Gene Expression In Brain Research Articles

Specific Silencing of Microglial Gene Expression in the Rat Brain by Nanoparticle-Based Small Interfering RNA Delivery.

Microglia are the major innate immune cells in the brain and are essential for maintaining homeostasis in a neuronal microenvironment. Currently, a genetic tool to modify microglial gene expression in specific brain regions is not available. In this report, we introduce a tailor-designed method that uses lipid and polymer hybridized nanoparticles (LPNPs) for the local delivery of small interfering RNAs (siRNAs), allowing the silencing of specific microglial genes in the hypothalamus. Our physical characterization proved that this LPNP-siRNA was uniform and stable. We demonstrated that, due to their natural phagocytic behavior, microglial cells are the dominant cell type taking up these LPNPs in the hypothalamus of rats. We then tested the silencing efficiency of LPNPs carrying a cluster of differentiation molecule 11b (CD11b) or Toll-like receptor 4 (TLR4) siRNA using different in vivo and in vitro approaches. In cultured microglial cells treated with LPNP-CD11b siRNA or LPNP-TLR4 siRNA, we found a silencing efficiency at protein expression levels of 65 or 77%, respectively. In line with this finding, immunohistochemistry and western blotting results from in vivo experiments showed that LPNP-CD11b siRNA significantly inhibited microglial CD11b protein expression in the hypothalamus. Furthermore, following lipopolysaccharide (LPS) stimulation of cultured microglial cells, gene expression of the TLR4 downstream signaling component myeloid differentiation factor 88 and its associated cytokines was significantly inhibited in LPNP-TLR4 siRNA-treated microglial cells compared with cells treated with LPNP-scrambled siRNA. Finally, after LPNP-TLR4 siRNA injection into the rat hypothalamus, we observed a significant reduction in microglial activation in response to LPS compared with the control rats injected with LPNP-scrambled siRNA. Our results indicate that LPNP-siRNA is a promising tool to manipulate microglial activity locally in the brain and may serve as a prophylactic approach to prevent microglial dysfunction-associated diseases.

Protective Effect of the Viola spathulata Extract on NCX3 Gene Expression in an Animal Model of Cerebral Ischemia.

Viola plant has been used traditionally to treat neurological disorders. We aimed at determining whether pretreatment with Viola spathulata extract can alleviate the severity of ischemic-reperfusion damages and exert its protective effects through the regulation of a sodium/calcium exchanger (NCX3) gene expression in a rat brain. Male Wistar rats were divided into two main groups: one main group for evaluating Neurologic Deficit Score (NDS) and Infarct Volume (IV) and the other group for the evaluation of NCX3 gene expression in the brain tissue. The latter group was subdivided into the intact, control (vehicle), sham, V5, and V10. The vehicle (control) subgroup received Dimethyl Sulfoxide (DMSO), and V5 and V10 subgroups received V. spathulata extract at the doses of 5 and 10 mg/kg (IP), respectively, for 7 days. After pretreatment, we carried out Middle Cerebral Artery Occlusion (MCAO) for 60 min. In the V5 and V10 subgroups, NDS and IV significantly decreased. MCAO upregulated NCX3 gene expression in the core, penumbra, and subcortical regions compared with the intact subgroup. The V5 subgroup significantly downregulated the NCX3 gene expression level in the core compared with the control subgroup. The V10 subgroup showed downregulation of the NCX3 gene expression level in the core, penumbra, and subcortex compared with the control subgroup. V. spathulata extract may have a neuroprotective role against MCAO-induced ischemic brain damage, possibly by preventing the alteration of NCX3 gene expression level. MCAO results Infarct Volume (IV) and Neurologic Deficit Score (NDS);MCAO upregulated NCX3 gene expression in brain tissues;Viola spathulata extract pretreatment decreased IV and NDS in brain ischemia;Viola spathulata pretreatment downregulated NCX3 gene expression in brain tissues. Stroke is the second leading cause of death and long term disability. Recently it has been reported that herbal extracts have protective role in ischemia injury. In Iranian traditional medicine Viola plant has a long history to treat disorders such as cancer. So we designed an animal study to investigate Viola plant extract in brain ischemia injury. Viola spathulata extract was administrated to rats for seven days, then animal model of brain ischemia was operated on them and some behavioral, histological and molecular factors were analyzed. Our findings showed that Viola spathulata extract improved behavioral disability, decreased infarct volume in brain tissue, and modulate Sodium/Calcium exchanger 3 gene expression. It could be concluded that Viola spathulata has the neuroprotective effect in animal stroke model and is a good candidate for nutritional supplements, although further studies are needed.

