mRNA In Cortex Research Articles

Post-ischemic protection of hepatocyte growth factor requires the type II transmembrane serine protease matriptase-A reciprocal regulation of the two for neuroprotection in stroke brain.

In a rat middle cerebral artery occlusion (MACo) model of ischemic stroke, intracerebroventricular administration of human recombinant hepatocyte growth factor (HGF) mitigated motor impairment and cortical infarction. Recombinant HGF reduced MCAo-induced TNFα and IL1β expression, and alleviated perilesional reactivation of microglia and astrocyte. All of the aforementioned beneficial effects of HGF were antagonized by an inhibitor to the type II transmembrane serine protease matriptase (MTP). MCAo upregulated MTP mRNA and protein in the lesioned cortex. MTP protein, not the mRNA, was increased further by recombinant HGF but reduced when MTP inhibitor (MTPi) was added to the treatment. Changes of the endogenous active HGF by MCAo, HGF or MTPi paralleled with the changes of MTP protein under the same conditions whilst neither HGF mRNA nor the total endogenous HGF protein were altered. These data showed that the therapeutic effects of HGF in stroke brain is attributed to its proteolytic activation and that MTP is a main protease of the event. MCAo enhanced MTP mRNA and thus protein expression; the initial use of the recombinant active HGF stabilized MCAo-induced MTP protein and subsequent activation of endogenous latent HGF which in turn stabilized further MTP protein. A reciprocal regulation between MTP and HGF appears to be present where MTP promotes HGF activation and the active HGF prevents MTP protein turnover. This study, for the first time, shows that MTP can participate in neural protection in stroke brain through activation of HGF. The cycles of HGF-MTP regulation achieved preservation of the neurological activity.

M6A regulation of cortical and retinal neurogenesis is mediated by the redundant m6A readers YTHDFs

Summarym6A modification plays an important role in regulating mammalian neurogenesis. However, whether and how the major cytoplasmic m6A readers, YTHDF1, YTHDF2, and YTHDF3 mediate this process is still not clear. Here, we demonstrate that Ythdf1 and Ythdf2 double deletion but not individual knockout recapitulates the phenotype of Mettl14 knockout in cortex. In addition, we find that Mettl14 knockout in retina causes protracted proliferation of retinal progenitors, decreased numbers of retinal neurons, and disturbed laminar structure. This phenotype is only reproduced when Ythdf1, Ythdf2, and Ythdf3 are knocked out simultaneously in retina. Analysis of YTHDF target mRNAs in mouse cortex and retina reveals abundant overlapping mRNAs related to neurogenesis that are recognized and regulated by both YTHDF1 and YTHDF2. Together our results demonstrate that the functionally redundant YTHDFs mediate m6A regulation of cortical and retinal neurogenesis.

Pathophysiology and system biology of rat c-BSA induced immune complex glomerulonephritis and pathway comparison with human gene sequencing data

Immune-complex glomerulonephritis (ICGN) is a major cause of nephrotic syndrome in adults and children. Cationic BSA (c-BSA) intravenous injection could produce significant albuminuria within a short time, and is a suitable in vivo experimental animal model to investigate the pathophysiology of ICGN and for drug screening, but lack of thorough study to clarify its dynamic pathophysiological alteration so far, as well as detailed changes in mRNA and LncRNA levels. The purpose of this study is to investigate the dynamic alteration in renal function, lipid metabolism and histopathology during the progress of c-BSA induced ICGN. RNA sequencing was used to identified differentially expressed mRNA and LncRNA in kidney cortex of ICGN. Results demonstrated that c-BSA induced ICGN model could completely exhibit clinical features of immune-mediated nephrotic syndrome with gradual declining renal function, and increased albuminuria and deteriorated histopathological injuries. The correlation analysis suggested that complement activation was the most key element in mediating of ICGN. RNA sequencing using rat kidney tissues combined with Gene Expression Omnibus (GEO) data of human glomerulonephritis showed the most enriched KEGG pathways in ICGN were Toll-like receptor signaling pathway, B cell receptor and Focal adhesion. The differential lncRNAs in ICGN rats were also screened, and the lncRNA-mRNA co-expression network was constructed to clarify lncRNA role in molecular mechanism of ICGN progression. Their human homogenous lncRNAs were also identified, such as ST3GAL5-AS1 and DIO3OS, which provide the potential lncRNA targets to treat ICGN. All the differential LncRNAs in ICGN kidneys caused by MMF were also identified and provided another possible pharmacological mechanism of MMF through lncRNA regulation. In summary, the current study firstly described the dynamic physiological changes of c-BSA induced ICGN, identified most key KEGG pathways, and provided lncRNA-mRNA regulatory network in ICGN.

