULTS: LPS induced hippocampus-dependent memory and working memory impairment, coinciding with decreased PV expression, reduced perisomatic boutons around the NeuN-positive cells and activated microglia in the hippocampus. Notably, the treatment of minocycline suppressed the microglial activation and rescued the PV expression as well as the perisomatic boutons around the NeuN-positive cells in the hippocampus, contributing to improved cognitive function. CONCLUSION: Our study suggests that the dysfunction of parvalbumin interneurons mediated by microglia plays a key role in LPS-induced cognitive impairments, which may serve a therapeutic strategy for cognitive disorders associated with systemic inflammation.

Effects of Mindfulness Exercise Guided by a Smartphone App on Negative Emotions and Stress in Non-Clinical Populations: A Systematic Review and Meta-Analysis.

BACKGROUND: Studies have acknowledged that mindfulness exercise guided by a smartphone app has a positive impact on mental health and physical health. However, mindfulness guided by a smartphone app on mental health is still in its infancy stage. Therefore, we conducted a meta-analysis evaluating the effect of mindfulness intervention guided by a smartphone app on negative emotions and stress in a non-clinical population with emotional symptoms. METHODS: We searched major databases, namely, Web of Science, PubMed, Scopus, China National Knowledge Infrastructure (CNKI), and Wanfang, to identify all of the relevant studies published in English or Chinese from their inception until November 9, 2021. The methodological quality of the included studies was assessed with Cochrane risk-of-bias bias assessment tool. Two researchers independently conducted document retrieval, study selection, data extraction, and methodological quality evaluation. RESULT: A total of eight studies were included in the study, with 574 subjects (experimental group: 348; control group: 226). A random effects model was selected to combine effect sizes. The results of the meta-analysis showed that mindfulness exercise guided by a smartphone app reduced negative emotions [standardized mean difference (SMD) = -0.232, 95% CI: -0.398 to -0.066, p = 0.006], depressive symptoms (SMD = -0.367, 95% CI: -0.596 to -0.137, p = 0.002), and anxiety symptoms (SMD = -0.490, 95% CI: -0.908 to -0.071, p = 0.022). CONCLUSIONS: The findings indicate the potentially beneficial effect of mindfulness exercise guided by a smartphone app on symptoms of depression and anxiety among individuals in a non-clinical population with emotional symptoms. Considering the small number and overall methodological weakness of the included studies and lack of randomized controlled trials (RCTs), the results should be interpreted with caution, and future rigorously designed RCTs are warranted to provide more reliable evidence.

Dynamic characteristic analysis of vertical screw conveyor in variable screw section condition.

Vertical screw conveyors are used widely in industry for elevating bulk materials over relatively short distances, but the problem of insufficient feeding and low conveying efficiency always exist in the vertical conveying process. In this paper, a vertical screw conveyor with variable screw section is presented, and the characteristics of vertical screw conveyor are investigated under the variable screw sections using discrete element method (DEM). The results show that the particle volume fraction in the inlet and the mass flow rate increase in the condition of variable screw section, and the screw rotational speed has a significant influence on mass flow rate. It is evident that the design of variable screw section provides an effective way in improving the particle feeding rate and the conveying efficiency.

Both Hypo-Connectivity and Hyper-Connectivity of the Insular Subregions Associated With Severity in Children With Autism Spectrum Disorders.

Some studies identified hypo-connectivity, while others showed hyper-connectivity of the insula in the autism spectrum disorders (ASD). These contradictory findings leave open the question of whether and to what extent functional connectivity of the insula is altered and how functional connectivity of the insula is associated with the severity of ASD. A newly emerging insular atlas that comprises multiple functionally differentiated subregions provides a new framework to interpret the functional significance of insular findings and uncover the mechanisms underlying the severity of ASD. Using the new insular atlas, the present study aimed to investigate the distinct functional connectivity of the insular subregions and their associations with ASD severity in a cohort of 49 children with ASD and 33 typically developing (TD) subjects. We found that compared with TD group, the ASD group showed different connectivity patterns in the left ventral agranular insula, right ventral dysgranular and granular insula, and dorsal dysgranular insula, characterized by significant hyper-connectivity and/or hypo-connectivity with special brain regions. Furthermore, both the hypo-connectivity and hyper-connectivity patterns of the insular subregions were significantly associated with the severity of ASD symptoms. Our research demonstrated distinct functional connectivity patterns of the insular subregions and emphasized the importance of the subdivisions within the insula to the potential impact of functional difference in children with ASD. Moreover, these results might help us to better understand the mechanisms underlying the symptoms in children with ASD and might elucidate potential biomarkers for clinical applications.

Cytochrome b genetic diversity and maternal origin of Chinese domestic donkey.

To clarify the origin of Chinese domestic donkeys, we investigated the mitochondrial Cytb gene from 244 animals from 13 native breeds. We found 55 variable sites in the Cytb gene sequence and subsequently defined 58 haplotypes. Analysis of haplotypes in combination with Cytb sequences revealed two mitochondrial origins in Chinese domestic donkeys, phenotypically expressed by the Somalian and Nubian lineages. The Somalian lineage predominated in Chinese domestic donkey breeds. Five specific Cytb gene SNPs diagnostic of each of the lineages were found in this study: 225(T-C), 237(C-T), 915(C-T), 1014(C-T), and 1134(A-G) mutations. They effectively distinguish the Nubian from the Somalian lineage in the mtDNA Cytb gene. Both lineages are from Africa and thus support the African maternal origins of Chinese domestic donkeys. No obvious geographic structure was found in Chinese domestic donkey breeds, but the population showed abundant genetic diversity.

Reconstruction of damaged cornea by autologous transplantation of epidermal adult stem cells.

PURPOSE: It is crucial for the treatment of severe ocular surface diseases such as Stevens-Johnson syndrome (SJS) and ocular cicatricial pemphigoid (OCP) to find strategies that avoid the risks of allograft rejection and immunosuppression. Here, we report a new strategy for reconstructing the damaged corneal surface in a goat model of total limbal stem cell deficiency (LSCD) by autologous transplantation of epidermal adult stem cells (EpiASC). METHODS: EpiASC derived from adult goat ear skin by explant culture were purified by selecting single cell-derived clones. These EpiASC were cultivated on denuded human amniotic membrane (HAM) and transplanted onto goat eyes with total LSCD. The characteristics of both EpiASC and reconstructed corneal epithelium were identified by histology and immunohistochemistry. The clinical characteristic of reconstructed corneal surface was observed by digital camera. RESULTS: Ten LSCD goats (10 eyes) were treated with EpiASC transplantation, leading to the restoration of corneal transparency and improvement of postoperative visual acuity to varying degrees in 80.00% (8/10) of the experimental eyes. The corneal epithelium of control groups either with HAM transplantation only or without any transplantation showed irregular surfaces, diffuse vascularization, and pannus on the entire cornea. The reconstructed corneal epithelium (RCE) expressed CK3, CK12, and PAX-6 and had the function of secreting glycocalyx-like material (AB-PAS positive). During the follow-up period, all corneal surfaces remained transparent and there were no serious complications. We also observed that the REC expressed CK1/10 weakly at six months after operation but not at 12 months after operation, suggesting that the REC was derived from grafted EpiASC. CONCLUSIONS: Our results showed that EpiASC repaired the damaged cornea of goats with total LSCD and demonstrated that EpiASC can be induced to differentiate into corneal epithelial cell types in vivo, which at least in part correlated with down-regulation of CK1/10 and upregulation of PAX-6.