Treatment of Murine Toxoplasmosis with Oral and Parenteral Artemether and Following by Detection of B1 Gene by Quantitative Real-Time PCR (qPCR) for Evaluating Parasite Density.

Background:Toxoplasma gondii is an obligate intracellular parasite that can infect humans and animals. As the choice drug have shown side effects, development a new drug with low toxicity will be necessary.Methods:BALB/c mice were infected with tachyzoiets of T. gondii. After treatment by oral and parenteral artemether (250 μg/mice) and sulfadiazine (50 μg/mice), we evaluated the rates of survival in treated and control mice. The fold change of B1 gene (target gene) expression in liver and brain of mice treated with parenteral artemether (i.p.), oral artemether (via gavage) and sulfadiazine, were detected by using the Real-Time quantitative PCR.Results:Both treatment with sulfadiazine and artemether showed significant prolongation in time to death of the infected mice compared to the control group. Median survival days for parenteral artemether, oral artemether, sulfadiazine and control group were 8, 11, 12 and 6 d respectively. Expression of B1 gene in liver and brain of mice after treatment with artemether and sulfadiazine were reduced in comparison to housekeeping gene (β-tubulin gene). The fold change (comparing to control group) for parenteral artemether, oral artemether, sulfadiazine is 0.034, 0.027 and 0.111 for liver and 0.220, 0.425 and 0.366 for brain respectively.Conclusion:Artemether is effective to control the tachyzoites of T. godii in vivo conditions and oral treatment is more effective than parenteral treatment. Due to its low cytotoxicity and its high effective action against the tachyzoietes of T. godii in susceptible animals.

Excess Folic Acid Supplementation before and during Pregnancy and Lactation Alters Behaviors and Brain Gene Expression in Female Mouse Offspring.

Use of folic acid (FA) during early pregnancy protects against birth defects. However, excess FA has shown gender-specific neurodevelopmental toxicity. Previously, we fed the mice with 2.5 times the recommended amount of FA one week prior to mating and during the pregnancy and lactation periods, and detected the activated expression of Fos and related genes in the brains of weaning male offspring, as well as behavioral abnormalities in the adults. Here, we studied whether female offspring were affected by the same dosage of FA. An open field test, three-chamber social approach and social novelty test, an elevated plus-maze, rotarod test and the Morris water maze task were used to evaluate their behaviors. RNA sequencing was performed to identify differentially expressed genes in the brains. Quantitative real time-PCR (qRT-PCR) and Western blots were applied to verify the changes in gene expression. We found increased anxiety and impaired exploratory behavior, motor coordination and spatial memory in FA-exposed females. The brain transcriptome revealed 36 up-regulated and 79 down-regulated genes in their brains at weaning. The increase of Tlr1; Sult1a1; Tph2; Acacb; Etnppl; Angptl4 and Apold1, as well as a decrease of Ppara mRNA were confirmed by qRT-PCR. Among these genes; the mRNA levels of Etnppl; Angptl4 and Apold1 were increased in the both FA-exposed female and male brains. The elevation of Sult1a1 protein was confirmed by Western blots. Our data suggest that excess FA alteres brain gene expression and behaviors in female offspring, of which certain genes show apparent gender specificity.

Long-Term Effects of prophylactic MgSO4 in Maternal Immune Activation Rodent Model at Adolescence and Adulthood

MgSO4 has been used for the last two decades as a neuroprotective treatment in a variety of preterm conditions. Despite the putative advantages of MgSO4 as a neuroprotective agent in the preterm brain, the long-term molecular and behavioral function of MgSO4 as a neuroprotective agent has not been fully elucidated. The objectives of this study were to investigate the long-term effect of antenatal MgSO4, during late gestational, on offspring’s behavior in a mouse maternal immune activation (MIA) model in adolescence and adulthood, and to explore its influence on brain gene expression (e.g., ErbB signaling, pro-inflammatory and dopaminergic markers) in adulthood

Expression of CRY2 Gene in the Brain Is Related to Human Navigation.

