Project description:The development of the human brain is a complex and precisely regulated process that unfolds over a protracted period of time. Human-specific features of this process, especially the ways in which highly complex neural circuits of the cerebral cortex form, are likely to be important factors in the evolution of human specializations. However, in addition to giving us remarkable cognitive and motor abilities, the formation of intricate neural circuits may have also increased our susceptibility to psychiatric and neurodegenerative disorders. Furthermore, substantial evidence suggests that the symptoms and progression of many brain disorders are dramatically influenced by genetic and developmental processes that define regional cell phenotypes and connectivity. Sex differences also play an important role in brain development and function and are a risk factor for several brain disorders, such as autism spectrum disorders (ASD) and depression. Thus understanding the spatiotemporal dynamics and functional organization of the brain transcriptome is essential to teasing out the keys to human neurodevelopment, sexual dimorphism, and evolution as well as our increased susceptibility to certain brain disorders. Most transcriptome studies of the developing brain have been restricted to rodents, and those performed in humans and nonhuman primates have included relatively small sample sizes and predominantly focused on few regions or developmental time points. Because many prominent features of human brain development significantly diverge from those of well-characterized model organisms, the translation of knowledge across species is difficult, and it is likely that many underlying genetic processes have gone undetected. In this study, we have taken a genome-wide approach to analyze the human transcriptome at single-exon resolution with ~1.4 million exon-level probe sets in 16 brain regions from donors representing both sexes and multiple ethnicities, across pre and postnatal development, including adolescence, and adulthood. We also generated genome-wide genotype data for 2.5 million single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for each specimen. Our analyses of the data revealed several features of the human brain transcriptome: spatiotemporal expression dynamics of individual and functionally related groups of genes, differential exon usage, sex-specific expression patterns and exon usage, and organization of the transcriptome into functional modules. We also profiled developmental trajectories of genes important for neurobiological themes and genes associated with ASD and schizophrenia. Finally, we present associations between specific SNPs and gene expression levels in different brain regions across development. The dataset presented here provides research opportunities and a wealth of information not previously available to the scientific community. Here we report the generation and analysis of genome-wide exon-level transcriptome data from 16 brain regions comprising the cerebellar cortex, mediodorsal nucleus of the thalamus, striatum, amygdala, hippocampus, and 11 areas of the neocortex. The dataset was generated from 1,340 samples collected from both hemispheres of 57 postmortem human brains, spanning from embryonic development to late adulthood and representing males and females of multiple ethnicities. We also performed genome-wide genotyping of 2.5 million single nucleotide polymorphisms (SNPs) and assessed copy number variations for all donors. We found that approximately 86% of protein-coding genes are expressed above background, and over 90% of these are differentially regulated at the whole transcript or exon level across regions and/or time. The majority of these spatiotemporal differences occur before birth, followed by a progressive increase in the similarity among regional transcriptome during the postnatal lifespan. Distinctive transcriptional patterns were also identified among neocortical areas, including an alternative isoform of ANKRD32 that is transiently upregulated in the late midfetal frontal cortex of human but not mouse. Developmentally and regionally regulated differences in gene expression and exon usage were also identified between males and females, including IGF2, an imprinted gene implicated in brain growth and cognitive function, and NLGN4X, a candidate gene for autism spectrum disorders. We found that the developing transcriptome is organized into functionally distinct large-scale networks of co-regulated transcripts. We also observed marked differences in expression trajectories of genes associated with specific neurodevelopmental processes, neural cell types, neurotransmitter systems, autism spectrum disorders, and schizophrenia. Association analysis of the SNP genotypes and transcriptome revealed potential polymorphic regulators of gene expression in different regions across development. This study provides a comprehensive, publicly available dataset on the spatiotemporal human brain transcriptome and new insights into the transcriptional foundations of brain development and evolution. This submission represents the transcriptome component of the study. Submitter did not submit SNP and CNV data due to privacy issue of patients.

