Gene Expression In Brain Regions Research Articles

Gestational hypothyroxinemia in dehal1ko mice: discordant T3-dependent gene expression in brain regions and autistic-like phenotype in the offspring

Gestational hypothyroxinemia in dehal1ko mice: discordant T3-dependent gene expression in brain regions and autistic-like phenotype in the offspring

Exploring Schizophrenia Classification Through Multimodal MRI and Deep Graph Neural Networks: Unveiling Brain Region-Specific Weight Discrepancies and Their Association With Cell-Type Specific Transcriptomic Features.

Schizophrenia (SZ) is a prevalent mental disorder that imposes significant health burdens. Diagnostic accuracy remains challenging due to clinical subjectivity. To address this issue, we explore magnetic resonance imaging (MRI) as a tool to enhance SZ diagnosis and provide objective references and biomarkers. Using deep learning with graph convolution, we represent MRI data as graphs, aligning with brain structure, and improving feature extraction, and classification. Integration of multiple modalities is expected to enhance classification. Our study enrolled 683 SZ patients and 606 healthy controls from 7 hospitals, collecting structural MRI and functional MRI data. Both data types were represented as graphs, processed by 2 graph attention networks, and fused for classification. Grad-CAM with graph convolution ensured interpretability, and partial least squares analyzed gene expression in brain regions. Our method excelled in the classification task, achieving 83.32% accuracy, 83.41% sensitivity, and 83.20% specificity in 10-fold cross-validation, surpassing traditional methods. And our multimodal approach outperformed unimodal methods. Grad-CAM identified potential brain biomarkers consistent with gene analysis and prior research. Our study demonstrates the effectiveness of deep learning with graph attention networks, surpassing previous SZ diagnostic methods. Multimodal MRI's superiority over unimodal MRI confirms our initial hypothesis. Identifying potential brain biomarkers alongside gene biomarkers holds promise for advancing objective SZ diagnosis and research in SZ.

Sex differences in baseline sleep and dark phase rebound sleep after chronic sleep fragmentation in the APPXPS1 and 5XFAD mouse models

AbstractBackgroundFragmentation of the daily sleep‐wake rhythm is a risk factor for Alzheimer’s disease (AD) (Li et al, Lancet Healthy Longev 1:e96‐e105 [2020]). While women have a higher AD incidence than men, whether women are more sensitive to sleep fragmentation (SF) is not known. Studies in female 3xTg‐AD mice (8‐11 months old) show that chronic SF for four weeks alters the daily sleep‐wake rhythm and stimulates AD‐like neuropathology (Duncan et al, Neuroscience 481:111‐122 [2022]).MethodTo investigate possible sex differences in the effects of sleep fragmentation, we studied two AD mouse models and matching wild‐type controls, APPxPS1‐knock‐in mice (6.2‐11 months old; N = 127) and 5XFAD mice (2.3‐3.3 months old; N = 52). All mice were exposed to 3‐4 weeks of SF or undisturbed sleep while individually housed in cages interfaced for piezo electric sleep recording for monitoring of daily sleep‐wake rhythms. SF consisted of four daily sessions (1 hour each) of enforced wakefulness (induced with toys and paintbrush stimulation) that were evenly distributed during the light phase, for 5 days/week. Immediately after the last SF session, mice in both groups were euthanized and cortical and hippocampal tissue was dissected and frozen. Amyloid‐beta levels were determined in soluble fractions using ELISA.ResultsSF redistributed sleep from the light phase (loss) to the dark phase (gain) in APPxPS1‐ki (p<0.0001) and 5XFAD (p<0.05) mice and WT controls. Overall, females slept less than males (p<0.001) and were more affected by SF. Dark phase “rebound” sleep after SF was greater in APPxPS1‐ki females (∼70% of undisturbed controls) than in APPxPS1 males or WT mice of either sex (∼20% of undisturbed controls) (p<0.001). Cortical amyloid‐beta levels were higher in female than male AD mice, but surprisingly, neither cortical nor hippocampal amyloid‐beta levels were affected by SF in either strain.ConclusionThese findings suggest an interaction between sex, AD mutations, and neuropathology on dark phase rebound sleep after chronic SF. To elucidate this interaction, on‐going studies are investigating the role of amyloid‐beta in sex‐differences in SF‐induced rebound sleep and potential sex differences in SF effects on gene expression in brain regions regulating sleep or circadian rhythms.