Navigation is a complex cognitive process. CRY2 gene has been proposed to play an important role in navigation behaviors in various non-human animal species. Utilizing a recently developed neuroimaging-transcriptomics approach, the present study reported a tentative link between the CRY2 gene and human navigation. Specifically, we showed a significant pattern similarity between CRY2 gene expression in the human brain and navigation-related neural activation in functional magnetic resonance imaging. To further illuminate the functionality of CRY2 in human navigation, we examined the correlation between CRY2 expression and various cognitive processes underlying navigation, and found high correlation of CRY2 expression with neural activity of multiple cognitive domains, particularly object and shape perception and spatial memory. Further analyses on the relation between the neural activity of human navigation and the expression maps of genes of two CRY2-related pathways, i.e., the magnetoreceptive and circadian-related functions, found a trend of correlation for the CLOCK gene, a core circadian regulator gene, suggesting that CRY2 may modulate human navigation through its role in circadian rhythm. This observation was further confirmed by a behavioral study where individuals with better circadian regularity in daily life showed better sense of direction. Taken together, our study presents the first neural evidence that links CRY2 with human navigation, possibly through the modulation of circadian rhythm.

A review and meta-analysis of gene expression profiles in suicide

Suicide claims over 800,000 deaths worldwide, making it a serious public health problem. The etiopathophysiology of suicide remains unclear and is highly complex, and postmortem gene expression studies can offer insights into the molecular biological mechanism underlying suicide. In the current study, we conducted a meta-analysis of postmortem brain gene expression in relation to suicide. We identified five gene expression datasets for postmortem orbitofrontal, prefrontal, or dorsolateral prefrontal cortical brain regions from the Gene Expression Omnibus repository. After quality control, the total sample size was 380 (141 suicide deaths and 239 deaths from other causes). We performed the analyses using two meta-analytic approaches. We further performed pathway and cell-set enrichment analyses. We found reduced expression of the KCNJ2 (Potassium Inwardly Rectifying Channel Subfamily J Member 2), A2M (Alpha-2-Macroglobulin), AGT (Angiotensinogen), PMP2 (Peripheral Myelin Protein 2), and VEZF1 (Vascular Endothelial Zinc Finger 1) genes (FDR p<0.05). Our findings support the involvement of astrocytes, stress response, immune system, and microglia in suicide. These findings will require further validation in additional large datasets.

Transcriptomics and machine learning to advance schizophrenia genetics: A case-control study using post-mortem brain data

Background and ObjectiveAlterations of the expression of a variety of genes have been reported in patients with schizophrenia (SCZ). Moreover, machine learning (ML) analysis of gene expression microarray data has shown promising preliminary results in the study of SCZ. Our objective was to evaluate the performance of ML in classifying SCZ cases and controls based on gene expression microarray data from the dorsolateral prefrontal cortex. MethodsWe apply a state-of-the-art ML algorithm (XGBoost) to train and evaluate a classification model using 201 SCZ cases and 278 controls. We utilized 10-fold cross-validation for model selection, and a held-out testing set to evaluate the model. The performance metric utilizes to evaluate classification performance was the area under the receiver-operator characteristics curve (AUC). ResultsWe report an average AUC on 10-fold cross-validation of 0.76 and an AUC of 0.76 on testing data, not used during training. Analysis of the rolling balanced classification accuracy from high to low prediction confidence levels showed that the most certain subset of predictions ranged between 80-90%. The ML model utilized 182 gene expression probes. Further improvement to classification performance was observed when applying an automated ML strategy on the 182 features, which achieved an AUC of 0.79 on the same testing data. We found literature evidence linking all of the top ten ML ranked genes to SCZ. Furthermore, we leveraged information from the full set of microarray gene expressions available via univariate differential gene expression analysis. We then prioritized differentially expressed gene sets using the piano gene set analysis package. We augmented the ranking of the prioritized gene sets with genes from the complex multivariate ML model using hypergeometric tests to identify more robust gene sets. We identified two significant Gene Ontology molecular function gene sets: “oxidoreductase activity, acting on the CH-NH2 group of donors” and “integrin binding.” Lastly, we present candidate treatments for SCZ based on findings from our study ConclusionsOverall, we observed above-chance performance from ML classification of SCZ cases and controls based on brain gene expression microarray data, and found that ML analysis of gene expressions could further our understanding of the pathophysiology of SCZ and help identify novel treatments.