Level of mRNA of orexin receptors of second type (ORXR2) in conditions of chronic alcoholation in structures of the rat brain

BACKGROUND: Orexin and its receptors are involved in the mechanisms of pathological craving for alcohol, but there is no unambiguous answer about the expression of the OX2R gene in the rat brain under conditions of alcohol addiction.
 AIM: The aim of this study was to determine the level of OX2R mRNA in brain structures in rats under conditions of prolonged alcoholization and during the period of abstinence.
 MATERIALS AND METHODS: Adult male Wistar rats were alcoholized with 15% ethanol as the only source of liquid for 6 months. The rats were decapitated after chronic alcoholization, as well as on the 1st and 7th days of alcohol withdrawal. Samples of brain structures (prefrontal cortex, hippocampus, ventral tegmental area) were frozen in liquid nitrogen and stored at 80C. Determination of the level of OX2R mRNA was carried out using the method of PCR-analysis.
 RESULTS: The level of ORXR2 gene expression significantly increased in the hippocampus on the 7th day of abstinence in relation to the group of intact animals and in relation to the group of chronically alcoholized rats. The level of OX2R mRNA in the prefrontal cortex and ventral tegmental area in animal groups of abstinence (1st and 7th days) did not change in relation to both alcohol and the intact animals.
 CONCLUSIONS: It is concluded that the orexin brain system may represent a new potential therapeutic target for the prevention of relapse in alcohol withdrawal. Together with the previously obtained data it was concluded that orexin receptor antagonists can be used to reduce the pathological craving for alcohol.

Endogenous human retrovirus-K is not increased in the affected tissues of Japanese ALS patients

Activation of human endogenous retrovirus-K (HERV-K) is one of the proposed risk factors for amyotrophic lateral sclerosis (ALS). The HERV-K envelope protein has been reported to show neurotoxicity, and development of therapy with reverse transcriptase inhibitors is being investigated. On the other hand, some reports have failed to show HERV-K activation in ALS. In this study, we analyzed the expression of HERV-K mRNA in the motor cortex and spinal cord of 15 Japanese patients with sporadic ALS and 19 controls using reverse transcriptase droplet digital PCR. This revealed no significant increase of HERV-K expression in ALS-affected tissues, suggesting that the association between ALS and HERV-K remains questionable.

Demethylbellidifolin, a potential aldose reductase inhibitor ameliorates diabetic nephropathy by regulating the polyol pathway

