Funded Grants

Evolutionary specializations and development of the human frontal cortex

Discovering the basis for the unique properties of the human brain is a major goal of modern science. Yet many fundamental gaps remain in our knowledge of human brain evolution, development and organization. How is it that our closest evolutionary relatives, chimpanzees, share 98.7% of our DNA and yet lack the higher order cognition and spoken language that make us human? At least in part, the answer is likely to lie in the frontal cortex, which, more than any other region of the human brain, defines us as a species (Kostovic, 1990; Goldman-Rakic, 1995; Fuster, 1997).

Our recent analysis has uncovered that distinct areas of the developing human frontal cortex can be distinguished from other cortical regions by transient, lasting, and combinatorial expression of genes. In addition, this initial study also revealed that the complexity of gene expression within different areas of the frontal cortex is more complex that previously thought. The majority of these human genes has not been previously characterized and encode a variety of proteins ranging from transcription factors, axon guidance molecules, ion channels, synaptic transmission proteins, and metabolic proteins. Furthermore, preliminary analysis revealed that majority of the genes are not expressed at detectable levels in the frontal cortex of the developing and adult mouse, suggesting that the higher frontal expression of these genes may be unique to humans and other mammals with highly developed and complex frontal/prefrontal cortex.

The proposed study aims to examine how our frontal cortex differs from other closely related species at the molecular and structural level during critical phases of cellular and cognitive development. We hypothesize that some of these genes will also be candidate genes that underlie the functional specialization of the human frontal cortex. Our approach is unique in the sense that we propose to analyze differences in gene expression in the developing frontal cortex of human, non-human primates, and mouse. We have chosen to specifically address developmental changes because major structural and connectivity differences between human and non-human primate brains likely arose as a result of differences during development. Thus, comparative functional genomics studies that examine developmental stages are much more likely to yield results of evolutionary significance than studies of adult brains. Once the candidate genes are identified, their expression and function in neurons of the developing frontal cortex will also be examined. We will selectively target those candidate genes that are expressed by the projection or pyramidal neurons, which occupy a central position in all cortical circuits. They constitute the sole output and the largest input system of the cortex, as well as represent the major target of projections from other brain regions.