Developing a blood‐derived gene expression biomarker specific for Alzheimer’s disease

AbstractBackgroundEarly detection, monitoring, and treatment of Alzheimer’s disease (AD) will require measurement of easily accessible and reliable fluid biomarkers. We compared brain and blood gene and pathway expression analyses to identify core features for discriminating AD from controls. The brain gene expression profile was generated using a dataset (GSE33000) from post‐mortem dorsolateral prefrontal cortex isolated from 624 AD patients and genotype‐matched control samples, while blood gene expression profiles were generated using GSE63060 (n=329) and GSE63061 (n=388) datasets derived from peripheral blood samples of two case‐controlled studies of the AddNeuroMed consortium.MethodThe gene expression datasets were retrieved from the Gene Expression Omnibus (GEO). Limma linear models were used to compute moderated T‐statistics and identify differentially expressed genes (DEGs) in the AD condition. Gene Set Enrichment Analysis (GSEA, applying the Piano R package to moderated T‐statistics from DEG analysis) was employed to identify significantly differentially regulated REACTOME and KEGG pathways. Comparison of the brain and blood‐derived analyses provided a common set of pathways modulated in AD patients.ResultDEG analysis revealed 680, 116, and 21 upregulated genes and 136, 160, and 45 downregulated genes in GSE33000 (Brain), GSE63060, and GSE63061 (Blood) datasets, respectively (FDR &lt; 0.05; upregulated: FC &gt; 1.15, downregulated: FC &lt; 0.8). Differential pathway expression analysis using GSEA (FDR &lt; 0.05) yielded 218, 196, and 202 REACTOME and 151, 69, and 125 KEGG pathways in GSE33000, GSE63060, and GSE63061 datasets, respectively.Notably, 21/115 and 56/103 up‐ and downregulated REACTOME pathways respectively, in the brain‐derived dataset were shared with the blood‐derived dataset (FDR &lt; 0.05). Strikingly, 52.4% and 23.8% of the upregulated pathways were dominated by immune system and hemostasis, respectively. Meanwhile, 42.9% and 10.7% of the downregulated pathways included cell cycle and signal transduction pathways, respectively.ConclusionSystematic analysis of genes and pathways differentially expressed in AD samples across brain and blood identified common signatures reproducible across studies and showed potential for distinguishing between AD and control patients. Our results suggest the potential of employing a blood‐based gene expression panel for early diagnosis and disease monitoring of AD.

LMNA-mediated nucleoskeleton dysregulation in Alzheimer disease.

Nucleoskeleton dysfunction has been implicated in Alzheimer disease (AD). Tubular invaginations of the nuclear envelope observed in AD brains are consistent with the accumulation of farnesylated prelamin A (encoded by the LMNA gene) that occurs in Hutchinson-Gilford Progeria Syndrome, a premature aging disorder caused by LMNA mutations. Proper function of the nuclear membrane is required for neuronal survival and for maintenance of genetic architecture. To determine whether dysregulated LMNA expression and prelamin A processing are responsible for nucleoskeleton dysfunction in AD, we performed differential gene expression and network analyses in human AD and age-matched control brains. Lamin A protein levels were evaluated in AD and control brains using mass spectrometry. Gene network analyses were carried out using induced pluripotent stem cell-derived neurons transduced with progerin or GFP controls in order to identify molecular pathways influenced by altered LMNA processing. In AD brains, we observed a significant increase in LMNA and a significant decrease in ZMPSTE24, resulting in a significant increase Lamin A protein levels, which we observe through mass spectrometry. We replicated these findings in laser capture microdissected neurons from AD brains, suggesting that the effect is neuronally driven. Thus, high levels of LMNA paired with low levels of ZMPSTE24 could result in the accumulation of farnesylated prelamin A and tubular invaginations in the nuclear membrane. LMNA-associated networks were also differentially expressed in AD brains. Genes within the dysregulated LMNA network were enriched in lysosomal and chromatin remodeling pathways. Our findings suggest that β-amyloid and tau accumulation disrupts prelamin A processing and downstream changes in the nuclear membrane. Alterations in the nucleoskeleton induce genomic instability, loss of proteostasis, and cellular senescence, which may accelerate AD pathogenesis.

