Rapid metabolic evolution in human prefrontal cortex

Abstract

Human evolution is characterized by the rapid expansion of brain size and drastic increase in cognitive capabilities. It has long been suggested that these changes were accompanied by modifications of brain metabolism. Indeed, human-specific changes on gene expression or amino acid sequence were reported for a number of metabolic genes, but actual metabolite measurements in humans and apes have remained scarce. Here, we investigate concentrations of more than 100 metabolites in the prefrontal and cerebellar cortex in 49 humans, 11 chimpanzees, and 45 rhesus macaques of different ages using gas chromatography-mass spectrometry (GC-MS). We show that the brain metabolome undergoes substantial changes, both ontogenetically and evolutionarily: 88% of detected metabolites show significant concentration changes with age, whereas 77% of these metabolic changes differ significantly among species. Although overall metabolic divergence reflects phylogenetic relationships among species, we found a fourfold acceleration of metabolic changes in prefrontal cortex compared with cerebellum in the human lineage. These human-specific metabolic changes are paralleled by changes in expression patterns of the corresponding enzymes, and affect pathways involved in synaptic transmission, memory, and learning.H uman evolution is characterized by rapid expansion of brain size and increase in cognitive capabilities, leading to the emergence of unique and complex cognitive skills. These changes have long been associated with changes in brain metabolism, in particular with respect to increased energy demand (1). Large brains are metabolically costly. Thus, humans allocate approximately 20% of their total energy to the brain, compared with 11-13% for apes and 2-8% for other mammalian species (2). This increased metabolic demand has been associated with elevated expression of genes involved in neuronal functions and energy metabolism (3, 4). These changes may have been evolutionary advantageous, as indicated by signatures of positive selection reported for the amino acid changes, which occur in the mitochondrial electron-transport chain proteins, in anthropoid primates and humans, as well as elevated expression of the energy metabolism pathways in the human brain (5, 6). On the histological level, human brains show the largest density of glia cells relative to neurons in the prefrontal cortex, which provides an indirect indication of increased neuronal metabolic demand (7).Changes in brain metabolism are also implicated in neuropsychiatric disorders, such as schizophrenia, which affect some of the human-specific cognitive abilities (8, 9). Furthermore, direct measurements of 21 metabolites in the prefrontal cortex of adult human controls compared with human schizophrenia patients, chimpanzees, and rhesus macaques, carried out using proton NMR spectroscopy have shown significant overlap between human-specific evolutionary changes and metabolic differences between controls and schizophrenia patients (10). Notably, this study has identified not ...

Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques

“…ACTB (also known as beta actin) and TUBB3 (also known as Tubulin beta-III) were used as loading controls (bands at the predicted weight of 42 kDa and 55 kDa). (B,D) Protein expression level of SYP and DLG4 in PFC development measured as the integrated optical density (IOD) from the Western blots bands (gray bars) and measured using published mass-spectrometry-based protein time-series (red lines) (Fu et al 2011), as well as mRNA expression levels measured using microarrays in this study (blue line). The y-axes show the expression values across samples.…”

“…Notably, besides genes, this network includes a number of neurotransmitters. To test whether human-specific changes identified at the mRNA expression level are reflected at the neurotransmitter level, we used a published time-series where metabolite concentrations were measured in the PFC of 50 humans, 12 chimpanzees, and 49 rhesus macaques by gas chromatography and mass spectrometry (Fu et al 2011). Among six neurotransmitters detected in this experiment, three (glutamate, gamma-aminobutyric acid [GABA] and aspartate) showed human-specific concentration profiles across development.…”

“…We further measured protein expression of the two markers in the PFC of the three species by Western blot and by use of labelfree proteomics time-series data measured in the PFC of 12 humans, 12 chimpanzees, and 12 rhesus macaques ( Fig. 6; Fu et al 2011). Both the Western blot and proteomic results showed that expression levels of the two synaptic marker proteins peaked at 4-8 yr of age in the human PFC and within the first year of life in the chimpanzee and macaque PFC.…”

Synaptogenesis and development of pyramidal neuron dendritic morphology in the chimpanzee neocortex resembles humans

“…This interpretation is supported by evidence that the cortical regions that develop later in human ontogeny also underwent the greatest expansion during human brain evolution (18,19), suggesting that evolutionary selection to enlarge these regions was accompanied by a prolongation of their development. Among these regions, the prefrontal cortex, which shows particularly extended maturation in humans relative to macaques, has also been reported to exhibit uniquely human neuroanatomical and molecular specializations (20)(21)(22)(23)(24)(25). However, because macaques and humans shared a last common ancestor ∼25 million y ago, it is currently unclear whether features that distinguish human cortical development (i.e., extended period of synaptogenesis and maturational delay of prefrontal pyramidal neurons) are unique to our lineage, or if they evolved before the divergence of modern humans and more closely related great ape species, such as chimpanzees.…”

Epigenetic regulation of fetal brain development and neurocognitive outcome

“…How is it possible then that a near-optimal fetal environment can still have an impact on structural cortical development when the babies are genetically identical? The answer likely relates to evolutionary changes that have operated on the mechanisms regulating brain development (7,8) and that have arisen to fabricate the most complex part of the human brain, namely the cerebral cortex (9, 10), with complex cellular and laminar organization ( Fig. 1 A and B) and protracted development that is not complete until final maturation of the cortical circuitry in the third decade of life ( Fig.…”