Project description:We have undertaken the first comprehensive analysis of gene expression influenced by acute LSD administration in the mammalian brain to elucidate the mechanism of action of this class of drugs. We have identified a number of genes that are predicted to be involved in the processes of synaptic plasticity, glutamatergic signaling and cytoskeletal architecture. Understanding these molecular events will lead to new insights into the etiology of disorders whose behavioral symptoms resemble the temporary effects of hallucinogenic drugs, and also may ultimately result in new therapies.
Project description:This SuperSeries is composed of the following subset Series: GSE33010: Human-specific patterns of gene expression in the brain (Arrays) GSE33587: Human-specific patterns of gene expression in the brain (RNA-Seq) Refer to individual Series
Project description:Connectivity webs mediate the unique biology of mammalian brain. Yet while cell and gene circuit maps are increasing in resolution, knowledge of the molecular interaction networks of the brain is limited. Here, we applied multidimensional biochemical fractionation with precision mass spectrometry to survey endogenous macromolecules in adult mouse brain. We defined a global ‘interactome’ landscape consisting of hundreds of multi-protein complexes, most never reported before. Brain selective assemblies exhibit distinctive biophysical and functional attributes, including enrichment for synaptic, RNA-binding and other evolutionarily conserved proteins showing tissue-, regional- and cell-type specificity. Strikingly, many macromolecules have links to diverse neurological disorders and disease variants, illustrating the broad pathophysiological relevance of the network. We validated a putative 15-member complex associated with Amyotrophic Lateral Sclerosis using reciprocal pulldowns and a transgenic rodent model, establishing balancing functions in alternative splicing and disease progression. This resource facilitates exploration of the mechanistic basis of neuronal function, synaptic plasticity and diseases of the central nervous system.
Project description:Circular RNAs (circRNAs) are an endogenous class of animal RNAs. Despite their abundance, their function and expression in the nervous system are unknown. Therefore, we sequenced RNA from different brain regions, primary neurons, isolated synapses, as well as during neuronal differentiation. Using these and other available data, we discovered and analyzed thousands of neuronal human and mouse circRNAs. circRNAs were extraordinarily enriched in the mammalian brain, well conserved in sequence, often expressed as circRNAs in both human and mouse, and sometimes even detected in Drosophila brains. circRNAs were overall upregulated during neuronal differentiation, highly enriched in synapses, and often differentially expressed compared to their mRNA isoforms. circRNA expression correlated negatively with expression of the RNA-editing enzyme ADAR1. Knockdown of ADAR1 induced elevated circRNA expression. Together, we provide a circRNA brain expression atlas and evidence for important circRNA functions and values as biomarkers. To assess circRNA expression in mammalian brain, we sequenced and analyzed mouse brain regions (hippocampus, cerebellum, prefrontal cortex and olfactory bulb), various neuronal differentiation (mouse P19 and human SH-SY5Y cells) and maturation (mouse cortical neurons) stages, and subcellular compartments in mouse (synaptoneurosomal fraction, cytoplasmic fraction, whole brain lysate).
Project description:We identified human-specific gene expression patterns in the brain by comparing expression with chimpanzee and rhesus macaque Comparative gene expression in human, chimpanzee, and rhesus macaque brain
Project description:Disruption of the Circadian Clock within the Cardiomyocyte Influences Myocardial Contractie Function, Metabolism, and Gene Expression Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally-based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variations in myocardial biology. We therefore generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse, in order to test this hypothesis. At 12 weeks of age, CCM mice exhibit normal myocardial contractile function in vivo, as assessed by echocardiography. Radiotelemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted in CCM hearts perfused ex vivo in the working mode, highlighting the intrinsic nature of this phenotype. Wild-type, but not CCM, hearts exhibited a marked diurnal variation in responsiveness to an elevation in workload (80mmHg plus 1 microM epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase versus the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, while cardiac efficiency was decreased, in CCM hearts. These observations were associated with no alterations in mitochondrial content or structure, and modest mitochondrial dysfunction, in CCM hearts. Gene expression microarray analysis identified 548 and 176 genes in atria and ventricles, respectively, whose normal diurnal expression patterns were altered in CCM mice. These studies suggest that the cardiomyocyte circadian clock influences myocardial contractile function, metabolism, and gene expression. Keywords: Comparison of circadian oscillations in gene expression in hearts taken from wildtype and transgenic animals