Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice.

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

Approach to a cerebral hernia caused by an intratumoral hemorrhage of a cystic oligodendroglioma: a case report.

The incidence of cerebral herniation caused by intratumoral hemorrhage (ITH) in cystic oligodendroglioma (COD) is exceedingly rare. This study presents a case of cerebral herniation subsequent to cystic oligodendroglioma (COD) and sudden intratumoral hemorrhage. Following initial emergency treatment and evaluation, we successfully circumvented the solid component of the tumor and proceeded with cystic puncture and external drainage to prevent the incidence of brain herniation and mitigate the severity of associated symptoms. Based on preoperative examination results, the cystic glioma was successfully resected, and the patient experienced an uneventful recovery. According to the pathological findings, the oligodendroglioma was classified as World Health Organization (WHO) grade III. The treatment efficacy was comparable to cases of the same pathological grade, in which neither intratumoral hemorrhage nor cerebral hernia was observed.

Hemorrhagic cerebral venous infarction after vein injury during intraoperative lesion resection: incidence, hemorrhagic stages, risk factors and prognosis.

Objective: Cerebral venous infarction (CVI) after vein injury during intraoperative lesion resection is associated with intracranial hemorrhage. We conducted this study to identify the incidence, clinical and imaging features, and prognosis of hemorrhage CVI. Methods: We performed a retrospective analysis of patients with confirmed CVI after vein injury who underwent craniotomy in our hospital. Postoperative clinical symptoms were observed, and imaging features were compared between patients with and without intracranial hemorrhages through CT examination. Variables were analyzed using univariate and multivariate regression analyses. Results: Among 2,767 patients who underwent craniotomy, 93 cases of injured veins were identified intraoperatively. Hemorrhagic CVI was found in 38% (35/93). Multivariate analysis revealed that midline approach, meningioma, postoperative seizures, disorders of consciousness and interval in hours < 72 h were identified as predictors of hemorrhagic CVI. After 3 months of follow-up, the prognosis was poor in 15 cases (16%, 15/93), including death (two cases), vegetative survival (four cases), and severe disability (nine cases). Conclusions: Hemorrhagic CVI, as a critical complication after venous injury, can have disastrous consequences. Do not injure known veins intraoperatively. In case of injury, requisite remedial measures should be adopted during and after surgery.

Connecting the Dots: The Cerebral Lymphatic System as a Bridge Between the Central Nervous System and Peripheral System in Health and Disease.

As a recently discovered waste removal system in the brain, cerebral lymphatic system is thought to play an important role in regulating the homeostasis of the central nervous system. Currently, more and more attention is being focused on the cerebral lymphatic system. Further understanding of the structural and functional characteristics of cerebral lymphatic system is essential to better understand the pathogenesis of diseases and to explore therapeutic approaches. In this review, we summarize the structural components and functional characteristics of cerebral lymphatic system. More importantly, it is closely associated with peripheral system diseases in the gastrointestinal tract, liver, and kidney. However, there is still a gap in the study of the cerebral lymphatic system. However, we believe that it is a critical mediator of the interactions between the central nervous system and the peripheral system.

Restoring the Function of Thalamocortical Circuit Through Correcting Thalamic Kv3.2 Channelopathy Normalizes Fear Extinction Impairments in a PTSD Mouse Model.

Impaired extinction of fear memory is one of the most common symptoms in post-traumatic stress disorder (PTSD), with limited therapeutic strategies due to the poor understanding of its underlying neural substrates. In this study, functional screening is performed and identified hyperactivity in the mediodorsal thalamic nucleus (MD) during fear extinction. Furthermore, the encoding patterns of the hyperactivated MD is investigated during persistent fear responses using multiple machine learning algorithms. The anterior cingulate cortex (ACC) is also identified as a functional downstream region of the MD that mediates the extinction of fear memory. The thalamocortical circuit is comprehensively analyzed and found that the MD-ACC parvalbumin interneurons circuit is preferentially enhanced in PTSD mice, disrupting the local excitatory and inhibitory balance. It is found that decreased phosphorylation of the Kv3.2 channel contributed to the hyperactivated MD, primarily to the malfunctioning thalamocortical circuit. Using a lipid nanoparticle-based RNA therapy strategy, channelopathy is corrected via a methoxylated siRNA targeting the protein phosphatase 6 catalytic subunit and restored fear memory extinction in PTSD mice. These findings highlight the function of the thalamocortical circuit in PTSD-related impaired extinction of fear memory and provide therapeutic insights into Kv3.2-targeted RNA therapy for PTSD.

