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Synapses are involved in the communication of information from one neuron to another. However, a systematic analysis of synapse density in the neocortex from a diversity of species is lacking, limiting what can be understood about the evolution of this fundamental aspect of brain structure. To address this, we quantified synapse density in supragranular layers II–III and infragranular layers V–VI from primary visual cortex and inferior temporal cortex in a sample of 25 species of primates, including humans. We found that synapse densities were relatively constant across these levels of the cortical visual processing hierarchy and did not significantly differ with brain mass, varying by only 1.9-fold across species. We also found that neuron densities decreased in relation to brain enlargement. Consequently, these data show that the number of synapses per neuron significantly rises as a function of brain expansion in these neocortical areas of primates. Humans displayed the highest number of synapses per neuron, but these values were generally within expectations based on brain size. The metabolic and biophysical constraints that regulate uniformity of synapse density, therefore, likely underlie a key principle of neuronal connectivity scaling in primate neocortical evolution.

The adaptive significance of human brain evolution has been frequently studied through comparisons with other primates. However, the evolution of increased brain size is not restricted to the human lineage but is a general characteristic of primate evolution. Whether or not these independent episodes of increased brain size share a common genetic basis is unclear. We sequenced and de novo assembled the transcriptome from the neocortical tissue of the most highly encephalized nonhuman primate, the tufted capuchin monkey ($\textit{Cebus apella}$). Using this novel data set, we conducted a genome-wide analysis of orthologous brain-expressed protein coding genes to identify evidence of conserved gene-phenotype associations and species-specific adaptations during three independent episodes of brain size increase. We identify a greater number of genes associated with either total brain mass or relative brain size across these six species than show species-specific accelerated rates of evolution in individual large-brained lineages. We test the robustness of these associations in an expanded data set of 13 species, through permutation tests and by analyzing how genome-wide patterns of substitution co-vary with brain size. Many of the genes targeted by selection during brain expansion have glutamatergic functions or roles in cell cycle dynamics. We also identify accelerated evolution in a number of individual capuchin genes whose human orthologs are associated with human neuropsychiatric disorders. These findings demonstrate the value of phenotypically informed genome analyses, and suggest at least some aspects of human brain evolution have occurred through conserved gene-phenotype associations. Understanding these commonalities is essential for distinguishing human-specific selection events from general trends in brain evolution.