Acute stress modulates the outcome of traumatic brain injury-associated gene expression and behavioral responses.

Psychological stress and traumatic brain injury (TBI) result in long-lasting emotional and behavioral impairments in patients. So far, the interaction of psychological stress with TBI not only in the brain but also in peripheral organs is poorly understood. Herein, the impact of acute stress (AS) occurring immediately before TBI is investigated. For this, a mouse model of restraint stress and TBI was employed, and their influence on behavior and gene expression in brain regions, the hypothalamic-pituitary-adrenal (HPA) axis, and peripheral organs was analyzed. Results demonstrate that, compared to single AS or TBI exposure, mice treated with AS prior to TBI showed sex-specific alterations in body weight, memory function, and locomotion. The induction of immediate early genes (IEGs, e.g., c-Fos) by TBI was modulated by previous AS in several brain regions. Furthermore, IEG upregulation along the HPA axis (e.g., pituitary, adrenal glands) and other peripheral organs (e.g., heart) was modulated by AS-TBI interaction. Proteomics of plasma samples revealed proteins potentially mediating this interaction. Finally, the deletion of Atf3 diminished the TBI-induced induction of IEGs in peripheral organs but left them largely unaltered in the brain. In summary, AS immediately before brain injury affects the brain and, to a strong degree, also responses in peripheral organs.

Exploring the correlation between genetic transcription and multi-temporal developmental autism spectrum disorder using resting-state functional magnetic resonance imaging.

The present investigation aimed to explore the neurodevelopmental trajectory of autism spectrum disorder (ASD) by identifying the changes in brain function and gene expression associated with the disorder. Previous studies have indicated that ASD is a highly inherited neurodevelopmental disorder of the brain that displays symptom heterogeneity across different developmental periods. However, the transcriptomic changes underlying these developmental differences remain largely unknown. To address this gap in knowledge, our study employed resting-state functional magnetic resonance imaging (rs-fMRI) data from a large sample of male participants across four representative age groups to stratify the abnormal changes in brain function associated with ASD. Partial least square regression (PLSr) was utilized to identify unique changes in gene expression in brain regions characterized by aberrant functioning in ASD. Our results revealed that ASD exhibits distinctive developmental trajectories in crucial brain regions such as the default mode network (DMN), temporal lobe, and prefrontal lobes during critical periods of neurodevelopment when compared to the control group. These changes were also associated with genes primarily located in synaptic tissues. The findings of this study suggest that the neurobiology of ASD is uniquely heterogeneous across different ages and may be accompanied by distinct molecular mechanisms related to gene expression.

Dietary emulsifier consumption alters gene expression in the amygdala and paraventricular nucleus of the hypothalamus in mice

Dietary emulsifier consumption promotes systemic low-grade inflammation, metabolic deregulation, and possibly an anxiety-like phenotype. The latter finding suggests that dietary emulsifiers impact brain areas that modulate stress responses. The goal of the current study was to test whether emulsifier consumption is associated with changes in gene expression in the amygdala and the paraventricular nucleus of the hypothalamus (PVN), two brain areas that are involved in behavioral and neuroendocrine responses to stress. Using RNA-Seq, we compared groups consuming either carboxymethylcellulose or polysorbate 80 for 12-weeks. A total of 243 genes were differentially expressed in the amygdala and PVN of emulsifier-treated mice compared to controls. There was minimal overlap of differentially expressed genes in CMC- and P80-treated animals, suggesting that each emulsifier acts via distinct molecular mechanisms to produce an anxiety-like phenotype. Furthermore, gene ontology and pathway analysis revealed that various stress, metabolic, and immune terms and pathways were altered by emulsifiers. These findings are the first to demonstrate that emulsifier consumption changes gene expression in brain regions that are critical for stress responding, providing possible molecular mechanisms that may underly the previously observed anxiety-like phenotype.

Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis.

Schizophrenia (SCZ) is a chronic, serious mental disorder. Although more than 200 SCZ-associated genes have been identified, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a (SET domain containing 1A) haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression in brain regions highly relevant to SCZ. Single-cell RNA sequencing revealed that Setd1a heterozygosity causes highly variable transcriptional adaptations across different cell types in prefrontal cortex (PFC) and striatum. The Foxp2+ neurons exhibit the most prominent gene expression changes among the different neuron subtypes in PFC, which correlate with changes in histone H3 lysine 4 trimethylation. Many of the genes dysregulated in Setd1a+/− mice are involved in neuron morphogenesis and synaptic function. Consistently, Setd1a+/− mice exhibit certain behavioral features of patients with SCZ. Collectively, our study establishes Setd1a+/− mice as a model for understanding SCZ and uncovers a complex brain region– and cell type–specific dysregulation that potentially underlies SCZ pathogenesis.

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.

Identification and comparative analysis of long non-coding RNAs in the brain of fire ant queens in two different reproductive states

BackgroundMany long non-coding RNAs (lncRNAs) have been extensively identified in higher eukaryotic species. The function of lncRNAs has been reported to play important roles in diverse biological processes, including developmental regulation and behavioral plasticity. However, there are no reports of systematic characterization of long non-coding RNAs in the fire ant Solenopsis invicta.ResultsIn this study, we performed a genome-wide analysis of lncRNAs in the brains of S. invicta from RNA-seq. In total, 1,393 novel lncRNA transcripts were identified in the fire ant. In contrast to the annotated lncRNA transcripts having at least two exons, novel lncRNAs are monoexonic transcripts with a shorter length. Besides, the transcriptome from virgin alate and dealate mated queens were analyzed and compared. The results showed 295 differentially expressed mRNA genes (DEGs) and 65 differentially expressed lncRNA genes (DELs) between virgin and mated queens, of which 17 lncRNAs were highly expressed in the virgin alates and 47 lncRNAs were highly expressed in the mated dealates. By identifying the DEL:DEG pairs with a high association in their expression (Spearman’s |rho|> 0.8 and p-value < 0.01), many DELs were co-regulated with DEGs after mating. Furthermore, several remarkable lncRNAs (MSTRG.6523, MSTRG.588, and nc909) that were found to associate with particular coding genes may play important roles in the regulation of brain gene expression in reproductive transition in fire ants.ConclusionThis study provides the first genome-wide identification of S. invicta lncRNAs in the brains in different reproductive states. It will contribute to a fuller understanding of the transcriptional regulation underpinning reproductive changes.

Immediate Early Gene Expression in Brain Regions Associated with the Social Behavioral Network After Male Competition in Medaka Fish.

In this study, we used the immediate early gene, egr-1, as a marker for neural activation and examined whether egr-1 expression is affected in brain regions associated with the social behavioral network (SBN) when social rank is determined and changed in male medaka fish (Oryzias latipes). Based on the behavioral contest protocol used in this study, we obtained four types of males: social ascending, social descending, dominant, and subordinate. In some brain regions associated with the SBN, we detected higher egr-1 expression in ascending and descending males than in dominant and subordinate males. Social-rank stable males (i.e., dominant and subordinate male fish) showed a similar level of egr-1 expression as the control male fish, which were housed without social stimulus of encountering another conspecific. These findings suggested that the transitioning of social rank could enhance neural activity in some brain regions associated with the SBN in male medaka. The use of medaka fish has many advantages in various fields of research such as genetics, developmental biology, environmental biology, and behavioral neurology. The findings of this study would contribute to future research exploring the roles of the SBN regions in regulating physiological and behavioral events associated with social-rank transition.