BackgroundLots of plants in genus Swertia are widely used in the traditional medicine as the treatment for T2DM and its complications in Asia. However, the pharmacodynamic material basis and underlying mechanisms of these plants are still incompletely studied. Inhibition of aldose reductase to regulate polyol pathway is considered to be one effective strategy to treat many complications arising from diabetes. AimThe inhibitory effect against aldose reductase of typical components from the genus Swertia were examined, and further verified in db/db mice model to explore its in vivo renal protective ability and underlying mechanism. MethodsHuman recombinant aldose reductase (AR) was applied to detect the inhibitory activity of these components from genus Swetia in vitro, and the most active one was further analyzed in molecular docking experiment. Then, db/db diabetic mice model were employed to investigate the renal protective effects in vivo. Oxidative stress and renal function related indicators were determined using biochemical kit. Histopathological examination of kidney was conducted to evaluate pathological variations. RT-PCR was applied to measure the level of AR mRNA in renal cortex. Expression of AR, TGF-β1, Collagen Ⅳ, Nephrin and Podocin in kidney tissues were assessed by Western blot. ResultsIt turned out that demethylbellidifolin (DMB) showed the strongest inhibitory activity against AR, with an IC50 of 1.29 ± 0.16 μM, by stabilizing the active site of AR. In vivo experiment confirmed that DMB could remarkably reduce blood glucose and albuminuria level, and alleviate oxidative stress response. Meanwhile, histopathological examination also displayed that the kidney damage in db/db mice was significantly improved after treatment with DMB. Further mechanism study indicated that DMB could prevent the accumulation of sorbitol, one of the polyol pathway products. Besides, DMB could also maintaining the integrity of podocytes structure by up-regulating the expression of Nephrin and Podocin, and exert renal protective effects by inhibiting the expression of AR, Collagen Ⅳ and TGF-β1 in the polyol pathway. ConclusionsThese findings indicated that genus Swertia could be an important plant sources of aldose reductase inhibitors, and one of its typical components, DMB, exerted a therapeutic role in the treatment of diabetic nephropathy by regulating the polyol pathway to relieve the injury of cells in the kidney, and may represent a promising renal protective medication for diabetic nephropathy therapy.

Acupuncture intervention prolongates thrombolysis time window by regulating cerebral cortex angiogenesis-related genes and proteins in cerebral infarction rats

To observe the effect of acupuncture on the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and endostatin (Endostatin, ES) mRNAs and proteins (angiogenesis related factors) in the ischemic penumbra region in rats with cerebral infarction (CI), so as to explore its underlying mechanisms in prolonging the time window of thrombolysis therapy for CI. A total of 48 male SD rats were randomly divided into sham operation, model, medication (6 h thrombolysis) and acupuncture (Acupunct)+medication groups (n=12 in each group). The CI model was established using modified auto-thrombus method. Six hours after thrombolysis, recombinant human tissue plasminogen activator (rt-PA,10 mg/kg) was given to rats of the thrombolysis group through tail vein. Acupuncture was applied at "Shuigou"(CV26) and bilateral "Neiguan" (PC6) 2 h after successful modeling, and the needles were retained for 30 minutes. Cerebral blood flow (CBF) was monitored during modeling in each group, and the neurological deficit score (0-7 points) was given 2 h and 24 h after successful modeling according to Bederson's methods. The cerebral infarction volume was observed after triphenyltetrazole chloride (TTC) staining. The protein and mRNA expression levels of VEGF, bFGF and ES in the ischemic penumbra region of the right cerebral cortex were detected by Western blot and real-time PCR, separately. The neurological deficit score at both 2 h and 24 h after modeling, percentage of cerebral infarction volume, and the expression levels of VEGF, bFGF and ES proteins and mRNAs in the model group were significantly higher than those of the sham operation group (P<0.01, P < 0.05). Compared with the model group, the neurological deficit score 24 h (not at 2 h) after modeling and percentage of cerebral infarction volume, and the expression levels of ES protein and mRNA in the Acupunct+medication group (not in the medication group) were notably lower (P<0.05, P<0.01), while the expression levels of VEGF and bFGF proteins and mRNAs in the Acupunct +medication group (not in the medication group) were considerably higher (P<0.01, P<0.05). No significant differences were found between medication and model groups in the CI percentage, VEGF, bFGF and ES proteins and mRNAs (P>0.05). The therapeutic effect of Acupunct +medication group was significantly superior to that of medication in lowering neurological deficit score, percentage of CI volume and expression of ES protein and mRNA and in up-regulating the expression of VEGF and bFGF proteins and mRNAs (P<0.05, P<0.01). Acupuncture and timely intervention can prolong the time window of thrombolysis in CI rats, which may be related to its function in up-regulating the expression of VEGF and bFGF mRNAs and proteins and in down-regulating the expression of ES mRNA and protein in ischemic cerebral cortex.

Neonatal maternal separation affects metabotropic glutamate receptor 5 expression and anxiety-related behavior of adult rats.

