Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis.

Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS autoimmune diseases.

Cspg4high microglia contribute to microgliosis during neurodegeneration.

Microglia play a critical role in the pathogenic process of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). Upon pathological stimulation, microglia are converted from a surveillant to an overactivated phenotype. However, the molecular characters of proliferating microglia and their contributions to the pathogenesis of neurodegeneration remain unclear. Here, we identify chondroitin sulfate proteoglycan 4 (Cspg4, also known as neural/glial antigen 2)-expressing microglia as a specific subset of microglia with proliferative capability during neurodegeneration. We found that the percentage of Cspg4+ microglia was increased in mouse models of PD. The transcriptomic analysis of Cspg4+ microglia revealed that the subcluster Cspg4high microglia displayed a unique transcriptomic signature, which was characterized by the enrichment of orthologous cell cycle genes and a lower expression of genes responsible for neuroinflammation and phagocytosis. Their gene signatures were also distinct from that of known disease-associated microglia. The proliferation of quiescent Cspg4high microglia was evoked by pathological α-synuclein. Following the transplantation in the adult brain with the depletion of endogenous microglia, Cspg4high microglia grafts showed higher survival rates than their Cspg4- counterparts. Consistently, Cspg4high microglia were detected in the brain of AD patients and displayed the expansion in animal models of AD. These findings suggest that Cspg4high microglia are one of the origins of microgliosis during neurodegeneration and may open up a avenue for the treatment of neurodegenerative diseases.

Construction of a Column Line Chart-Based Predictive Model for Postoperative Pulmonary Infection Severity in Tracheostomized Patients with Cranial Brain Injuries.

Objective: To explore the construction of a column line chart-based predictive model for postoperative pulmonary infection severity in tracheostomized patients with cranial brain injuries. Methods: The study included 187 patients with cranial brain injuries who underwent tracheostomy between December 2021 and June 2023. These patients were categorized into moderate-to-severe and mild groups based on the severity of postoperative pulmonary infections. Logistic regression analysis was employed to pinpoint the autonomous risk elements for the severity of postoperative pulmonary infection in tracheostomized patients with cranial brain injuries, and a column line chart predictive model was established using these identified independent risk factors. Receiver Operating Characteristic (ROC) curves and calibration curves were used to assess the predictive performance and clinical application potential of the column line chart model for postoperative pulmonary infection risk in tracheostomized patients with cranial brain injuries. Results: Among the 187 patients, 83 (44.39%) experienced moderate-to-severe pulmonary infection. Factors such as age ≥60 years, GCS score <8, a history of long-term smoking, ASA >II, non-washable tracheal tubes, malnutrition, using a ventilator, and longer operative time were more prevalent in the moderate-to-severe group compared to the mild group (P < .05). Multivariate logistic regression analysis revealed that age ≥60 years, GCS score <8, a history of long-term smoking, ASA >II, non-washable tracheal tubes, malnutrition, using a ventilator, and longer operative time were independent risk factors for moderate-to-severe pulmonary infection in tracheostomized patients with cranial brain injuries (P < .05). Build a predictive model based on the above six independent risk factors and plot the ROC curve. ROC curve analysis demonstrated that the AUC values for age ≥60 years, GCS score <8, a history of long-term smoking, ASA >II, non-washable tracheal tubes, malnutrition, using a ventilator, and longer operative time in the column line chart model were 0.578, 0.654, 0.711, 0.652, 0.892, 0.598, 0.712, and 0.752, respectively, indicating good predictive performance of the model. Conclusion: The column line chart-based predictive model for postoperative pulmonary infection severity in tracheostomized patients with cranial brain injuries has a high discriminative power and predictive accuracy. It provides a reliable and intuitive means of predicting the severity of postoperative pulmonary infections in these individuals, enabling healthcare personnel to implement timely intervention measures, thus reducing the occurrence of pulmonary infections.

Causal relationships between gut microbiota and Aneurysmal Subarachnoid Hemorrhage: A Bidirectional Mendelian Randomization Study.