NeMO-AD, a new neuroscience multi-omic visualization and analysis platform for Alzheimer's disease research.

Recent years have resulted in tremendous progress in understanding Alzheimer's disease (AD) via the generation and analysis of multi-omic data. In addition, the BRAIN initiative has been mapping gene expression in the normal brain. However, a barrier for the broad usage of these data has been limited access and the requirement for informatics support to allow biologists to meaningfully access this wealth of information. To address this challenge, we extended the Neuroscience Multi-Omic (NeMO) Analytics (nemoanalytics.org) platform to include a focus on Alzheimer's disease ("NeMO-AD"). NeMO Analytics gene expression tools are powered by gEAR (umgear.org) and consist of six components: (i) An expression browser, for visualization of gene expression across multiple datasets; (ii) A dataset compare tool for comparing all the genes between two groups; (iii) An elaborate single cell workbench; (iv) A dataset uploader that allows the user to upload their own multi-omic data; (v) A dataset curator that allows the user to define visualization preferences (e.g., data presentation as bar, line, x-y scatter, violin plot, tSNE, or SVG); and (vi) A dataset manager, which allows you to organize datasets into profiles and manage privacy and dataset sharing. NeMO Analytics also allows the visualization of epigenetic data via integration of the Epiviz tool (https://epiviz.github.io/). Currently, NeMO-AD consists of 32 impactful AD datasets, including bulk RNA-seq (40.6%), microarray (43.8), single-cell RNA-seq (12.5%) and single-nuclei RNA-seq (3.1%) from both human (40.6%) and mouse models (59.4%). The datasets have been organized into 8 different "profiles" (collections of similarly themed datasets, allowing for side-by-side visualization): specific brain regions, experimental models of AD, microglia, therapeutic targets, AD progression, molecular brain aging, biomarkers and other. Users can create their own profiles and upload their own datasets which can be made public, private or shared with collaborator(s). NeMO-AD offers biologists access to impactful multi-omic data relevant to Alzheimer's disease that can be explored without assistance from bioinformaticians. The broad usage of this platform to share and disseminate data could result in a more rapid progression of AD research.

PRIME uncovers circadian oscillation patterns and links with Alzheimer’s disease in untimed genome‐wide gene expression data across multiple regions of human brain

AbstractBackgroundThe disruption of brain circadian rhythm is a major symptom of AD patients. Recent studies and accumulating clinic evidence have suggested that this symptom usually occurs in the early phase of AD and probably precedes cognitive impairment development; however, the full circadian rhythm orchestration of gene expression in the human brain and its inherent associations with AD currently remain unknown. The main barrier to studying circadian rhythmic patterns of the whole‐genome gene expression is the requirement of time labels of brain tissues, which is hard to obtain or inaccurate. Indeed, current existing circadian rhythm analyses rely on the timestamps of samples.MethodThis study aims to explore the relationships between circadian rhythms of brain regions and AD with untimed genome‐wide gene expression data. To this end, we developed and presented an innovative, comprehensive, unsupervised machine‐learning based approach based on principal component analysis (PCA) and matrix factorization (MF), called PRIME, to detect and analyze oscillation patterns in untimed high‐dimensional data across multiple brain regions. PRIME captures oscillatory patterns in the latent space underlying the gene expression data without requiring time stamps of brain tissue samples.ResultTo demonstrate PRIME’s utility, firstly, we validated it by a time course expression dataset from mouse liver (Figs. 1‐2) as a cross‐species and cross‐organ validation, because this dataset has systematically recorded time labels. Then, we applied it to studying oscillation patterns in genome‐wide gene expression from 19 human brain regions of controls and AD patients. Our experiments showed that there exist clear synchronized oscillation patterns in 15 union brain regions of normal controls (Fig. 3). In sharp contrast, the synchronized oscillation patterns became either disappear or weakened for AD‐affected brains (Fig. 4). Additionally, we provided necessary rules to infer AD’s impacts on human brain regions (Table 1).ConclusionWe developed a novel comprehensive approach, called PRIME, to detect and analyze rhythmic oscillation patterns in untimed high‐dimensional gene expression data across multiple datasets. It is worth noting that our approach discovered the circadian rhythmic patterns without the need for the sample’s timestamps.