Exposure to early life stress leads to long-term neurochemical and behavioral alterations. Stress-induced psychiatric disorders, such as depression, have recently been linked to dysregulation of glutamate signaling, mainly via its postsynaptic receptors. The role of metabotropic glutamate receptor 5 (mGluR5) in stress-induced psychopathology has been the target of several studies in humans. In rodents, blockade of mGluR5 produces antidepressant-like actions, whereas mice lacking mGluR5 exhibit altered anxiety-like behaviors and learning. In this study, we used well-known rodent models of early life stress based on mother-infant separation during the first 3 weeks of life in order to examine the effects of neonatal maternal separation on mGluR5 expression and on anxiety-related behavior in adulthood. We observed that brief (15 min) neonatal maternal separation, but not prolonged (3h), induced increases in mGluR5 mRNA and protein expression levels in medial prefrontal cortex and mGluR5 protein levels in dorsal, but not ventral, hippocampus of adult rat brain. Behavioral testing using the open-field and the elevated-plus maze tasks showed that brief maternal separations resulted in increased exploratory and decreased anxiety-related behavior, whereas prolonged maternal separations resulted in increased anxiety-related behavior in adulthood. The data indicate that the long-lasting effects of neonatal mother-offspring separation on anxiety-like behavior and mGluR5 expression depend on the duration of maternal separation and suggest that the increased mGluR5 receptors in medial prefrontal cortex and hippocampus of adult rats exposed to brief neonatal maternal separations may underlie their heightened ability to cope with stress.

Identification of the Potential Gene Regulatory Networks and Therapeutics in Aged Mice With Postoperative Neurocognitive Disorder.

Postoperative neurocognitive disorder (PND) is one of the most common postoperative neurological complications in aged patients, characterized by mental disorder, anxiety, personality changes, and impaired memory. At present, the molecular mechanism of PND remains largely unclear, and the ideal biomarker for clinical diagnosis and prognosis are lacking. Circular RNA (circRNA) and microRNA (miRNA), as unique non-coding RNAs, affecting the regulation of miRNAs on genes and further intervening in the progression of diseases through the sponge action between the two. Besides, it could be served as novel biomarkers in various diseases. In order to detect the differential expression profiles of genes caused by PND, a total of 26 18-month-old male C57BL/6 mice were randomly assigned to control group and PND group. Behavioral tests showed that mice in the PND group had impaired cognitive function compared with the control group. Three mice in each group were randomly selected to harvest the brain for analysis the expressions of circRNAs, miRNAs, and mRNAs in the prefrontal cortex by next-generation sequencing (NGS) technology. Differentially expressed genes, including 1192 circRNAs, 27 miRNAs, and 266 mRNAs were identified, and its accuracy was further confirmed by qRT-PCR. Bioinformatics analysis results suggested that neuroinflammation was the main pathological mechanism of PND. The construction of competitive endogenous RNA (ceRNA) networks and the identification of hub genes provided possible therapeutic targets for PND. Cinnarizine and Clemastine were predicted to have the potential therapeutic effects on PND. This is the first study to explore the differential expression profiles of genes and their regulation mechanisms in PND, our results provided new clues and targets for the treatment of this refractory disease.

Hidden talents: Poly (I:C)-induced maternal immune activation improves mouse visual discrimination performance and reversal learning in a sex-dependent manner.

While there is a strong focus on the negative consequences of maternal immune activation (MIA) on developing brains, very little attention is directed towards potential advantages of early life challenges. In this study, we utilized a polyinosine-polycytidylic acid (poly(I:C)) MIA model to test visual pairwise discrimination (PD) and reversal learning (RL) in mice using touchscreen technology. Significant sex differences emerged in that MIA reduced the latency for males to make a correct choice in the PD task while females reached criterion sooner, made fewer errors, and utilized fewer correction trials in RL compared to saline controls. These surprising improvements were accompanied by the sex-specific upregulation of several genes critical to cognitive functioning, indicative of compensatory plasticity in response to MIA. In contrast, when exposed to a 'two-hit' stress model (MIA + loss of the social component of environmental enrichment [EE]), mice did not display anhedonia but required an increased number of PD and RL correction trials. These animals also had significant reductions of CamK2a mRNA in the prefrontal cortex. Appropriate functioning of synaptic plasticity, via mediators such as this protein kinase and others, are critical for behavioral flexibility. Although EE has been implicated in, delaying the appearance of symptoms associated with certain brain disorders, these findings are in line with evidence that it also makes individuals more vulnerable to its loss. Overall, with the right 'dose', early life stress exposure can confer at least some functional advantages, which are lost when the number or magnitude of these exposures become too great.