Reversal of hyperactive higher-order thalamus attenuates defensiveness in a mouse model of PTSD.

Posttraumatic stress disorder (PTSD) is a highly prevalent and debilitating psychiatric disease often accompanied by severe defensive behaviors, preventing individuals from integrating into society. However, the neural mechanisms of defensiveness in PTSD remain largely unknown. Here, we identified that the higher-order thalamus, the posteromedial complex of the thalamus (PoM), was overactivated in a mouse model of PTSD, and suppressing PoM activity alleviated excessive defensive behaviors. Moreover, we found that diminished thalamic inhibition derived from the thalamic reticular nucleus was the major cause of thalamic hyperactivity in PTSD mice. Overloaded thalamic innervation to the downstream cortical area, frontal association cortex, drove abnormal defensiveness. Overall, our study revealed that the malfunction of the higher-order thalamus mediates defensive behaviors and highlighted the thalamocortical circuit as a potential target for treating PTSD-related overreactivity symptoms.

Meshed neuronal mitochondrial networks empowered by AI-powered classifiers and immersive VR reconstruction.

Mitochondrial networks are defined as a continuous matrix lumen, but the morphological feature of neuronal mitochondrial networks is not clear due to the lack of suitable analysis techniques. The aim of the present study is to develop a framework to capture and analyze the neuronal mitochondrial networks by using 4-step process composed of 2D and 3D observation, primary and secondary virtual reality (VR) analysis, with the help of artificial intelligence (AI)-powered Aivia segmentation an classifiers. In order to fulfill this purpose, we first generated the PCs-Mito-GFP mice, in which green fluorescence protein (GFP) could be expressed on the outer mitochondrial membrane specifically on the cerebellar Purkinje cells (PCs), thus all mitochondria in the giant neuronal soma, complex dendritic arborization trees and long projection axons of Purkinje cells could be easily detected under a laser scanning confocal microscope. The 4-step process resolved the complicated neuronal mitochondrial networks into discrete neuronal mitochondrial meshes. Second, we measured the two parameters of the neuronal mitochondrial meshes, and the results showed that the surface area (µm2) of mitochondrial meshes was the biggest in dendritic trees (45.30 ± 53.21), the smallest in granular-like axons (3.99 ± 1.82), and moderate in soma (27.81 ± 22.22) and silk-like axons (17.50 ± 15.19). These values showed statistically different among different subcellular locations. The volume (µm3) of mitochondrial meshes was the biggest in dendritic trees (9.97 ± 12.34), the smallest in granular-like axons (0.43 ± 0.25), and moderate in soma (6.26 ± 6.46) and silk-like axons (3.52 ± 4.29). These values showed significantly different among different subcellular locations. Finally, we found both the surface area and the volume of mitochondrial meshes in dendritic trees and soma within the Purkinje cells in PCs-Mito-GFP mice after receiving the training with the simulating long-term pilot flight concentrating increased significantly. The precise reconstruction of neuronal mitochondrial networks is extremely laborious, the present 4-step workflow powered by artificial intelligence and virtual reality reconstruction could successfully address these challenges.

Intraparenchymal atypical meningioma in the posterior fossa: a case report and literature review.

Intraparenchymal meningiomas without dural attachments are extremely rare. A 32-year-old female adult was admitted to our hospital, complaining of occasional dizziness. The patient had no neurological deficits. MRI demonstrated a lesion with mild edema located in the left cerebellar parenchyma. CT revealed calcification within the mass. Gross total resection was achieved. The histopathological examination indicated that the lesion was an atypical meningioma (WHO-II). We herein report an extremely rare case of an intraparenchymal meningioma located in the left cerebellar hemisphere. The significance of the differential diagnosis of lesions in the cerebellum should be emphasized.

Insights into the Effect of Catalytic Intratumoral Lactate Depletion on Metabolic Reprogramming and Immune Activation for Antitumoral Activity.