Integrative analysis of eQTL and GWAS summary statistics reveals novel genes related to Alzheimer's disease

AbstractBackgroundLarge‐scale genome wide association studies (GWASs) have identified many genetic variants associated with Alzheimer’s disease (AD) and related traits. While many GWAS findings were found to co‐localize with expression quantitative trait loci (eQTL), it is of great interest to investigate the functional effect of GWAS hits on the downstream transcriptomic level. Considering the lack of gene expression data from the brain tissue, we propose to integrate the summary statistics from AD GWAS and brain eQTL analysis to investigate potential transcriptomic alterations inside AD brains. We further validate our findings using the brain gene expression data from the ROS/MAP cohort.MethodWe used the GWAS summary statistics from IGAP[1] and brain eQTL results from BRAINEAC[2]. Summary Mendelian Randomization (SMR) and Heterogeneity in Dependent Instruments (HEIDI) tests were applied to identify highly significant genes related to AD in temporal cortex, frontal cortex and hippocampal regions. For significant genes identified from each region, we further performed differential gene expression analysis using the RNA‐Seq data from the corresponding brain tissue in the Mayo Clinic cohort. SNPs from these genes were tested for association with FDG intensity and thickness of corresponding brain regions using the data from ADNI. Finally, we performed pathway analysis using ClueGO.ResultSMR and HEIDI test identified 32 genes significantly associated with AD in the transcriptomic level, but only in temporal cortex. 10 of them were further validated with altered expression in AD temporal cortex region in the Mayo cohort (Fig.1). 19 SNPs from these genes were significantly related to the FDG intensity and thickness of temporal cortex regions, predominantly present in TOMM40 and NECTIN genes. Top pathways enriched by these genes are Neutrophil degranulation and cell surface interactions at vascular wall (Fig.2).ConclusionWe identified several SNPs with potential regulatory role in mediating the expression level of genes, which are found altered in AD brains and associated with multiple neuroimaging phenotypes. With evidence from multiple sources, these SNPs, their downstream genes and related pathways could serve as potential targets for further therapeutic intervention of AD.

Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family.

Schizophrenia is a complex genetic disorder involving many common variants with modest effects and rare mutations with high penetrance. Rare mutations associated with schizophrenia are highly heterogeneous and private for affected individuals and families. Identifying such mutations can help establish the molecular diagnosis, elucidate the pathogenesis, and provide helpful genetic counseling for affected patients and families. We performed a whole-exome sequencing analysis to search for rare pathogenic mutations co-segregating with schizophrenia transmitted in a dominant inheritance in a two-generation multiplex family. We identified a rare missense mutation H1574R (Histidine1574Arginine, rs199796552) of KMT2C (lysine methyltransferase 2C) co-segregating with affected members in this family. The mutation is a novel deleterious mutation of KMT2C, not reported before in the literature. The KMT2C encodes a histone 3 lysine 4 (H3K4)-specific methyltransferase and involves epigenetic regulation of brain gene expression. Mutations of KMT2C have been found in neurodevelopmental disorders, such as Kleefstra syndrome, intellectual disability, and autism spectrum disorders. Our finding suggests that schizophrenia might be one of the clinical phenotype spectra of KMT2C mutations, and KMT2C might be a novel risk gene for schizophrenia. Nevertheless, the co-segregation of this mutation with schizophrenia in this family might also be due to chance; functional assays of this mutation are needed to address this issue.

Standardizing workflows in imaging transcriptomics with the abagen toolbox.