BACKGROUND AND PURPOSE: Aneurysmal Subarachnoid Hemorrhage (aSAH) poses a significant health burden globally, necessitating a deeper understanding of its etiology and potential preventive strategies. Recent research has suggested a possible link between gut microbiota composition and the risk of vascularity, prompting investigation into this association using Mendelian Randomization (MR) analysis. Here, we aimed to elucidate the causal relationship between gut microbiota composition and aSAH risk utilizing MR analysis. METHODS: We employed four distinct MR methodologies, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode, to assess the causal nexus between gut microbiota composition and aSAH risk. Genetic instrumental variables (IVs) associated with gut microbiome composition were selected from a comprehensive multiethnic genome-wide association study (GWAS) involving 18,473 individuals across diverse geographic regions. Sensitivity analyses were conducted to detect potential heterogeneity and pleiotropy. RESULTS: Our Mendelian Randomization (MR) analyses unveiled a substantial and statistically significant causal relationship between gut microbiota composition and the risk of Aneurysmal Subarachnoid Hemorrhage (aSAH). Employing the Inverse Variance Weighted (IVW) method, we observed negative associations between aSAH and specific taxonomic levels of gut microbiota. Specifically, the IVW approach identified significant associations with one order, Victivallales (PIVW=0.047, OR: 0.78, 95 % CI: 0.62-0.99), one family, Porphyromonadaceae (PIVW=0.03, OR: 0.64, 95 % CI: 0.43-0.95), one class, Lentisphaeria (PIVW=0.047, OR: 0.78, 95 % CI: 0.62-0.99), and three genera: Bilophila (PIVW=0.02, OR: 0.68, 95 % CI: 0.50-0.93), Fusicatenibacter (PIVW=0.04, OR: 0.69, 95 % CI: 0.49-0.98), and Ruminococcus1 (PIVW=0.01, OR: 0.51, 95 % CI: 0.32-0.84). These findings were consistent across various MR methodologies, underscoring the robustness of our results. Sensitivity analyses further validated the stability of our findings, with no evidence of heterogeneity or pleiotropy detected. CONCLUSION: Our study provides compelling evidence supporting a causal relationship between gut microbiota composition and the risk of aSAH. These findings underscore the potential therapeutic implications of modulating gut microbiota to prevent and manage aSAH. Further research is warranted to explore the underlying mechanisms and develop targeted interventions aimed at mitigating aSAH risk through gut microbiota modulation.

RGS5 augments astrocyte activation and facilitates neuroinflammation via TNF signaling.

Astrocytes contribute to chronic neuroinflammation in a variety of neurodegenerative diseases, including Parkinson's disease (PD), the most common movement disorder. However, the precise role of astrocytes in neuroinflammation remains incompletely understood. Herein, we show that regulator of G-protein signaling 5 (RGS5) promotes neurodegenerative process through augmenting astrocytic tumor necrosis factor receptor (TNFR) signaling. We found that selective ablation of Rgs5 in astrocytes caused an inhibition in the production of cytokines resulting in mitigated neuroinflammatory response and neuronal survival in animal models of PD, whereas overexpression of Rgs5 had the opposite effects. Mechanistically, RGS5 switched astrocytes from neuroprotective to pro-inflammatory property via binding to the receptor TNFR2. RGS5 also augmented TNFR signaling-mediated pro-inflammatory response by interacting with the receptor TNFR1. Moreover, interrupting RGS5/TNFR interaction by either RGS5 aa 1-108 or small molecular compounds feshurin and butein, suppressed astrocytic cytokine production. We showed that the transcription of astrocytic RGS5 was controlled by transcription factor early B cell factor 1 whose expression was reciprocally influenced by RGS5-modulated TNF signaling. Thus, our study indicates that beyond its traditional role in G-protein coupled receptor signaling, astrocytic RGS5 is a key modulator of TNF signaling circuit with resultant activation of astrocytes thereby contributing to chronic neuroinflammation. Blockade of the astrocytic RGS5/TNFR interaction is a potential therapeutic strategy for neuroinflammation-associated neurodegenerative diseases.

