The human brain is distinguished by costly energetic demands and enhanced plasticity. This combination of factors underlies some of the most unique cognitive capacities of our species. The brain's capacity for learning is greatest during childhood and involves the formation and refinement of new neuronal connections. This process is driven by high rates of energy consumption. This research project will identify the genetic changes during evolution that brought about the human brain and explore the causal link between the development of brain plasticity and metabolism.

A major aim of this project involves charting the changes in the brain's energy utilization during the different maturational stages of humans. To accomplish this goal, the interdisciplinary team is using positron emission tomography scans of brain glucose consumption over the course of development from birth to adult stages. These results will be integrated with the patterns presented by RNA and protein data on the thousands of genes that are expressed at changing levels in different brain regions across the same developmental stages. Comparative data on the developmental expression of proteins and neuron morphology in great apes and macaque monkeys are also being obtained to determine whether the progression of molecular and cellular changes in human brain development are distinctively different from our close relatives. The investigators expect to find coordinated expression patterns in brain energetic and brain plasticity genes showing evidence that adaptive evolution occurred in their regulatory machinery during the origin of humans. The results should provide important clues about the organization and function of the molecular machinery that underpins the type of human brain plasticity that gives our species its exceptional capacity to incorporate experience and learning into the production of culture.

By focusing attention on brain energetic and brain plasticity genes that show adaptive evolution during recent human ancestry but are currently fixed across human populations, this project's focus on shared genes that define human cognitive abilities reinforces the conclusion of a common humanity. Thus the results of this project should be of interest to the general public and to scientists across a wide variety of disciplines, including anthropology, neuroscience, molecular evolution, bioenergetics, endocrinology and pediatrics. Experimental determination of total brain energetics during growth will enhance our ability to understand the age-specific tradeoffs that the acquisition of larger brains would have required during human evolutionary history, while also providing a new context in which to understand metabolic diseases such as diabetes. Furthermore, this project will advance research and education by providing training opportunities for individuals at the undergraduate, graduate and postdoctoral levels.

Project Report

This project has extensively studied human brain energetics and plasticity. Specifically, how the costly metabolic demands of the brain enhance the ability to remodel in response to molecular and environmental signals, i.e. learn. Within the first few years following birth, humans have an extended developmental period where the brain is more plastic compared to other primates. We found that glucose consumption (energy use) in the brain peaks at ~4-5 years of age, rather than at birth, when the relative brain size is largest, as was previously assumed. During this period, there is an inversely proportional slowing of the body growth rate. This suggests that the majority of glucose consumption is being devoted to brain development and provides an explanation for prolonged growth during childhood as compared to other primates. Examination of the chimpanzee neocortex synaptic density and dendritric morphology using immunohistochemistry, electron microscopy, and Golgi staining, found a pattern of extended neocortical development similar to humans. This suggests that the prolonged period of postnatal plasticity (learning) preceded the divergence of these two closely related species. We described structural differences in 13 genes following transcriptome sequencing of the gorilla brain planum temporale region compared to human. Four of these genes function in energy use and metabolism. This approach to transcript identification complements computational inferential methods. Using microarrays, we identified age-related gene expression patterns involved in the extended period of growth and plasticity. We found that patterns of expression in a subset of ~40 genes are significantly associated with age. Ten of these genes are associated with nervous system development and energy metabolism with three having regulatory regions having undergone adaptive evolution during recent human evolution. We found that children have more variable gene expression patterns than adults in the neocortex. This suggests brain plasticity in childhood is detectable at the level of gene expression. Moreover, there is an enrichment of variably expressed immune related genes in childhood. We localized the pattern of expression for some of these genes to microglia and neurons. We have characterized age-related expression profiles of long nonprotein-coding ribonucleic acids (lncRNAs), identifying eight lncRNA genes with distinct patterns that correspond with other age related trends involved in brain development. This analysis provides insight into the evolutionary genetics of this transcriptome component, which may have diverse regulatory functions. Epigenetic modifications during brain development may contribute to the development of, or resistance to, various mental disorders including posttraumatic stress disorder (PTSD). Comparative phylogenetic analysis of ~7000 CpG sites, potential targets of DNA methylation, in human, chimpanzee, orangutan, macaque, mouse, rat, cow, horse, dog, opossum, platypus, and chicken genomes was performed to trace the phylogenetic history of this potential epigenetic modification. We found that 93% of 203 CpG sites shown elsewhere to be associated with genes involved in PTSD, are shared with species other than humans. This indicates that DNA sequences associated with development of PTSD originated deep in evolutionary history; however, the topic is complicated because most people exposed to trauma do not develop PTSD. Examination of 15 CpG sites in four genes resulted in identification of differential methylation in a single CpG site following a traumatic event. Not only does the methylation state differ from pre- to post-trauma, it also differs between those that develop PTSD and those that do not. However, we found that PTSD symptom severity is not linked to this site. We employed novel approaches for data collection and analysis. Analyses involving human brain samples typically use postmortem brain samples. We were fortunate to have obtained in vivo brain samples collected during surgery. We have obtained a great deal of sequence and microarray data that has been made publicly available. This project has played an integral role in the career development of two graduate students, both of which earned their PhDs while making significant contributions to this research, as well as five post-doctoral researchers who have formed lasting collaborations and who have presented data at a number of National and International conferences. In addition, two graduate students and one summer student received training in computational methods and laboratory techniques by participating in portions of this project. Several of our publications have received media attention including our comparative work using the dolphin genome as well as our work establishing energy use in the brain during childhood and its link to slower body growth rate, providing evidence of a cross-discipline, high societal impact of the project as a whole. In total, this project has resulted in 28 publications in peer-reviewed journals, three book chapters, and participants funded on this project shared the results of their research at 19 National and International conferences. We look forward to continuing and expanding on this exciting area of research.

Agency
National Science Foundation (NSF)
Institute
Division of Behavioral and Cognitive Sciences (BCS)
Application #
0827546
Program Officer
Elizabeth Tran
Project Start
Project End
Budget Start
2008-09-15
Budget End
2014-08-31
Support Year
Fiscal Year
2008
Total Cost
$1,771,119
Indirect Cost
Name
Wayne State University
Department
Type
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202