Todd M. Preuss, Ph.D. - US grants

? DESCRIPTION (provided by applicant): Recent methodological advances in genomics and neuroscience have made it possible, for the first time, to determine how the human brain differs from that of other species. This research has revealed differences ranging from long-range neuronal connectivity to molecular changes, such as gene expression. Identifying these human-specific characteristics is vitally important for understanding common neurological and psychiatric diseases such as schizophrenia, autism, and Alzheimer's, diseases that have no definite counterparts in other primates and involve regions of the brain that underwent dramatic changes in size and internal organization in human evolution. However, the molecular mechanisms that underlie these diseases remain elusive. Our preliminary study of DNA methylation provides clues to these mechanisms, demonstrating that genes associated with neuropsychiatric disorders exhibit highly divergent DNA methylation patterns in human brains compared to non-human primate brains. Moreover, several human-specific gene co-expression networks that are strongly associated with neuropsychiatric disorders are enriched in genes that harbor human-specific DNA methylation signatures. In light of these observations, and of the emerging link between epigenomic markers and neuropsychiatric disorders, the systematic study of human epigenomic specializations promises to deepen our understanding of the molecular mechanisms that contribute to neuropsychiatric diseases and foster development of novel therapeutic interventions. The objectives of this project are to: (1) identify human-brain specific DNA methylation patterns; (2) elucidate the role of DNA methylation changes in the regulation of human-specific gene expression and co- expression networks; and (3) test the relevance of these epigenomic and transcriptomic changes in the context of neuropsychiatric diseases. We will examine two higher-order cortical regions from multiple human, chimpanzee, and macaque brains, drawing on the extensive collections of archival brain tissue available at the Yerkes National Primate Research Center. This comparative framework will enable us to pinpoint DNA methylation changes that accompanied changes in human brain structure and function. The link between human brain molecular specialization and human neuropsychiatric disorders will be verified by comparing control human brains to brains of schizophrenia patients, obtained from the Dallas Brain Collection (DBC) at UT Southwestern. The proposed studies of this multiple-PI and collaborator effort will leverage complementary and intersecting interests in epigenetics and evolution (Yi), comparative primate neurobiology (Preuss), and molecular neuroscience (Konopka). The application of our combined expertise to the analysis of the rich collection of DBC brain-disorder samples will promote discoveries of novel epigenetic mechanisms of neuropsychiatric disorders and provide the foundation for new insights and novel clinical approaches.

This project will investigate features of neural system organization that can be linked to altered social behavior, including reduced or increased aggression. Two species of canids, experimentally domesticated silver foxes (Vulpes vulpes) and domestic dogs (Canis familiaris), have been selectively bred by humans for altered social behavior. These behavioral changes occurred alongside a restricted set of genetic changes, creating an unparalleled opportunity to link the evolution of behavioral characteristics (phenotypes) to neural phenotypes. Recent technological advancements enable detailed, non-invasive studies of brain anatomy at relatively low cost. This project will take advantage of these innovations to create high-resolution three-dimensional (3D) brain maps using structural magnetic resonance imaging, diffusion tensor imaging, and digitized histology. Expected products of this research include: (1) identification of features of neural organization that are linked to reduced or increased sociality or aggression, expected to be generalizable to other species, (2) the production of online fox and dog brain atlases that will be publicly available as a research tool for the general scientific community, (3) training opportunities for young scientists, and (4) outreach efforts using blog and social media posts for the general public. Because dogs are a "common denominator" across various cultures, this research has a unique opportunity to be personally relevant and compelling to people from all walks of society, and to enhance public appreciation for science.

Both experimentally-domesticated foxes and domestic dogs are distinguished from their wild forebears by altered social approach-avoidance behavior. Previous research in rodents and primates, and the researchers' own preliminary data, allow for the formation of well-grounded hypotheses about neural adaptations that result from selection pressure on social approach-avoidance behavior. Specifically, this project will investigate limbic and fronto-limbic systems governing social behavior and response selection. In order to identify features of neural system organization associated with altered social behavior, whole-brain white and gray matter organization will be compared (a) between various breeds of domestic dogs, each tested for social approach-avoidance/aggression behavior, and (b) between strains of foxes bred for social avoidance behavior, which react aggressively to social contact, versus foxes bred for social approach behavior, which are tame and friendly like dogs, versus wild type foxes. Whole-brain MRI and DTI images will be collected using 3.0 and 9.4 Tesla MRI scanners. Histology images will be digitally scanned and aligned to MRI images. Analyses will include voxel-based morphometry, tract-based spatial statistics, probabilistic tractography, and k-means connectivity-based parcellation. The research will advance knowledge about how evolution modified brain organization in response to selection for social approach and avoidance.