Aldosterone contributes to hypertension in male mice inducibly overexpressing human endothelin-1 in endothelium

Mechanisms of blood pressure (BP) regulation by endothelin (ET)-1 produced by endothelial cells are complex and remain unclear. Long-term exposure to human ET-1 (hET-1) in mice inducibly overexpressing hET-1 in the endothelium (ieET-1) caused sustained BP elevation. ET-1 has been shown to stimulate the release of aldosterone. Whether aldosterone plays a role in hET-1 overexpression-induced BP elevation and vessel injury is unknown. Nine- to 12-week-old male ieET-1 mice and control mice expressing a tamoxifen-inducible Cre recombinase (CreERT2) in the endothelial cells (ieCre) were treated with tamoxifen for 5 days and studied 3 months later. Endothelial hET-1 overexpression increased plasma aldosterone levels, which was reversed by 2-week treatment with atrasentan, an endothelin type A receptors blocker. Aldosterone synthase and cryptochrome 2 adrenal cortex mRNA expression was decreased in ieET-1 mice. Two-week treatment with eplerenone, a mineralocorticoid receptor antagonist, reduced systolic BP by 10 mmHg in ieET-1 mice during rest time. Saline challenge-induced sodium excretion and renal cortex thiazide-sensitive sodium-chloride cotransporter mRNA expression were decreased in ieET-1 mice. The sensitivity of mesenteric arteries to contraction by norepinephrine was increased in ieET-1 mice, and was abrogated by eplerenone treatment, whereas sensitivity of endothelium-independent relaxation responses to sodium nitroprusside was enhanced. Resistance artery remodeling was reduced in eplerenone-treated ieET-1 vs. ieET-1 and ieCre mice. These results demonstrate that aldosterone contributes to BP elevation and vascular norepinephrine sensitivity and remodeling caused by hET-1 overexpression in endothelium in mice.

ARYL HYDROCARBON RECEPTOR ANTAGONISTS - A NEW ENTRY IN ANTIHYPERTENSIVE ARMAMENTARIUM OF OBSTRUCTIVE SLEEP APNEA?

Objective: To investigate aryl hydrocarbon receptor (AhR) metabolic circuitry as a druggable target in chronic intermittent hypoxia (CIH) induced hypertension (HTA). Design and method: This study was approved by Nova Medical School's Ethics Committee and followed national and international regulations. We used a rat model of CIH-induced HTA to disclose the hypothesis that the aryl hydrocarbon receptor (AHR) is activated by IH, once it shares the same binding partner of HIF-1alpha and promotes pro-oxidant, pro-inflammatory (NF-kB) and pro-fibrotic events in common with CIH. AhR activation was measured by the mRNA and protein levels of its hallmark target gene Cyp1a1. Blood pressure, heart rate and locomotor activity were measured daily by radiotelemetry. A CIH paradigm of 21% to 5% of O2, 5.6 cycles/h, 10.5 h/day was used in their inactive/sleep period. Results: Upon established hypertension (21 days exposure to IH), we observed an increase in Cyp1a1 mRNA (hallmark of AhR activation) in kidney cortex (6-fold), kidney medulla (3-fold) and liver (3-fold), but not in other tissues. Increased renal expression of Ahr and markers of inflammation (Rela), epithelial to mesenchymal transition markers, the rate-controlling step of gluconeogenesis, Pepck1, and members of HIF-pathway, namely, Hif-3alpha were also observed. The ratio kynurenin/tryptophan (inflammatory index) was also increased in the kidney. The chronicity of IH increased the protein levels of cyp1a1 protein (western blot). Daily administration (14 days) of AHR antagonist, CH-223191 (5 mg.kg-1.day-1, gavage), simultaneously to CIH prevented the increase in systolic blood pressure (SBP) by 53 ± 12% and in diastolic blood pressure (DBP) by 44 ± 16%. Moreover, this AhR antagonist administration upon already established HTN reversed the increase in SBP by 52 ± 12%. Despite the antihypertensive effect seen in the rats’ active phase, in the inactive period, CH22319 did not revert the non-dipping blood pressure profile associated to CIH. Conclusions: CIH caused an activation of AHR signaling particularly in the kidney and its pharmacological blockade had a significant impact reverting already established HTN. This first evidence inspires innovative research opportunities for the understanding and treatment of this particular type of HTN.