SUN-235 Deficient Fear Extinction in PRKAR1A-Defective Mice

Background: The role of the cAMP/PKA signaling in molecular pathways involved in fear memory is well established: PKA is required for fear memory formation and is a constraint for fear extinction. Previously we reported that a Prkar1a heterozygote (HZ) mouse that was developed in our lab to investigate Carney complex (CNC), the disease caused by PRKAR1A mutations, showed brain region-specific increased PKA activity that was associated with anxiety-like behavioral phenotype and threat bias (Keil, 2010, 2013). We hypothesized that Prkar1a+/- (HZ) mice would have deficits in fear extinction behavior. Brain derived neurotrophic factor (BDNF) has a critical role in formation of fear memory and its transcription is regulated by PKA/CREB. A mouse model with down regulation of PKA provides an opportunity for the first time to investigate the effect of altered PKA signaling on fear conditioning and extinction.Method: Fear conditioning, fear extinction learning, and fear extinction recall were tested in adult male HZ and wild-type (WT) mice as follows: fear conditioning training followed 24hr later by extinction training (new context), then 24hr later by extinction recall training. Percentage of time freezing was used to assess conditioned fear response. We measured BDNF gene expression in brain regions after completion of extinction recall training.Results: As expected, fear conditioning (learning) behavior was similar in HZ and WT mice. However, HZ mice showed a significant deficit in the early phase of fear extinction learning compared to WT. There was no difference in extinction recall between genotypes. Alterations in BDNF gene expression in the prefrontal cortex and amygdala was associated with deficit in fear extinction.Conclusion: Mice with a downregulation of Prkar1a gene demonstrate intact fear conditioning but impaired fear extinction learning, consistent with prior studies that report that PKA inhibition is necessary to facilitate extinction learning. Prkar1a+/- mice provide a valuable model to investigate impaired fear extinction to identify mechanisms for therapeutic targets for anxiety and trauma-related disorders.

Molecular Mechanisms of Intranasal Insulin in SAMP8 Mice.

Research on intranasal delivery of drugs, peptides, and proteins has grown over the past decade as an alternate way to deliver substrates to the brain. Recent work has shown intranasal (INL) delivery of insulin improves memory and cognition in healthy subjects as well as patients with Alzheimer's disease (AD) and in AD mouse models. However, the molecular mechanism(s) for the beneficial effect of insulin on memory are still unclear. Using the SAMP8 mouse model of AD, we investigated the impact of INL insulin on protein and gene expression in brain regions including the olfactory bulb, hypothalamus, and hippocampus. We found genes and proteins in the insulin receptor signaling pathway were not activated by the doses tested. However, we did find the expression of genes present in the hippocampus involved in other pathways, especially those related to inflammation, were altered due to age and with a dose of INL insulin previously shown to improve cognition. These alternate pathways could be targets of insulin when delivered via the INL route to aid in memory improvement.

30 - ANALYSIS OF GENE EXPRESSION VARIANCE AND GENETIC REGULATION OF GENE EXPRESSION BASED ON VARIANCE ASSOCIATION MAPPING

The objective of this work is the application of advanced computational and statistical methods to identify interactions between genetic variants of brain-expressed genes. The focus is particularly on the SNPs that significantly influence the gene expression in a non-additive manner. The phenomenon, called epistasis, is one of the possible explanations of the missing heritability of complex disorders resulting from classical SNP-by-SNP analysis of Genome Wide Association Studies. The discovery of epistatic interaction at genome-wide level has always been challenging due to the extremely high number of tests required in the absence of biological hypotheses. However, epistasis on gene expression as an intermediate phenotype may be more tractable due the larger effect size expected with respect to disease traits, and its quantitative nature. In this project, we apply a step-wise approach to the identification and replication of SNP-SNP interactions in brain transcriptome data based on variance association mapping, which allows for the prioritization of genes for subsequent epistasis discovery based on the identification of genes with genotype-dependent variance. We have implemented a method for variance association mapping on brain (DLPFC) RNASeq data (from CommonMind Consortium) and identified a set of candidate expression variance QTL. Epistasis-discovery was then performed, resulting with the identification of statistically significant cis and trans effects, for which replication in additional brain datasets is ongoing. To evaluate the biological medical relevance of the interactions, bioinformatics analyses are in progress. Our results, which putatively identify complex gene-gene interactions contributing to the regulation of brain gene expression, could highlight functional mechanisms that may underlie common psychiatric disorders.