Advantages of Small Bone-Window Craniotomy Under Microscope Combined Postoperative Intracranial Pressure Monitoring in the Treatment of Hypertensive Intracerebral Hemorrhage.

OBJECTIVE: The aim of this study is to analyze the clinical effect of small bone-window craniotomy with microscope combined postoperative ICP monitoring, and further explore an appropriate treatment for HICH patients. METHODS: One hundred fifty patients with HICH were selected according to inclusion and exclusion criteria and divided into 3 groups at random, 50 each group. Patients in 3 groups were treated with conventional craniotomy, small bone-window craniotomy and small bone-window craniotomy combined ICP monitoring respectively. The surgical efficiency, treatment effect and outcomes were recorded and analyzed. RESULTS: The intraoperative blood loss and operation time of small window groups were significantly less than that of conventional group, and the hematoma clearance rate in small window groups were significantly higher than in conventional group (P < 0.05). Compared with conventional group, the hospital stays and mannitol dose used were less in small window groups and least in small window combined ICP monitoring group (P < 0.05). The complication rate in small window combined ICP monitoring group was 10%, which was significantly lower than in conventional group (26%, P < 0.05), while no significant difference was found between small window group (18%) compared with the other 2 groups respectively (P > 0.05). The difference of morality rate between 3 groups wasn't significant (P > 0.05). Three treatment significantly increased the Barthel index score, and the improvement of small window combined ICP monitoring group was significantly higher than in other 2 groups respectively (P < 0.05), while the difference between this two groups wasn't significant (P > 0.05). CONCLUSION: Small bone-window craniotomy is more efficient and convenient than conventional craniotomy in the treatment of HICH. In the meantime, small bone-window craniotomy simultaneous with ICP monitoring significantly improved clinical effect and treatment outcomes of HICH patients.

Extracellular αB-crystallin modulates the inflammatory responses.

Neuroinflammation is considered a challenging clinical problem. Chronic inflammatory responses play important roles in the onset and progression of various neurodegenerative diseases, including multiple sclerosis (MS). Previous studies have shown that astrocytes express small heat shock protein αB-crystallin (CRYAB) which is capable of inhibiting inflammatory responses in astrocytes per se. However, the underlying mechanisms of CRYAB-induced modulation of neuroinflammation are still not fully understood. In the present study, we investigated the role of extracellular CRYAB in the interaction between microglia and astrocytes in the context of MS-associated neuroinflammation. We found that the expression of CRYAB was profoundly increased in EAE mice. CRYAB was preferentially expressed in astrocytes and could be secreted via exosomes. Levels of exosomal CRYAB secreted from astrocytes were markedly increased under stress conditions. Furthermore, incubation of immortalized astrocytes or microglia cell lines with CRYAB remarkably suppressed astrocytes and microglia-mediated inflammatory responses in both autocrine and paracrine manners. Our results reveal a novel function for extracellular CRYAB in the regulation of neuroinflammation. Targeting extracellular CRYAB-modulated neuroinflammation is a potential therapeutic intervention for MS.

NG2 glia regulate brain innate immunity via TGF-ß2/TGFBR2 axis.

BACKGROUND: Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson's disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. METHODS: Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. RESULTS: We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-ß2 (TGF-ß2)-TGF-ß type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-ß2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. CONCLUSIONS: These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.

Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin.

