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Brain Organization comparison between Human and Nonhuman Primates
Science 24 Nov 2017: Vol. 358, Issue 6366, pp. 1027-1032 Molecular and cellular reorganization of neural circuits in the human lineage André M. M. Sousa, et.al. Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA. Department of Anthropology and School of Biomedical Sciences, Kent State University, Kent, OH, USA. Program in Computational Biology and Bioinformatics, Departments of Molecular Biophysics and Biochemistry and Computer Science, Yale University, New Haven, CT, USA. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa, Italy. Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, New Haven, CT, USA. Departments of Pharmacology and Biochemistry and Molecular Biology, Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA. Institut de Biologia Evolutiva, Consejo Superior de Investigaciones Científicas, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, Barcelona, Catalonia, Spain. Alamogordo Primate Facility, Holloman Air Force Base, NM, USA. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA. Neuroscience Program, Michigan State University, East Lansing, MI, USA. Department of Genetics, Yale School of Medicine, New Haven, CT, USA. Howard Hughes Medical Institute, Yale University, New Haven, CT, USA. Laboratory of Human Genetics and Genomics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Yale Center for Genomic Analysis, Yale School of Medicine, New Haven, CT, USA. Department of Psychiatry and Langley Porter Psychiatric Institute, University of California, San Francisco, San Francisco, CA, USA. Allen Institute for Brain Science, Seattle, WA, USA. Department of Psychiatry and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain. Centro Nacional de Analisis Genomico, Barcelona, Catalonia, Spain. Department of Anthropology, The George Washington University, Washington, DC, USA. Program in Cellular Neuroscience, Neurodegeneration, and Repair and Yale Child Study Center, Yale School of Medicine, New Haven, CT, USA. [paraphrase] To better understand the molecular and cellular differences in brain organization between human and nonhuman primates, we performed transcriptome sequencing of 16 regions of adult human, chimpanzee, and macaque brains. Integration with human single-cell transcriptomic data revealed global, regional, and cell-type–specific species expression differences in genes representing distinct functional categories. We validated and further characterized the human specificity of genes enriched in distinct cell types through histological and functional analyses, including rare subpallial-derived interneurons expressing dopamine biosynthesis genes enriched in the human striatum and absent in the nonhuman African ape neocortex. Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease. Although the human brain is about three times as large as those of our closest living relatives, the nonhuman African great apes (chimpanzee, bonobo, and gorilla), increased size and neural cell counts alone fail to explain its characteristic functionalities. The brain has also undergone microstructural, connectional, and molecular changes in the human lineage, changes likely mediated by divergent spatiotemporal gene expression. Here, we profiled the mRNA and small noncoding RNA transcriptomes of 16 adult brain regions involved in higher-order cognition and behavior of human (H) (Homo sapiens); chimpanzee (C) (Pan troglodytes), our closest extant relative; and rhesus macaque (M) (Macaca mulatta), a commonly studied nonhuman primate. We integrated these profiles with single-cell transcriptomic data from the human brain, histological data from adult and developmental brains of these and other primates (bonobo, gorilla, orangutan, pig-tailed macaque, baboon, and capuchin), and multimodal data from human primary and induced pluripotent stem cell (iPSC)–derived neural cultures. In doing so, we have investigated the evolutionary, cellular, and developmental framework that makes the human brain unique. We generated transcriptional profiles of 247 tissue samples representing hippocampus, amygdala, striatum, mediodorsal nucleus of thalamus, cerebellar cortex, and 11 areas of the neocortex from six humans, five chimpanzees, and five macaques. To minimize biases in comparative transcriptome analyses, we used the XSAnno pipeline to create a common annotation set of 26,514 orthologous mRNAs, including 16,531 protein-coding genes and 3253 long intergenic noncoding (linc) RNAs. We reannotated all chimpanzee and macaque microRNAs (miRNAs) based on annotated human precursor sequences. Assessment of global correlation between regions and species by unsupervised hierarchical clustering revealed clustering of the miRNA data set primarily by species. In contrast, cerebellar mRNA samples from all species formed a distinct cluster separated from other brain regions, indicating that the various cerebella are more similar to each other than to other brain regions within the same species. Within each species, hierarchical clustering of mRNA or miRNA data sets were calculated based on pairwise correlation matrices of brain regions and confirmed by multiscale bootstrap resampling and intraspecies genetic distance measurements. This revealed a similar pattern of interregional hierarchical clustering, reflecting known topographical proximity and functional overlap. Our analysis of transcriptomic data revealed global, regional, and cell-type–specific species expression differences in protein-coding and noncoding genes. Genes with human-specific differential expression patterns include those encoding transcription factors, ion channels, and neurotransmitter biosynthesis enzymes and receptors. Changes in the regional and cellular expression patterns of these genes could affect function of neural circuits by altering transcription of other genes, intrinsic electrophysiological properties, or synaptic transmission. Neuromodulatory systems show broad expression differences between species. One example includes a rare and molecularly heterogeneous subpopulation of interneurons expressing dopamine biosynthesis genes TH and DDC, which are enriched in the human striatum and neocortex as compared with nonhuman African apes. These cells originate in the subpallial ganglionic eminences and likely migrate into the striatum and neocortex during late prenatal and early postnatal development. We also observed an increase in TH expression during postnatal development and young adulthood, suggesting that TH expression and/or the migration of TH+ interneurons may be dynamically regulated and protracted. The absence of TH+ interneurons from the cortex of nonhuman African apes, and their decreased density in the striatum of nonhuman primates, may result from several mechanisms. First, these cells could have been lost due to genetic disruptions affecting interneuron migration, differentiation, or survival. These disruptions may have occurred in the common ancestor of African apes before being reversed in the human lineage (homoplasy) or, in a less-likely scenario, may have occurred independently in the Gorilla and Pan lineages. A second possibility is that these interneurons are present in the nonhuman African ape cortex but do not express TH, do so only transiently, or die before our ability to detect them. Commensurate with this possibility, the molecular profile of mouse cortical SST-positive interneurons is malleable, and sensory stimuli can cause a switch from the production of TH and dopamine to SST in rat hypothalamic interneurons. Finally, TH+ interneurons of nonhuman African apes may have lost their ability to deviate to the cortex from the rostral migratory stream. Indeed, some human TH+ interneurons migrating via the rostral migratory stream to the olfactory bulb divert to the prefrontal cortex, and our observation of SP8+/TH+ coexpression is consistent with a rostral migratory stream origin. However, other routes of migration are possible, as suggested by our observation of TH+ interneurons in the external capsule of newborn human brain. Neuromodulatory transmitters, in particular dopamine, are involved in distinctly human aspects of cognition and behavior, such as working memory, reasoning, reflective exploratory behavior, and overall intelligence. By analyzing brain regions involved in these processes, we show that evolutionary modifications in gene expression and the distribution of neurons associated with neuromodulatory systems may underlie cognitive and behavioral differences between species. Cortical TH+ interneurons are depleted in patients affected by Parkinson’s disease or dementia with Lewy bodies, and these alterations may contribute to cognitive impairments. As these results demonstrate, the resource we present here may aid future studies on the evolution and neuroscience of primates. [end of paraphrase]
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