Physical positioning markedly enhances brain transduction after intrathecal AAV9 infusion.

Several neurological disorders may benefit from gene therapy. However, even when using the lead vector candidate for intrathecal administration, adeno-associated virus serotype 9 (AAV9), the strength and distribution of gene transfer to the brain are inconsistent. On the basis of preliminary observations that standard intrathecal AAV9 infusions predominantly drive reporter gene expression in brain regions where gravity might cause cerebrospinal fluid to settle, we tested the hypothesis that counteracting vector "settling" through animal positioning would enhance vector delivery to the brain. When rats are either inverted in the Trendelenburg position or continuously rotated after intrathecal AAV9 infusion, we find (i) a significant 15-fold increase in the number of transduced neurons, (ii) a marked increase in gene delivery to cortical regions, and (iii) superior animal-to-animal consistency of gene expression. Entorhinal, prefrontal, frontal, parietal, hippocampal, limbic, and basal forebrain neurons are extensively transduced: 95% of transduced cells are neurons, and greater than 70% are excitatory. These findings provide a novel and simple method for broad gene delivery to the cortex and are of substantial relevance to translational programs for neurological disorders, including Alzheimer's disease and related dementias, stroke, and traumatic brain injury.

Dual influences of early life stress induced by limited bedding on walking adaptability and Bdnf/TrkB and Drd1/Drd2 gene expression in different mouse brain regions

Introduction Evidence suggests early life stress impairs development, quality of life and increases vulnerability to disease. One important aspect of the stress experience is its impact on cognitive-motor performance, which includes the ability to adapt walking according to the environmental conditions. This study aimed to investigate how early-life stress affects walking adaptability of mice, while investigating BDNF/TrkB and Drd1/Drd2 expression in different brain regions.Methods Briefly, we exposed male C56BL/6 to the limited bedding protocol (LB) from post-natal day (PND) 2 to PND9 and then tested animals in the ladder walking task at PND60. RT-qPCR was used to investigate gene expression in the mPFC, hippocampus, motor cortex and cerebellum 2 h after the taskResults LB induced a wide range of variability and therefore two distinct subgroups of animals within the LB group were established: a) superior performance (LB-SP); and b) inferior performance (LB-IP), compared to controls. Additionally, Drd1 gene expression was increased in the mPFC of LB-IP animals and in the cerebellum of LB-SP animals, while Drd2 expression was reduced in the hippocampus of the LB-IP group. BDNF exon IV gene expression in the mPFC and motor cortex was increased in both the LB-IP and LB-SP subgroups. TrkB gene expression in the hippocampus was reduced in the LB-IP group. A strong negative correlation was found between walking adaptability performance and BDNF exon IV gene expression in the motor cortex. Conversely, a positive correlation was found between walking adaptability performance and TrkB expression in the mPFC and a negative correlation in the hippocampus. Both Drd1 and Drd2 gene expression were negatively correlated with the ability to adapt walking.Conclusions Overall, our findings suggest exposure to early life stress leads to distinct walking adaptability phenotypes, which may be related to Drd1, Drd2, Bdnf exon IV and TrkB gene expression in brain regions that influence walking adaptability.

Correction to 'Transcriptional regulation of brain gene expression in response to a territorial intrusion in sticklebacks'.