Chronic neuroinflammation is a common feature of the ageing brain and some neurodegenerative disorders. However, the molecular and cellular mechanisms underlying the regulation of innate immunity in the central nervous system remain elusive. Here we show that the astrocytic dopamine D2 receptor (DRD2) modulates innate immunity through αB-crystallin (CRYAB), which is known to suppress neuroinflammation. We demonstrate that knockout mice lacking Drd2 showed remarkable inflammatory response in multiple central nervous system regions and increased the vulnerability of nigral dopaminergic neurons to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Astrocytes null for Drd2 became hyper-responsive to immune stimuli with a marked reduction in the level of CRYAB. Preferential ablation of Drd2 in astrocytes robustly activated astrocytes in the substantia nigra. Gain- or loss-of-function studies showed that CRYAB is critical for DRD2-mediated modulation of innate immune response in astrocytes. Furthermore, treatment of wild-type mice with the selective DRD2 agonist quinpirole increased resistance of the nigral dopaminergic neurons to MPTP through partial suppression of inflammation. Our study indicates that astrocytic DRD2 activation normally suppresses neuroinflammation in the central nervous system through a CRYAB-dependent mechanism, and provides a new strategy for targeting the astrocyte-mediated innate immune response in the central nervous system during ageing and disease.

Exploring the causal links between cigarette smoking, alcohol consumption, and aneurysmal subarachnoid hemorrhage: a two-sample Mendelian randomization analysis.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) represents a critical health concern characterized by elevated mortality and morbidity rates. Although both genetic predisposition and lifestyle choices influence aSAH susceptibility, understanding the causative associations between cigarette smoking, alcohol consumption, and aSAH risk remains imperative. Mendelian randomization (MR) offers a robust methodological framework for dissecting these associations, leveraging genetic variants as instrumental variables. Objective: In this study, a two-sample Mendelian randomization (TSMR) approach was employed to elucidate the causal connections between genetically determined cigarette smoking, alcohol consumption, and aSAH risk. Methods: Genetic instruments associated with cigarette smoking and alcohol consumption were sourced from the genome-wide association study (GWAS) and Sequencing Consortium of Alcohol and Nicotine use (GSCAN). Using a genome-wide association study (GWAS) dataset that encompassed aSAH cases and controls of European ancestry, TSMR, which utilized the inverse variance weighting (IVW) method, was employed to estimate the causal effects. Rigorous criteria were applied for selecting instrumental variables to ensure a robust Mendelian randomization analysis. Results: A significant causal association was found between genetically determined cigarette smoking and an increased risk of aSAH, with a 1-standard deviation (SD) increase in cigarette use genetically linked to a 96% relative risk elevation [OR-IVW = 1.96, 95% confidence interval (CI) = 1.28-3.01, p = 0.0021]. However, genetically determined alcohol consumption did not exhibit a statistically significant association with aSAH risk (OR-IVW = 1.22, 95% CI = 0.61-2.45, p = 0.578). Conclusion: The Mendelian randomization analysis revealed a causal nexus between cigarette smoking and an increased risk of aSAH, advocating for targeted smoking cessation interventions within genetically predisposed cohorts. The results regarding the relationship between alcohol consumption and aSAH were affected by insufficient statistical power. A prudent interpretation of the findings highlights the limitations of Mendelian randomization in elucidating intricate genetic epidemiological relationships. Ongoing research involving larger cohort sizes and advanced methodological approaches is essential for comprehending the genetic underpinnings of aSAH.

Nicotinamide Mononucleotide Ameliorates Sleep Deprivation-Induced Gut Microbiota Dysbiosis and Restores Colonization Resistance against Intestinal Infections.

Gut microbiota-mediated colonization resistance (CR) is crucial in protecting the host from intestinal infections. Sleep deprivation (SD) is an important contributor in the disturbances of intestinal homeostasis. However, whether and how SD affects host CR remains largely unknown. Here, it is shown that SD impairs intestinal CR in mice, whereas nicotinamide mononucleotide (NMN) supplementation restores it. Microbial diversity and metabolomic analyses suggest that gut microbiota and metabolite profiles in SD-treated mice are highly shaped, whereas NMN reprograms these differences. Specifically, the altered gut microbiota in SD mice further incurs the disorder of secondary bile acids pool accompanied by a decrease in deoxycholic acid (DCA). Conversely, NMN supplementation retakes the potential benefits of DCA, which is associated with specific gut microbiota involved in primary bile acids metabolic flux. In animal models of infection, DCA is effective in preventing and treating bacterial infections when used alone or in combination with antibiotics. Mechanistically, DCA alone disrupts membrane permeability and aggravates oxidative damage, thereby reducing intestinal pathogen burden. Meanwhile, exogenous DCA promotes antibiotic accumulation and destroys oxidant-antioxidant system, thus potentiating antibiotic efficacy. Overall, this work highlights the important roles of gut microbiota and bile acid metabolism in the maintenance of intestinal CR.