Lactate, a characteristic metabolite of the tumor microenvironment (TME), drives immunosuppression and promotes tumor progression. Material-engineered strategies for intratumoral lactate modulations demonstrate their promise for tumor immunotherapy. However, understanding of the inherent interconnections of material-enabled lactate regulation, metabolism, and immunity in the TME is scarce. To address this issue, urchin-like catalysts of the encapsulated Gd-doped CeO2 , syrosingopine, and lactate oxidase are used in ZIF-8 (USL, where U, S, and L represent the urchin-like Gd-doped CeO2 @ZIF-8, syrosingopine, and lactate oxidase, respectively) and orthotopic tumor models. The instructive relationships of intratumoral lactate depletion, metabolic reprogramming, and immune activation for catalytic immunotherapy of tumors is illustrated. The catalysts efficiently oxidize intratumoral lactate and significantly promote tumor cell apoptosis by in situ-generated ·OH, thereby reducing glucose supply and inducing mitochondrial damage via lactate depletion, thus reprogramming glycometabolism. Subsequently, such catalytic metabolic reprogramming evokes both local and systemic antitumor immunity by activating M1-polarizaed macrophages and CD8+ T cells, leading to potent antitumor immunity. This study provides valuable mechanistic insights into material-interfered tumor therapy through intratumoral lactate depletion and consequential connection with metabolic reprogramming and immunity remodeling, which is thought to enhance the efficacy of immunotherapy.

An ECM-Mimicking, Injectable, Viscoelastic Hydrogel for Treatment of Brain Lesions.

Brain lesions can arise from traumatic brain injury, infection, and craniotomy. Although injectable hydrogels show promise for promoting healing of lesions and health of surrounding tissue, enabling cellular ingrowth and restoring neural tissue continue to be challenging. It is hypothesized that these challenges arise in part from the mismatch of composition, stiffness, and viscoelasticity between the hydrogel and the brain parenchyma, and this hypothesis is tested by developing and evaluating a self-healing hydrogel that not only mimics the composition, but also the stiffness and viscoelasticity of native brain parenchyma. The hydrogel is crosslinked by dynamic boronate ester bonds between phenylboronic acid grafted hyaluronic acid (HA-PBA) and dopamine grafted gelatin (Gel-Dopa). This HA-PBA/Gel-Dopa hydrogel could be injected into a lesion cavity in a shear-thinning manner with rapid hemostasis, high tissue adhesion, and efficient self-healing. In an in vivo mouse model of brain lesions, the multi-functional injectable hydrogel is found to support neural cell infiltration, decrease astrogliosis and glial scars, and close the lesions. The results suggest a role for extracellular matrix-mimicking viscoelasticity in brain lesion healing, and motivate additional experimentation in larger animals as the technology progresses toward potential application in humans.

Regulation of TFEB nuclear localization by HSP90AA1 promotes autophagy and longevity.

TFEB (transcription factor EB) regulates multiple genes involved in the process of macroautophagy/autophagy and plays a critical role in lifespan determination. However, the detailed mechanisms that regulate TFEB activity are not fully clear. In this study, we identified a role for HSP90AA1 in modulating TFEB. HSP90AA1 was phosphorylated by CDK5 at Ser 595 under basal condition. This phosphorylation inhibited HSP90AA1, disrupted its binding to TFEB, and impeded TFEB's nuclear localization and subsequent autophagy induction. Pro-autophagy signaling attenuated CDK5 activity and enhanced TFEB function in an HSP90AA1-dependent manner. Inhibition of HSP90AA1 function or decrease in its expression significantly attenuated TFEB's nuclear localization and transcriptional function following autophagy induction. HSP90AA1-mediated regulation of a TFEB ortholog was involved in the extended lifespan of Caenorhabditis elegans in the absence of its food source bacteria. Collectively, these findings reveal that this regulatory process plays an important role in modulation of TFEB, autophagy, and longevity.Abbreviations : AL: autolysosome; AP: autophagosome; ATG: autophagy related; BafA1: bafilomycin A1; CDK5: cyclin-dependent kinase 5; CDK5R1: cyclin dependent kinase 5 regulatory subunit 1; CR: calorie restriction; FUDR: 5-fluorodeoxyuridine; HSP90AA1: heat shock protein 90 alpha family class A member 1; MAP1LC3: microtubule associated protein 1 light chain 3; NB: novobiocin sodium; SQSTM1: sequestosome 1; TFEB: transcription factor EB; WT: wild type.

SLC1A5 enhances malignant phenotypes through modulating ferroptosis status and immune microenvironment in glioma.