Identification of major depressive disorder disease-related genes and functional pathways based on system dynamic changes of network connectivity

BackgroundMajor depressive disorder (MDD) is a leading psychiatric disorder that involves complex abnormal biological functions and neural networks. This study aimed to compare the changes in the network connectivity of different brain tissues under different pathological conditions, analyzed the biological pathways and genes that are significantly related to disease progression, and further predicted the potential therapeutic drug targets.MethodsExpression of differentially expressed genes (DEGs) were analyzed with postmortem cingulate cortex (ACC) and prefrontal cortex (PFC) mRNA expression profile datasets downloaded from the Gene Expression Omnibus (GEO) database, including 76 MDD patients and 76 healthy subjects in ACC and 63 MDD patients and 63 healthy subjects in PFC. The co-expression network construction was based on system network analysis. The function of the genes was annotated by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Human Protein Reference Database (HPRD, http://www.hprd.org/) was used for gene interaction relationship mapping.ResultsWe filtered 586 DEGs in ACC and 616 DEGs in PFC for further analysis. By constructing the co-expression network, we found that the gene connectivity was significantly reduced under disease conditions (P = 0.04 in PFC and P = 1.227e−09 in ACC). Crosstalk analysis showed that CD19, PTDSS2 and NDST2 were significantly differentially expressed in ACC and PFC of MDD patients. Among them, CD19 and PTDSS2 have been targeted by several drugs in the Drugbank database. KEGG pathway analysis demonstrated that the function of CD19 and PTDSS2 were enriched with the pathway of Glycerophospholipid metabolism and T cell receptor signaling pathway.ConclusionCo-expression network and tissue comparing analysis can identify signaling pathways and cross talk genes related to MDD, which may provide novel insight for understanding the molecular mechanisms of MDD.

Dysregulation of Protein Kinase C in Adult Depression and Suicide: Evidence From Postmortem Brain Studies.

BackgroundSeveral lines of evidence suggest the abnormalities of protein kinase C (PKC) signaling system in mood disorders and suicide based primarily on the studies of PKC and its isozymes in the platelets and postmortem brain of depressed and suicidal subjects. In this study, we examined the role of PKC isozymes in depression and suicide.MethodsWe determined the protein and mRNA expression of various PKC isozymes in the prefrontal cortical region (Brodmann area 9) in 24 normal control subjects, 24 depressed suicide (DS) subjects, and 12 depressed nonsuicide (DNS) subjects. The levels of mRNA in the prefrontal cortex were determined by quantitative real-time reverse transcription PCR, and the protein expression was determined by western blotting.ResultsWe observed a significant decrease in mRNA expression of PKCα, PKCβI, PKCδ, and PKCε and decreased protein expression in either the membrane or the cytosol fraction of PKC isozymes PKCα, PKCβI, PKCβII, and PKCδ in DS and DNS subjects compared with normal control subjects.ConclusionsThe current study provides detailed evidence of specific dysregulation of certain PKC isozymes in the postmortem brain of DS and DNS subjects and further supports earlier evidence for the role of PKC in the platelets and brain of the adult and teenage depressed and suicidal population. This comprehensive study may lead to further knowledge of the involvement of PKC in the pathophysiology of depression and suicide.