Podocytes are likely the therapeutic target of IgA nephropathy with isolated hematuria: Evidence from repeat renal biopsy.

Background: The present study aimed to prove the progression of immunoglobulin A nephropathy (IgAN) patients with isolated hematuria based on repeat renal biopsy data for the first time. Methods: 29 IgAN patients with isolated hematuria who received repeat renal biopsies were analyzed retrospectively, while 29 non-isolated hematuria IgAN patients with similar age and background were randomly selected as the control group. Clinical parameters were collected at the time of biopsy. The treatment strategies (conservative treatment with RASS blocker or immunosuppressive treatment) were choosen according to the pathological results at the first renal biopsy. The activity and chronicity indexes of renal lesions were evaluated. Markers of cell inflammation and proliferation were tseted by immunochemistry. The ultrastructure of podocytes was observed by transmission electron microscopy (TEM). Podocyte and oxidative stress marker (NPHS2 and 4-HNE) were detected by immunofluorescence. Results: The IgAN patients with isolated hematuria had better clinical indicators than those with no-isolated hematuria, such as better renal function, higher albumin and lower uric acid. The interval between two biopsies in IgAN patients with isolated hematuria was 630 (interquartile range, 409.5-1,171) days. The hematuria of the patients decreased significantly from 30 (IQR, 4.00-35.00) RBC/ul in the first biopsy to 11 (IQR, 2.50-30.00) RBC/ul in the repeated biopsy (p < 0.05). The level of triglyceride decreased significantly (p < 0.05). The other clinical indicators were not statistically significant (p > 0.05). Deposits of IgA and C3 in the glomerulus were persistent. The activity index decreased, especially cellular crescent formation, while the chronicity index increased. The ultrastructure of podocytes was improved after treatment. The oxidative stress products of podocytes reduced after treatment. Conclusion: Although the clinical indicators of the IgAN patients with isolated hematuria were in the normal range, various acute and chronic pathological changes have occurred, and irreversible chronic changes have been progressing. Cell inflammation and proliferation persisted. Oxidative stress of podocytes was likely to be the therapeutic target. This study provided a strong basis for the progress of IgAN with isolated hematuria through pathological changes before and after treatment. This study will help clinicians recognize the harm of hematuria, change the traditional treatment concept, and help such patients get early treatment.

MSC p43 required for axonal development in motor neurons.

Neuron connectivity and correct neural function largely depend on axonal integrity. Neurofilaments (NFs) constitute the main cytoskeletal network maintaining the structural integrity of neurons and exhibit dynamic changes during axonal and dendritic growth. However, the mechanisms underlying axonal development and maintenance remain poorly understood. Here, we identify that multisynthetase complex p43 (MSC p43) is essential for NF assembly and axon maintenance. The MSC p43 protein was predominantly expressed in central neurons and interacted with NF light subunit in vivo. Mice lacking MSC p43 exhibited axon degeneration in motor neurons, defective neuromuscular junctions, muscular atrophy, and motor dysfunction. Furthermore, MSC p43 depletion in mice caused disorganization of the axonal NF network. Mechanistically, MSC p43 is required for maintaining normal phosphorylation levels of NFs. Thus, MSC p43 is indispensable in maintaining axonal integrity. Its dysfunction may underlie the NF disorganization and axon degeneration associated with motor neuron degenerative diseases.

Intestinal Dopamine Receptor D2 is Required for Neuroprotection Against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Dopaminergic Neurodegeneration.