You have accessMoreSectionsView PDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditEmail Cite this article Sanogo Yibayiri O., Band Mark, Blatti Charles, Sinha Saurabh and Bell Alison M. 2016Correction to ‘Transcriptional regulation of brain gene expression in response to a territorial intrusion in sticklebacks’Proc. R. Soc. B.2832016208220162082http://doi.org/10.1098/rspb.2016.2082SectionYou have accessCorrectionCorrection to ‘Transcriptional regulation of brain gene expression in response to a territorial intrusion in sticklebacks’ Yibayiri O. Sanogo Yibayiri O. Sanogo Google Scholar Find this author on PubMed Search for more papers by this author , Mark Band Mark Band Google Scholar Find this author on PubMed Search for more papers by this author , Charles Blatti Charles Blatti Google Scholar Find this author on PubMed Search for more papers by this author , Saurabh Sinha Saurabh Sinha Google Scholar Find this author on PubMed Search for more papers by this author and Alison M. Bell Alison M. Bell http://orcid.org/0000-0001-8933-8494 Google Scholar Find this author on PubMed Search for more papers by this author Yibayiri O. Sanogo Yibayiri O. Sanogo Google Scholar Find this author on PubMed Search for more papers by this author , Mark Band Mark Band Google Scholar Find this author on PubMed Search for more papers by this author , Charles Blatti Charles Blatti Google Scholar Find this author on PubMed Search for more papers by this author , Saurabh Sinha Saurabh Sinha Google Scholar Find this author on PubMed Search for more papers by this author and Alison M. Bell Alison M. Bell http://orcid.org/0000-0001-8933-8494 Google Scholar Find this author on PubMed Search for more papers by this author Published:26 October 2016https://doi.org/10.1098/rspb.2016.2082This article corrects the followingResearch ArticleTranscriptional regulation of brain gene expression in response to a territorial intrusionhttps://doi.org/10.1098/rspb.2012.2087 Yibayiri O. Sanogo, Mark Band, Charles Blatti, Saurabh Sinha and Alison M. Bell volume 279issue 1749Proceedings of the Royal Society B: Biological Sciences24 October 2012Proc. R. Soc. B279, 4929–4938. (12 November 2012; Published online 24 October 2012) (doi:10.1098/rspb.2012.2087)It has come to our attention that the direction of regulation reported in Sanogo et al. [1] is incorrect. Genes that were upregulated in experimental males were, in fact, downregulated and vice versa.The following sentence on page 4932 that begins, ‘“Upregulation” indicates higher expression in experimental males compared with controls’ should instead read ‘“upregulation” indicates higher expression in control males compared with experimentals’.The following caption to figure 1 that states, ‘where “up” refers to higher expression in experimental males’ should instead read ‘where “up” refers to higher expression in control males’.In electronic supplementary material, tables S4–S7, the sign of the fold change (FC) is opposite.Footnotes© 2016 The Author(s)Published by the Royal Society. All rights reserved.ReferencesReference1Sanogo YO, Band M, Blatti C, Sinha S, Bell AM. 2012Transcriptional regulation of brain gene expression in response to a territorial intrusion. Proc. R. Soc. B 279, 4929–4938. (doi:10.1098/rspb.2012.2087) Link, ISI, Google Scholar Previous Article VIEW FULL TEXT DOWNLOAD PDF FiguresRelatedReferencesDetailsCited by Southey B, Rodriguez-Zas S, Rhodes J, Sweedler J and Vaudry H (2020) Characterization of the prohormone complement in Amphiprion and related fish species integrating genome and transcriptome assemblies, PLOS ONE, 10.1371/journal.pone.0228562, 15:3, (e0228562) Related articlesTranscriptional regulation of brain gene expression in response to a territorial intrusion24 October 2012Proceedings of the Royal Society B: Biological Sciences This Issue26 October 2016Volume 283Issue 1841 Article InformationDOI:https://doi.org/10.1098/rspb.2016.2082PubMed:27798313Published by:Royal SocietyOnline ISSN:1471-2954History: Published online26/10/2016Published in print26/10/2016 License:© 2016 The Author(s)Published by the Royal Society. All rights reserved. Citations and impact Subjectsbehaviourgenomicsneuroscience Large datasets are available through Proceedings B's partnership with Dryad

Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes.

Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome and related autism spectrum disorders (Amir et al., 1999). MeCP2 is believed to be required for proper regulation of brain gene expression, but prior microarray studies in Mecp2 knock-out mice using brain tissue homogenates have revealed only subtle changes in gene expression (Tudor et al., 2002; Nuber et al., 2005; Jordan et al., 2007; Chahrour et al., 2008). Here, by profiling discrete subtypes of neurons we uncovered more dramatic effects of MeCP2 on gene expression, overcoming the "dilution problem" associated with assaying homogenates of complex tissues. The results reveal misregulation of genes involved in neuronal connectivity and communication. Importantly, genes upregulated following loss of MeCP2 are biased toward longer genes but this is not true for downregulated genes, suggesting MeCP2 may selectively repress long genes. Because genes involved in neuronal connectivity and communication, such as cell adhesion and cell-cell signaling genes, are enriched among longer genes, their misregulation following loss of MeCP2 suggests a possible etiology for altered circuit function in Rett syndrome.