Glioma is the most common type of primary malignant tumor in the central nervous system with limited treatment satisfaction. Finding new therapeutic targets has remained a major challenge. Ferroptosis is a novel and distinct type of programmed cell death, playing a regulatory role in the progression of tumors. However, the role of ferroptosis or ferroptosis-related genes (FRGs) in glioma progression has not been extensively studied. In our study, a novel ferroptosis-related prognostic model, including 7 genes, was established, in which patients classified into the high-risk group had more immuno-suppressive status and worse prognosis. Among these 7 genes, we screened solute carrier family 1 member 5 (SLC1A5), an FRG, as a possible new target for glioma treatment. Our results showed that the expression of SLC1A5 was significantly upregulated in glioblastoma tissues compared with the low-grade gliomas. In addition, SLC1A5 knockdown could significantly inhibit glioma cell proliferation and invasion, and reduce the sensitivity of ferroptosis via the GPX4-dependent pathway. Furthermore, SLC1A5 was found to be related to immune response and SLC1A5 knockdown decreased the infiltration and M2 polarization of tumor-associated macrophages. Pharmacological inhibition of SLC1A5 by V9302 was confirmed to promote the efficacy of anti-PD-1 therapy. Overall, we developed a novel prognostic model for glioma based on the seven-FRGs signature, which could apply to glioma prognostic and immune status prediction. Besides, SLC1A5 in the model could regulate the proliferation, invasion, ferroptosis and immune state in glioma, and be applied as a prognostic biomarker and potential therapeutic target for glioma.

Case report: An illusive cortical venous infarction mimicking glioma hemorrhage.

Cortical vein thrombosis (CVT) is a rare subtype of cerebral venous thrombosis. Because CVT is rare and its clinical and imaging findings are atypical, the misdiagnosis of CVT may be extremely high. We report a case of cortical venous infarction (CVI) secondary to CVT. Due to the atypical symptoms, we were perplexed about confirming the diagnosis between CVI and glioma hemorrhage. Eventually, CVT was confirmed by pathology combined with imaging.

Astrocytic NDRG2-PPM1A interaction exacerbates blood-brain barrier disruption after subarachnoid hemorrhage.

Blood-brain barrier (BBB) injury critically exacerbates the poor prognosis of patients with subarachnoid hemorrhage (SAH). The massively increased matrix metalloproteinases 9 (MMP-9) plays a deleterious role in BBB. However, the main source and mechanism of MMP-9 production after SAH remain unclear. We reported that the increased MMP-9 was mainly derived from reactive astrocytes after SAH. Ndrg2 knockout in astrocytes inhibited MMP-9 expression after SAH and attenuated BBB damage. Astrocytic Ndrg2 knockout decreased the phosphorylation of Smad2/3 and the transcription of MMP-9. Notably, cytoplasmic NDRG2 bound to the protein phosphatase PPM1A and restricted the dephosphorylation of Smad2/3. Accordingly, TAT-QFNP12, a novel engineered peptide that could block the NDRG2-PPM1A binding and reduce Smad2/3 dephosphorylation, decreased astrocytic MMP-9 production and BBB disruption after SAH. In conclusion, this study identified NDRG2-PPM1A signaling in reactive astrocytes as a key switch for MMP-9 production and provided a novel therapeutic avenue for BBB protection after SAH.

The Impacts of Workplace Environment on Coal Miners' Emotion and Cognition Depicted in a Mouse Model.

Most coal mine accidents are caused by the unsafe behavior of employees. Previous studies have shown that there is a significant connection among the working environment, the psychological state of employees, and unsafe behaviors. However, the internal biological mechanism has not been revealed. To explore the physiological and psychological alterations of coal mine workers and the underlying mechanisms that cause unsafe behaviors, the current study established a novel coal mine environment biological simulation (CEBS) model in mice. This model recreated the underground workplace environment facts in coal mines such as temperature, humidity, and noise, and mice were employed to receive these conditioning stresses according to the 8-h work. Animal behavior tests were performed to evaluate the evolution of the mental state including anxiety and depression, as well as the abilities of learning and memory during the 4-week environmental simulation. CEBS mice showed the adaptation process of anxiety from occurrence to stability in the process of environmental simulation, and also suffered from severe depression compared to the control mice. In addition, impaired spatial memory was also implicated in mice after 4-week CEBS. The behavior results of CEBS mice were consistent with the previous psychological investigation of coal workers. In summary, a novel mouse model was established in this study to depict the occurrence of negative emotions and impaired cognition in coal miners by simulating the underground workplace environment, which provided a basis for further exploring the biological mechanism of miners' unsafe behavior.