Daily oscillation of cognitive factors is modified in the temporal cortex of an amyloid β(1-42)-induced rat model of Alzheimer’s disease

Alzheimer’s disease (AD) is a devastating disease characterized by loss of synapses and neurons in the elderly. Accumulation of the β-amyloid peptide (Aβ) in the brain is thought to be central to the pathogenesis of AD. ApoE plays a key role in normal and physiological clearance of Aß, since it facilitates the peptide intra- and extracellular proteolytic degradation. Besides the cognitive deficit, AD patients also show alterations in their circadian rhythms. The objective of this study was to investigate the effects of an i.c.v. injection of Aβ (1-42) peptide on the 24 h rhythms of Apo E, BMAL1, RORα, Bdnf and trkB mRNA and Aβ levels in the rat temporal cortex. We found that an i.c.v. injection of Aβ aggregates phase shifts daily Bdnf expression as well as Apo E, BMAL1, RORα, Aβ and decreased the mesor of TrkB rhythms. Thus, elevated Aβ peptide levels might modify the temporal patterns of cognition-related factors, probably; by affecting the clock factors rhythms as well as in the 24 h rhythms of Apo E.

Involvement of the nuclear factor-\u03baB transcriptional complex in prefrontal cortex immune activation in bipolar disorder

Bipolar disorder and schizophrenia have multiple clinical and genetic features in common, including shared risk associated with overlapping susceptibility loci in immune-related genes. Higher activity of the nuclear factor-κB (NF-κB) transcription factor complex, which regulates the transcription of multiple immune markers, has been reported to contribute to immune activation in the prefrontal cortex in schizophrenia. These findings suggest the hypothesis that elevated NF-κB activity is present in the prefrontal cortex in bipolar disorder in a manner similar to that seen in schizophrenia. Therefore, we quantified levels of NF-κB-related mRNAs in the prefrontal cortex of 35 matched pairs of bipolar disorder and unaffected comparison subjects using quantitative PCR. We found that transcript levels were higher in the prefrontal cortex of bipolar disorder subjects for several NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs, and were lower for an NF-κB inhibitor. Transcript levels for NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs levels were also highly correlated with each other. This pattern of elevated transcript levels for NF-κB-related markers in bipolar disorder is similar to that previously reported in schizophrenia, suggesting that cortical immune activation is a shared pathophysiological feature between the two disorders.

The TLR3 induction increases content of interferons in rat's brain by TRAIL signaling during long-term alcoholization

The pathogenetic mechanisms associated with alcohol use include dysregulation of the innate immune system mechanisms in the brain. TLR3 expression is increased in the postmortem material of the prefrontal cortex of humans. An increase in the TLR3 signaling activity leads to the induction of interferons (IFN). IFN are associated with depressive symptoms and, therefore, may play a role in the pathogenesis of alcoholism; however, the exact mechanisms of intracellular signaling mediated by the influence of ethanol are not fully elucidated and their study was the purpose of this work. The experimental results showed that ethanol and the TLR3 agonist Poly (I:C) increased the content of TLR3, IFNβ, and IFNγ mRNA in the prefrontal cortex. In addition, expression of the TRAIL encoding gene also increased, and this increase positively correlaed with the mRNA content of TLR3, IFNβ and IFNγ both under alcoholization conditions and after injections of the TLR3 agonist. The data obtained may indicate that alcoholization is able to activate TLR3-TRAIL-IFN-signaling in the prefrontal cortex of the brain.