Extended exposure to a palatable cafeteria diet alters gene expression in brain regions implicated in reward, and withdrawal from this diet alters gene expression in brain regions associated with stress

Like people, rodents exposed to energy-rich foods over-eat and become overweight. Removal of this diet activates stress systems, which may explain why people have difficulty dieting. We exposed rats to energy-rich foods in order to identify changes in the brain induced by that diet and by its removal. Sprague Dawley rats were fed lab-chow or an energy-rich cafeteria diet (plus chow). Following 6 or 15 weeks, half of each group was switched to the opposing diet. Rats were culled 48-h later. We measured fat mass, plasma hormones, and assessed brains for mRNA expression of several genes. Cafeteria-fed rats consumed more kilojoules, weighed more and had elevated leptin (plus reduced CORT at 15 weeks) relative to chow-fed rats. Fifteen weeks of cafeteria diet suppressed μ-opioid and CB1 receptor mRNA in the VTA, but elevated amygdala GR, and 6 weeks of cafeteria diet reduced BDNF, compared to chow-fed rats. Rats switched to the cafeteria diet ate similar amounts as rats maintained on the diet, and switching to cafeteria diet after 15 weeks reduced amygdala GR expression. Rats switched to chow ate less than rats maintained on chow, and switching to chow following 15 weeks of cafeteria diet increased hypothalamic CRH mRNA. Therefore, 15 weeks of cafeteria diet produced changes in brain regions implicated in reward processes. Switching these rats to chow activated the HPA axis, while switching chow-fed rats to the cafeteria diet decreased GR expression in the amygdala, a region associated with stress. These findings have implications for dieting in humans.

Gene expression profile and functional analysis of Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with largely unknown genetic mechanisms. Identifying altered neuronal gene expression in brain regions differentially affected by AD may provide the diagnostic or therapeutic targets of AD. The gene expression profile of AD was analyzed with bioinformatics. Function analysis was performed with Database for Annotation, Visualization and Integrated Discovery (DAVID), and TransFind was used to predict the possible transcriptional regulators in AD. Finally, connectivity map (cMap) database was used to explore small molecules targeted for AD. The AD gene signatures associated with 6 different brain regions were identified. Functional analysis revealed that biological processes involved with metabolism, protein ubiquitination, and vasculature development were found dysregulated, and synaptic signaling pathways were found perturbated in AD. The WT1 was identified as an important transcriptional regulator in AD, and cMap database predicted that small molecules, such as histone deacetylase (HDAC) inhibitor, may be candidate drugs in the treatment of AD. According to our in silico analysis, Wilms' tumor suppressor may play regulatory roles in AD development and progress. The HDAC inhibitor could possibly be used to treat AD.

Roux en Y Gastric Bypass Increases Ethanol Intake in the Rat

Roux en Y gastric bypass (RYGB) surgery is currently the most effective therapy employed to treat obesity and its associated complications. In addition to weight loss and resolution of metabolic syndromes, such as diabetes, the RYGB procedure has been reported to increase alcohol consumption in humans. Using an outbred rodent model, we demonstrate that RYGB increases postsurgical ethanol consumption, that this effect cannot be explained solely by postsurgical weight loss and that it is independent of presurgical body weight or dietary composition. Altered ethanol metabolism and postsurgical shifts in release of ghrelin were also unable to account for changes in alcohol intake. Further investigation of the potential physiological factors underlying this behavioral effect identified altered patterns of gene expression in brain regions associated with reward following RYGB surgery. These findings have important clinical implications as they demonstrate that RYGB surgery leads directly to increased alcohol intake in otherwise alcohol nonpreferring rat and induces neurobiological changes in brain circuits that mediate a variety of appetitive behaviors.