Adiponectin/AdiopR1 signaling prevents mitochondrial dysfunction and oxidative injury after traumatic brain injury in a SIRT3 dependent manner.

Mitochondrial dysfunction and oxidative injury, which contribute to worsening of neurological deficits and poor clinical outcomes, are hallmarks of secondary brain injury after TBI. Adiponectin (APN), beyond its well-established regulatory effects on metabolism, is also essential for maintaining normal brain functions by binding APN receptors that are ubiquitously expressed in the brain. Currently, the significance of the APN/APN receptor (AdipoR) signaling pathway in secondary injury after TBI and the specific mechanisms have not been conclusively determined. In this study, we found that APN knockout aggravated brain functional deficits, increased brain edema and lesion volume, and exacerbated oxidative stress as well as apoptosis after TBI. These effects were significantly alleviated after APN receptor agonist (AdipoRon) treatment. Moreover, we found that AdipoR1, rather than AdipoR2, mediated the protective effects of APN/AdipoR signaling against oxidative stress and brain injury after TBI. In neuron-specific AdipoR1 knockout mice, mitochondrial damage was more severe after TBI, indicating a potential association between APN/AdipoR1 signaling inactivation and mitochondrial damage. Mechanistically, neuron-specific knockout of SIRT3, the most important deacetylase in the mitochondria, reversed the neuroprotective effects of AdipoRon after TBI. Then, PRDX3, a critical antioxidant enzyme in the mitochondria, was identified as a vital downstream target of the APN/SIRT3 axis to alleviate oxidative injury after TBI. Finally, we revealed that APN/AdipoR1 signaling promotes SIRT3 transcription by activating the AMPK-PGC pathway. In conclusion, APN/AdipoR1 signaling plays a protective role in post-TBI oxidative damage by restoring the SIRT3-mediated mitochondrial homeostasis and antioxidant system.

Risk factors influencing cerebral venous infarction after meningioma resection.

BACKGROUND: Cerebral venous infarction (CVI) is a serious complication after meningioma resection. The risk factors of postoperative cerebral venous infarction after surgical resection of meningioma can be determined through large samples and this study can add evidence to the literature. METHODS: The clinical and imaging data of 1127 patients with intracranial meningiomas who underwent resection in our hospital were retrospectively collected and analyzed. CVI was evaluated by postoperative imaging and clinical manifestations. Univariate and multivariate analyses were performed to identify risk factors associated with CVI. RESULTS: Overall, 4.7% (53/1127) of patients experienced CVI after meningioma resection. Multivariate analysis revealed superficial meningioma, moderate to severe peritumoral edema, peritumoral critical vein and WHO grade II-III as independent predictors of a postoperative CVI. After timely intervention, the symptoms were clearly alleviated in one month, and the prognosis was good, but injury to key veins could cause irreversible neurological disorders. CONCLUSIONS: Intraoperative protection of veins is the primary way to prevent CVI. The present study identified several significant and independent risk factors for postoperative venous infarction, thereby enabling the identification of high-risk patients who require special attention during clinical and surgical management.

The comprehensive and systematic identification of BLCA-specific SF-regulated, survival-related AS events.

Bladder urothelial carcinoma (BLCA) is a complex disease with high morbidity and mortality. Changes in alternative splicing (AS) and splicing factor (SF) can affect gene expression, thus playing an essential role in tumorigenesis. This study downloaded 412 patients' clinical information and 433 samples of transcriptome profiling data from TCGA. And we collected 48 AS signatures from SpliceSeq. LASSO and Cox analyses were used for identifying survival-related AS events in BLCA. Finally, 1,645 OS-related AS events in 1,129 genes were validated by Kaplan-Meier (KM) survival analysis, ROC analysis, risk curve analysis, and independent prognostic analysis. Finally, our survey provides an AS-SF regulation network consisting of five SFs and 46 AS events. In the end, we profiled genes that AS occurred in pan-cancer and five SFs' expression in tumor and normal samples in BLCA. We selected CLIP-seq data for validation the interaction regulated by RBP. Our study paves the way for potential therapeutic targets of BLCA.