NOX1/NADPH oxidase affects the development of autism-like behaviors in a maternal immune activation model

Autism spectrum disorder (ASD) is a neurodevelopmental disorder caused by genetic and environmental factors. Among the environmental factors, maternal infection is known as one of the principal risk factors for ASD. On the other hand, postmortem studies suggested the relationship of oxidative stress with ASD etiology. However, the role of oxidative stress in the development of ASD remains unclear. Here, we report the involvement of NOX1/NADPH oxidase, an enzyme generating reactive oxygen species (ROS), in behavioral and anatomical abnormalities in a maternal immune activation (MIA) model. In the MIA model of gestational polyinosinic-polycytidylic acid (poly(I:C)) exposure, increased serum levels of IL-6 were observed in both wild-type (WT) and Nox1-deficient mice (Nox1KO). Following the comparable induction of MIA in the two genotypes, impairment of social preference and defects in motor coordination were observed in WT offspring but not in offspring deficient in Nox1. MIA up-regulated NOX1 mRNA in the cerebral cortex and cerebellum of the fetus but not in the adult offspring. Although the development of cortical neurons was unaffected by MIA in either genotype, the dropout of Purkinje cells in lobule VII of MIA-affected offspring was significantly ameliorated in Nox1KO. Taken together, these results suggested that NOX1/NADPH oxidase plays an essential role in some behavioral phenotypes observed in ASD, possibly by promoting the loss of Purkinje cells in the cerebellum.

PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia.

SummaryThe immune checkpoint inhibitor programmed cell death protein 1 (PD-1) plays a critical role in immune regulation. Recent studies have demonstrated functional PD-1 expression in peripheral sensory neurons, which contributes to neuronal excitability, pain, and opioid analgesia. Here we report neuronal expression and function of PD-1 in the central nervous system (CNS), including the spinal cord, thalamus, and cerebral cortex. Notably, GABA-induced currents in spinal dorsal horn neurons, thalamic neurons, and cortical neurons are suppressed by the PD-1-neutralizing immunotherapeutic Nivolumab in spinal cord slices, brain slices, and dissociated cortical neurons. Reductions in GABA-mediated currents in CNS neurons were also observed in Pd1−/− mice without changes in GABA receptor expression. Mechanistically, Nivolumab binds spinal cord neurons and elicits ERK phosphorylation to suppress GABA currents. Finally, both GABA-mediated analgesia and anesthesia are impaired by Pd1 deficiency. Our findings reveal PD-1 as a CNS-neuronal inhibitor that regulates GABAergic signaling and GABA-mediated behaviors.

Key role of the 5-HT1A receptor addressing protein Yif1B in serotonin neurotransmission and SSRI treatment

Altered function of serotonin receptor 1A (5-HT1AR) has been consistently implicated in anxiety, major depressive disorder and resistance to antidepressants. Mechanisms by which the function of 5-HT1AR (expressed as an autoreceptor in serotonergic raphe neurons and as a heteroreceptor in serotonin [5-HT] projection areas) is altered include regulation of its expression, but 5-HT1AR trafficking may also be involved. We investigated the consequences of the lack of Yif1B (the 5-HT1AR trafficking protein) on 5-HT neurotransmission in mice, and whether Yif1B expression might be affected under conditions known to alter 5-HT neurotransmission, such as anxious or depressive states or following treatment with fluoxetine (a selective serotonin reuptake inhibitor) in humans, monkeys and mice. Compared with wild-type mice, Yif1B-knockout mice showed a significant decrease in the forebrain density of 5-HT projection fibres and a hypofunctionality of 5-HT1A autoreceptors expressed on raphe 5-HT neurons. In addition, social interaction was less in Yif1B-knockout mice, which did not respond to the antidepressant-like effect of acute fluoxetine injection. In wild-type mice, social defeat was associated with downregulated Yif1B mRNA in the prefrontal cortex, and chronic fluoxetine treatment increased Yif1B expression. The expression of Yif1B was also downregulated in the postmortem prefrontal cortex of people with major depressive disorder and upregulated after chronic treatment with a selective serotonin reuptake inhibitor in monkeys. We found sex differences in Yif1B expression in humans and monkeys, but not in mice under the tested conditions. These data support the concept that Yif1B plays a critical role in 5-HT1AR functioning and brain 5-HT homeostasis. The opposite changes in its expression observed in anxious or depressive states and after therapeutic fluoxetine treatment suggest that Yif1B might be involved in vulnerability to anxiety and depression, and fluoxetine efficacy.