Project description:An inter-regional cortical tract is one of the most fundamental architectural motifs that integrates neural circuits to orchestrate and generate complex functions of the human brain. To understand the mechanistic significance of inter-regional projections on development of neural circuits, we investigated an in vitro neural tissue model for inter-regional connections, in which two cerebral organoids are connected with a bundle of reciprocally extended axons. The connected organoids produced more complex and intense oscillatory activity than conventional or directly fused cerebral organoids, suggesting the inter-organoid axonal connections enhance and support the complex network activity. In addition, optogenetic stimulation of the inter-organoid axon bundles could entrain the activity of the organoids and induce robust plasticity of the macroscopic circuit. These results demonstrated that the projection axons could serve as a structural hub that boosts functionality of the organoid-circuits. This model could contribute to further investigation on development and functions of macroscopic neuronal circuits in vitro.
Project description:An inter-regional cortical tract is one of the most fundamental architectural motifs that integrates neural circuits to orchestrate and generate complex functions of the human brain. To understand the mechanistic significance of inter-regional projections on development of neural circuits, we investigated an in vitro neural tissue model for inter-regional connections, in which two cerebral organoids are connected with a bundle of reciprocally extended axons. The connected organoids produced more complex and intense oscillatory activity than conventional or directly fused cerebral organoids, suggesting the inter-organoid axonal connections enhance and support the complex network activity. In addition, optogenetic stimulation of the inter-organoid axon bundles could entrain the activity of the organoids and induce robust short-term plasticity of the macroscopic circuit. These results demonstrated that the projection axons could serve as a structural hub that boosts functionality of the organoid-circuits. This model could contribute to further investigation on development and functions of macroscopic neuronal circuits in vitro.
Project description:Healthcare providers are routinely being assessed for metrics designed to assess the quality of the care they deliver. There is growing consensus that these measurements, which typically assess the percentage of patients meeting a specific standard of care, should be adjusted for the clinical complexity of the providers. This study will assess whether adjusting for the social complexity of the patient panel adds significantly to adjustment for clinical complexity in explaining apparent differences in quality of care provided by Primary care providers and clinics.
Project description:Cornelia de Lange syndrome (CdLS) is a complex multisystem developmental disorder caused by mutations in cohesin subunits and regulators. While the precise molecular mechanisms are not well defined, they point toward a global deregulation of the transcriptional gene expression program. Indeed, cohesin is associated with the boundaries of chromosome domains in addition to enhancers and promoters connecting the 3D genome organization with transcriptional control and gene expression. Here we show that connected gene communities, built with noncoding regulatory elements and genes physically interacting in the 3D chromosomal space, provide a molecular explanation for the pathoetiology of CdLS. Indeed, NIPBL and cohesin are important constituents of connected gene communities, both being centrally positioned at active noncoding regulatory elements. Interestingly, mutations in SMC1A and NIPBL lead to coordinated gene expression changes in connected communities. Our findings suggest a model where CdLS is explained by coordinated modulation of connected gene communities.
Project description:The effect of a short-term calorie restricted diet was evaluated in cerebral cortex in seven strains of mice The dietary intervention was initiated at 8 weeks of age and continued until 22 weeks of age
Project description:The complexity of the mature adult brain is a result of both developmental processes and experience-dependent circuit formation. One way to look at the process of brain development is to examine gene expression changes, and previous studies have used microarrays to address this in a global manner. However, the transcriptome is more complex than gene expression levels alone, as both alternative splicing and RNA editing occur to generate a more diverse set of mature transcripts. The aim of the current study was to develop a high-resolution transcriptome dataset of mouse cortical development using RNA sequencing (RNA-Seq), thus assaying exon usage and RNA editing as well as overcoming some of the inherent limitations of microarrays. We found a large number of differentially expressed genes, but also altered splicing and RNA editing between embryonic and adult cerebral cortex. Each dataset was validated both technically and biologically, and in each case tested we found our RNA-Seq observations to have high predictive validity. We propose this dataset, and the accompanying analysis, to be a helpful resource in the understanding of changes in gene expression during development. Three young adult cerebral cortices four embryonic cerebral cortices
Project description:We carried out the first analysis of alternative splicing complexity in human tissues using mRNA-Seq data. New splice junctions were detected in 20% of multiexon genes, many of which are tissue specific. By combining mRNA-Seq and EST-cDNA sequence data, we estimate that transcripts from 95% of multiexon genes undergo alternative splicing and that there are 100,000 intermediate- to high-abundance alternative splicing events in major human tissues. From a comparison with quantitative alternative splicing microarray profiling data, we also show that mRNA-Seq data provide reliable measurements for exon inclusion levels. Keywords: mRNA expression 32-nucleotide sequence reads from six human tissues including brain, cerebral cortex, heart, liver, lung and skeletal muscle.