Gene expression fundamentally shapes the structural and functional architecture of the human brain. Open-access transcriptomic datasets like the Allen Human Brain Atlas provide an unprecedented ability to examine these mechanisms in vivo; however, a lack of standardization across research groups has given rise to myriad processing pipelines for using these data. Here, we develop the abagen toolbox, an open-access software package for working with transcriptomic data, and use it to examine how methodological variability influences the outcomes of research using the Allen Human Brain Atlas. Applying three prototypical analyses to the outputs of 750,000 unique processing pipelines, we find that choice of pipeline has a large impact on research findings, with parameters commonly varied in the literature influencing correlations between derived gene expression and other imaging phenotypes by as much as ρ ≥ 1.0. Our results further reveal an ordering of parameter importance, with processing steps that influence gene normalization yielding the greatest impact on downstream statistical inferences and conclusions. The presented work and the development of the abagen toolbox lay the foundation for more standardized and systematic research in imaging transcriptomics, and will help to advance future understanding of the influence of gene expression in the human brain.

CXCL13 Neutralization Attenuates Neuropsychiatric Manifestations in Lupus-Prone Mice

Neuropsychiatric lupus (NPSLE), the nervous system presentation of systemic lupus erythematosus (SLE), remains challenging to treat due to its unclear pathogenesis and lack of available targeted therapies. A potential contributor to disease progression is brain tertiary lymphoid structures (TLS); these ectopic lymphoid follicles that can develop tissue-targeted antibodies have recently been described in the MRL/lpr lupus mouse strain, a classic model for studying NPSLE. The brains of MRL/lpr mice show a significant increase of CXCL13, an important chemokine in lymphoid follicle formation and retention that may also play a role in the disease progression of NPSLE. The aim of the present study was to inhibit CXCL13 and examine the effect of this intervention on lymphoid formation and the development of neurobehavioral manifestations in lupus mice. Female MRL/lpr mice were injected with an anti-CXCL13 antibody, an IgG1 isotype-matched antibody, or PBS either three times a week for 12 weeks intraperitoneally (IP) starting at 6-8 weeks of age, or continuously intracerebroventricularly (ICV) with an osmotic pump over a two-week period starting at 15 weeks of age. Cognitive dysfunction and depression-like behavior were assessed at the end of treatment. When treatment was delivered IP, anti-CXCL13 treated mice showed significant improvement in cognitive function when compared to control treated mice. Depression-like behavior was attenuated as well. Furthermore, mice that received anti-CXCL13 by the ICV route showed similar beneficial effects. However, the extent of lymphocyte infiltration into the brain and the general composition of the aggregates were not substantively changed by anti-CXCL13 irrespective of the mode of administration. Nevertheless, analysis of brain gene expression in anti-CXCL13 treated mice showed significant differences in key immunological and neuro-inflammatory pathways that most likely explained the improvement in the behavioral phenotype. Our results indicate that CXCL13 affects the behavioral manifestations in the MRL/lpr strain and is important to the pathogenesis of murine NPSLE, suggesting it as a potential therapeutic target.

Maternal nematode infection upregulates expression of Th2/Treg and diapedesis related genes in the neonatal brain

Intestinal nematode infections common during pregnancy have recently been shown to have impacts that extend to their uninfected offspring including altered brain gene expression. If maternal immune signals reach the neonatal brain, they might alter neuroimmune development. We explored expression of genes associated with four distinct types of T cells (Th1, Th2, Th17, Treg) and with leukocyte transendothelial migration and endocytosis transport across the blood–brain barrier (BBB) in the postnatal brain of offspring of nematode-infected mice, through secondary analysis of a whole brain gene expression database. Th1/Th17 expression was lowered by maternal infection as evidenced by down-regulated expression of IL1β, Th1 receptors and related proteins, and of IL22 and several Th17 genes associated with immunopathology. In contrast, Th2/Treg related pathways were upregulated as shown by higher expression of IL4 and TGF-β family genes. Maternal infection also upregulated expression of pathways and integrin genes involved in transport of leukocytes in between endothelial cells but downregulated endosome vesicle formation related genes that are necessary for endocytosis of immunoglobulins across the BBB. Taken together, pup brain gene expression indicates that maternal nematode infection enhanced movement of leukocytes across the neonatal BBB and promoted a Th2/Treg environment that presumably minimizes the proinflammatory Th1 response in the pup brain.