Project description:The human hand can detect both form and texture information of a contact surface. The detection of skin displacement (sustained stimulus) and changes in skin displacement (transient stimulus) are thought to be mediated in different tactile channels; however, tactile form perception may use both types of information. Here, we studied whether both the temporal frequency and the temporal coherency information of tactile stimuli encoded in sensory neurons could be used to recognize the form of contact surfaces. We used the fishbone tactile illusion (FTI), a known tactile phenomenon, as a probe for tactile form perception in humans. This illusion typically occurs with a surface geometry that has a smooth bar and coarse textures in its adjacent areas. When stroking the central bar back and forth with a fingertip, a human observer perceives a hollow surface geometry even though the bar is physically flat. We used a passive high-density pin matrix to extract only the vertical information of the contact surface, suppressing tangential displacement from surface rubbing. Participants in the psychological experiment reported indented surface geometry by tracing over the FTI textures with pin matrices of the different spatial densities (1.0 and 2.0 mm pin intervals). Human participants reported that the relative magnitude of perceived surface indentation steeply decreased when pins in the adjacent areas vibrated in synchrony. To address possible mechanisms for tactile form perception in the FTI, we developed a computational model of sensory neurons to estimate temporal patterns of action potentials from tactile receptive fields. Our computational data suggest that (1) the temporal asynchrony of sensory neuron responses is correlated with the relative magnitude of perceived surface indentation and (2) the spatiotemporal change of displacements in tactile stimuli are correlated with the asynchrony of simulated sensory neuron responses for the fishbone surface patterns. Based on these results, we propose that both the frequency and the asynchrony of temporal activity in sensory neurons could produce tactile form perception.

Project description:The development of the human brain is a complex and precisely regulated process that unfolds over a protracted period of time. Human-specific features of this process, especially the ways in which highly complex neural circuits of the cerebral cortex form, are likely to be important factors in the evolution of human specializations. However, in addition to giving us remarkable cognitive and motor abilities, the formation of intricate neural circuits may have also increased our susceptibility to psychiatric and neurodegenerative disorders. Furthermore, substantial evidence suggests that the symptoms and progression of many brain disorders are dramatically influenced by genetic and developmental processes that define regional cell phenotypes and connectivity. Sex differences also play an important role in brain development and function and are a risk factor for several brain disorders, such as autism spectrum disorders (ASD) and depression. Thus understanding the spatiotemporal dynamics and functional organization of the brain transcriptome is essential to teasing out the keys to human neurodevelopment, sexual dimorphism, and evolution as well as our increased susceptibility to certain brain disorders. Most transcriptome studies of the developing brain have been restricted to rodents, and those performed in humans and nonhuman primates have included relatively small sample sizes and predominantly focused on few regions or developmental time points. Because many prominent features of human brain development significantly diverge from those of well-characterized model organisms, the translation of knowledge across species is difficult, and it is likely that many underlying genetic processes have gone undetected. In this study, we have taken a genome-wide approach to analyze the human transcriptome at single-exon resolution with ~1.4 million exon-level probe sets in 16 brain regions from donors representing both sexes and multiple ethnicities, across pre and postnatal development, including adolescence, and adulthood. We also generated genome-wide genotype data for 2.5 million single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for each specimen. Our analyses of the data revealed several features of the human brain transcriptome: spatiotemporal expression dynamics of individual and functionally related groups of genes, differential exon usage, sex-specific expression patterns and exon usage, and organization of the transcriptome into functional modules. We also profiled developmental trajectories of genes important for neurobiological themes and genes associated with ASD and schizophrenia. Finally, we present associations between specific SNPs and gene expression levels in different brain regions across development. The dataset presented here provides research opportunities and a wealth of information not previously available to the scientific community.

Dataset Information

Distinct spatio-temporal and spectral brain patterns for different thermal stimuli perception.

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