A wealth of evidence has suggested that gastrointestinal dysfunction is associated with the onset and progression of Parkinson's disease (PD). However, the mechanisms underlying these links remain to be defined. Here, we investigated the impact of deregulation of intestinal dopamine D2 receptor (DRD2) signaling in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration. Dopamine/dopamine signaling in the mouse colon decreased with ageing. Selective ablation of Drd2, but not Drd4, in the intestinal epithelium, caused a more severe loss of dopaminergic neurons in the substantia nigra following MPTP challenge, and this was accompanied by a reduced abundance of succinate-producing Alleoprevotella in the gut microbiota. Administration of succinate markedly attenuated dopaminergic neuronal loss in MPTP-treated mice by elevating the mitochondrial membrane potential. This study suggests that intestinal epithelial DRD2 activity and succinate from the gut microbiome contribute to the maintenance of nigral DA neuron survival. These findings provide a potential strategy targeting neuroinflammation-related neurological disorders such as PD.

Central dopaminergic control of cell proliferation in the colonic epithelium.

Parkinson's disease (PD) is an age-related neurodegenerative disease, mainly characterized by the loss of dopaminergic (DA) neurons in the substantia nigra. Several non-motor symptoms, including those associated with gastrointestinal dysfunction, precede the classical motor symptoms in PD. However, the mechanisms underlying gastrointestinal dysfunction in the prodromal phase of PD remain elusive. Here, we investigated the contribution of the central DA system to cell proliferation in the colonic epithelium. Degeneration of nigrostriatal DA pathway induced by striatal 6-hydroxydopamine (6-OHDA) injection resulted in a marked reduction in cell proliferation in the colonic epithelium as assessed by Ki-67 and bromodeoxyuridine labeling assays. RNA-sequencing analysis confirmed the suppression of cell cycle-related gene expression in the colonic epithelium of 6-OHDA-lesioned mice. Mesencephalic DA neuron degeneration also caused the gut microbiota dysbiosis. Moreover, 6-OHDA-lesioned mice showed profoundly increased vulnerability to dextran sulfate sodium-induced colitis. Together, our study uncovers a crucial role for the integrity of nigral DA neurons in the maintenance of colonic epithelial cell homeostasis. Our data also provide a new strategy for protecting intestinal homeostasis in PD.

Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis.

Astrocyte activation is associated with progressive inflammatory demyelination in multiple sclerosis (MS). The molecular mechanisms underlying astrocyte activation remain incompletely understood. Recent studies have suggested that classical neurotransmitter receptors are implicated in the modulation of brain innate immunity. We investigated the role of dopamine signaling in the process of astrocyte activation. Here, we show the upregulation of dopamine D2 receptor (DRD2) in reactive astrocytes in MS brain and noncanonical role of astrocytic DRD2 in MS pathogenesis. Mice deficient in astrocytic Drd2 exhibit a remarkable suppression of reactive astrocytes and amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates the expression of 6-pyruvoyl-tetrahydropterin synthase, which modulates NF-κB activity through protein kinase C-δ. Pharmacological blockade of astrocytic DRD2 with a DRD2 antagonist dehydrocorybulbine remarkably inhibits the inflammatory response in mice lacking neuronal Drd2. Together, our findings reveal previously an uncharted role for DRD2 in astrocyte activation during EAE-associated CNS inflammation. Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases.

Expression of ventral diencephalon-enriched genes in zebrafish.

Dopaminergic (DA) neurons in the vertebrate di- and mesencephalon play essential roles in movement control, endocrine modulation and many other important physiological activities. To identify genes that may regulate the specification and differentiation of diencephalic DA neurons in zebrafish, the spatial and temporal expression pattern of a set of genes was investigated. In situ hybridization analysis revealed that expression of DNA binding inhibitor 3 (Id3), early B cell factor 2 (Ebf2), Ebf3, Iroquois related homeobox 1 (Irx1), Kruppel-like factor 7 (Klf7), mab-21-like 1 (Mab21l1), fatty acid binding protein 7 (Fabp7) and stathmin-like 4 (Stmn4), were enriched in the diencephalon of zebrafish. Among these genes, Id3 was expressed specifically in a subset of DA neurons in the ventral diencephalon, with co-expression of neurogenin1 (Ngn1). Alteration of expression levels of Id3 inhibited maturation of developing DA neurons. Taken together, our study provides genetic characteristics of DA neurons in the diencephalon of zebrafish.

