Major changes in the structure, functional complexity, and size of the brain led to the cognitive abilities of extant humans. Adaptive changes in early hominoid evolution likely laid the foundation for more recent changes on the human lineage. We will use an integrated approach – bridging cognitive neuroscience and molecular evolution – to identify and characterize recent molecular innovations involved in cognitive abilities unique to humans. We will achieve this by comparing humans and apes using the following three complementary strategies: 1) We will identify “human cognition” genes that originated recently on the primate lineage by gene duplication and show signatures of adaptive evolution (genome level). 2) Comparative expression analyses between human and ape brains will shed light on differences that evolved at the transcriptome and proteome levels. We will distinguish between neutral and selective expression changes. 3) We will pinpoint genes associated with higher cognitive function in humans by a comparative study of a complex neurocognitive disorder (schizophrenia) and normal controls (transcript level, proteome level). The functional relevance of changes in candidate genes derived from approaches 1-3 will be elucidated using transgenic mice. We will cross different transgenic mouse lines to combine candidate genes with the long-term goal to reconstruct adaptive changes that led to the emergence of neurological functions that form the basis of aspects of human cognitive abilities. Our approach and the groups involved provide a highly interdisciplinary framework (molecular evolution, bioinformatics, molecular neuroscience, and clinical psychiatry). Thus, it reflects the spirit of the program and is likely to foster to high-quality research that is likely to attract wide interest in society at large.