Little is known about how the human brain differs from that of our closest relatives. To investigate the genetic basis of human specializations in brain organization and cognition, we compared gene expression profiles for the cerebral cortex of humans, chimpanzees, and rhesus macaques by using several independent techniques. We identified 169 genes that exhibited expression differences between human and chimpanzee cortex, and 91 were ascribed to the human lineage by using macaques as an outgroup. Surprisingly, most differences between the brains of humans and non-human primates involved up-regulation, with Ϸ90% of the genes being more highly expressed in humans. By contrast, in the comparison of human and chimpanzee heart and liver, the numbers of up-and down-regulated genes were nearly identical. Our results indicate that the human brain displays a distinctive pattern of gene expression relative to non-human primates, with higher expression levels for many genes belonging to a wide variety of functional classes. The increased expression of these genes could provide the basis for extensive modifications of cerebral physiology and function in humans and suggests that the human brain is characterized by elevated levels of neuronal activity.

Evidence from comparative studies of gene expression and evolution suggest that human neocortical neurons may be characterized by unusually high levels of energy metabolism. The current study examined whether there is a disproportionate increase in glial cell density in the human frontal cortex in comparison with other anthropoid primate species (New World monkeys, Old World monkeys, and hominoids) to support greater metabolic demands. Among 18 species of anthropoids, humans displayed the greatest departure from allometric scaling expectations for the density of glia relative to neurons in layer II͞III of dorsolateral prefrontal cortex (area 9L). However, the human glia-neuron ratio in this prefrontal region did not differ significantly from allometric predictions based on brain size. Further analyses of glia-neuron ratios across frontal areas 4, 9L, 32, and 44 in a sample of humans, chimpanzees, and macaque monkeys showed that regions involved in specialized human cognitive functions, such as ''theory of mind'' (area 32) and language (area 44) have not evolved differentially higher requirements for metabolic support. Taken together, these findings suggest that greater metabolic consumption of human neocortical neurons relates to the energetic costs of maintaining expansive dendritic arbors and long-range projecting axons in the context of an enlarged brain.allometry ͉ human evolution ͉ prefrontal cortex ͉ brain energy metabolism ͉ language evolution H umans are distinguished from other primates by a dramatically enlarged neocortex and the elaboration of cognitive capacities that have culminated in the evolution of language, technological innovation, and complex social behavior. Expansion of the human brain entails high metabolic costs (1). Although the human brain comprises only Ϸ2% of body mass, it captures Ϸ20% of the body's total glucose utilization (2). At the same time, because the metabolic rate per gram of neural tissue generally decreases with larger brain size, the human brain is more energetically efficient than that in smaller-brained primate species (3). Despite this evidence for relatively lower mass-specific brain metabolism in humans, recent microarray studies have shown that genes involved in neuronal signaling and energy production are up-regulated in the human neocortex compared with chimpanzees and other great apes (4, 5). Furthermore, evidence for positive selection in the human lineage for genes that encode components of the mitochondrial electrontransport chain suggests that there has been evolutionary pressure for high rates of aerobic energy consumption in metabolically active cells, such as neurons (6). Taken collectively, these findings suggest that neuronal activity level and energy expenditure per neuron have become enhanced in human evolution, even as mass-specific rates of brain metabolism declined. This pattern is consistent with a model that predicts that, with increases in brain size, a progressively smaller fraction of the total neuron population may be concurrently active, lea...

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