Nuclear isoform of FGF13 regulates post-natal neurogenesis in the hippocampus through an epigenomic mechanism.

The hippocampus is one of two niches in the mammalian brain with persistent neurogenesis into adulthood. The neurogenic capacity of hippocampal neural stem cells (NSCs) declines with age, but the molecular mechanisms of this process remain unknown. In this study, we find that fibroblast growth factor 13 (FGF13) is essential for the post-natal neurogenesis in mouse hippocampus, and FGF13 deficiency impairs learning and memory. In particular, we find that FGF13A, the nuclear isoform of FGF13, is involved in the maintenance of NSCs and the suppression of neuronal differentiation during post-natal hippocampal development. Furthermore, we find that FGF13A interacts with ARID1B, a unit of Brahma-associated factor chromatin remodeling complex, and suppresses the expression of neuron differentiation-associated genes through chromatin modification. Our results suggest that FGF13A is an important regulator for maintaining the self-renewal and neurogenic capacity of NSCs in post-natal hippocampus, revealing an epigenomic regulatory function of FGFs in neurogenesis.

Ventral mesencephalon-enriched genes that regulate the development of dopaminergic neurons in vivo.

Mesodiencephalic dopaminergic (mDA) neurons are critical for movement control and other physiological activities. However, the molecular mechanisms underlying their development are poorly understood. We aimed to establish the expression profiles of genes involved in this process and unravel genetic programs that control late development of mDA neurons. We compared genome-wide gene expression profiles of developing mouse ventral mesencephalon (VM) using microarrays. We identified a set of genes that show spatially and temporally restricted expression in the VM in an Ngn2 (neurogenin 2)-dependent manner and are potentially important for mDA neuron development. Functional analysis on mice lacking the VM-specific gene early B-cell factor 1 (Ebf1) revealed that Ebf1 is essential for the terminal migration of mDA neurons in the substantia nigra pars compacta. Thus, we identified a set of VM-enriched genes that are important for mDA neuron development. Our analysis also provides a genetic framework for further investigation of the molecular mechanisms mediating mDA neuron development.

Activation of phosphatidylinositol-linked D1-like receptor modulates FGF-2 expression in astrocytes via IP3-dependent Ca2+ signaling.

Fibroblast growth factor-2 (FGF-2) is predominantly synthesized and secreted by astrocytes in adult brain. Our previous study showed that activation of classical dopamine receptor D(1) or D(2) elicits FGF-2 biosynthesis and secretion in astrocytes. Here, we report that astrocytic FGF-2 expression is also regulated by phosphatidylinositol (PI)-linked D(1)-like receptor. SKF83959, a selective PI-linked D(1)-like receptor agonist, upregulates the levels of FGF-2 protein in striatal astrocyte cultures in classical dopamine D(1) and D(2) receptor-independent manner. The conditional medium derived from SKF83959-activated astrocytes promoted the number of TH(+) neurons in vitro. Treatment of astrocytes with SKF83959 increased intracellular calcium in two phases. Inhibition of intracellular calcium oscillation by inositol 1,4,5-triphosphate (IP3) inhibitors blocked the SKF83959-induced increase in FGF-2 expression. Moreover, intraperitoneal administration of SKF83959 reversed l-methyl-4-phenyl-l,2,3,6-tetrahydropypridine (MPTP)-induced reduction in FGF-2 expression in both the striatum and ventral midbrain and resulted in marked protection of dopaminergic neurons from MPTP-induced neurotoxicity. These results indicate that IP3/Ca(2+)/calmodulin-dependent protein kinase is an uncharted intracellular signaling pathway that is crucial for the regulation of FGF-2 synthesis in astrocytes. PI-linked D(1)-like receptor plays an important role in the regulation of astrocytic FGF-2 expression and neuroprotection which may provide a potential target for the drug discovery in Parkinson's disease.