Mblk-1 regulates sugar responsiveness in honey bee (Apis mellifera) foragers.

Brain transcriptional regulatory network for behavior demonstrates that brain gene expression in the honey bee can be accurately predicted from the expression transcription factors (TFs), but roles for specific TFs are less understood. Mushroom bodies (MBs) are important for learning, memory and sensory integration in the honey bee brain. A TFs, Mblk-1, expressed preferentially in the large-type Kenyon cells of the honeybee MBs is predicted to be involved in brain function by regulating transcription of its target genes in honey bee. However, its function and the mechanism of regulation in behavior of honey bee is still obscure. Here we show that Mblk-1 had significantly higher expression in the brains of forager bees relative to nurse bees. Mblk-1 was significantly inhibited in bees fed small interfering RNA. In addition, inhibition of Mblk-1 decreased sucrose responsiveness in foragers. Finally, we determined that Mblk-1 regulated the messenger RNA of AmGR1. These findings suggest that Mblk-1 may target AmGR1 to regulate the sucrose responsiveness of foragers.

Wild guppies from populations exposed to higher predation risk exhibit greater vasotocin brain gene expression

AbstractIntraspecific variation in social behaviour is often observed among animal populations. Local predation risk can be a key driver of these differences, with populations that are exposed to greater threat typically showing greater aggregation and reduced intraspecific aggression. The Trinidadian guppy,Poecilia reticulata, is found in populations that vary dramatically in predation risk and show greater grouping and reduced agonism in high‐predation populations compared to low‐predation populations. The neurohormonal mechanisms that underpin these differences in behaviour across populations remain unknown and elucidating these mechanisms may help us to understand the evolution of behavioural diversity in this species. We predicted that guppies naturally exposed to higher predation risk would show greater expression of the isotocin system and reduced expression of the vasotocin system when compared to low‐predation fish, because these peptides are thought to promote gregariousness and aggressivity respectively. We collected guppies of both sexes from high‐ and low‐predation sites, replicated in two different Trinidadian rivers, and measured the brain gene expression of isotocin and vasotocin along with their central receptors. Contrary to our prediction, we found that high‐predation guppies showed greater expression of vasotocin, while we did not find evidence that the populations differed in isotocin expression, nor in the expression of the receptors. These results support the hypothesis that vasotocin may act as a neural substrate for social variation in fishes but call into question generalisations about its specific role across species.

Maternal oxytocin administration modulates gene expression in the brains of perinatal mice.

Oxytocin (OXT) is widely used to facilitate labor. However, little is known about the effects of perinatal OXT exposure on the developing brain. We investigated the effects of maternal OXT administration on gene expression in perinatal mouse brains. Pregnant C57BL/6 mice were treated with saline or OXT at term (n=6-7/group). Dams and pups were euthanized on gestational day (GD) 18.5 after delivery by C-section. Another set of dams was treated with saline or OXT (n=6-7/group) and allowed to deliver naturally; pups were euthanized on postnatal day 9 (PND9). Perinatal/neonatal brain gene expression was determined using Illumina BeadChip Arrays and real time quantitative PCR. Differential gene expression analyses were performed. In addition, the effect of OXT on neurite outgrowth was assessed using PC12 cells. Distinct and sex-specific gene expression patterns were identified in offspring brains following maternal OXT administration at term. The microarray data showed that female GD18.5 brains exhibited more differential changes in gene expression compared to male GD18.5 brains. Specifically, Cnot4 and Frmd4a were significantly reduced by OXT exposure in male and female GD18.5 brains, whereas Mtap1b, Srsf11, and Syn2 were significantly reduced only in female GD18.5 brains. No significant microarray differences were observed in PND9 brains. By quantitative PCR, OXT exposure reduced Oxtr expression in female and male brains on GD18.5 and PND9, respectively. PC12 cell differentiation assays revealed that OXT induced neurite outgrowth. Prenatal OXT exposure induces sex-specific differential regulation of several nervous system-related genes and pathways with important neural functions in perinatal brains.