One of the most important functional specializations of the human cerebral cortex is that of the perisylvian cortex and the other subcortical regions with which it is connected. These regions are involved in human higher cognition and behavior, including language. Surprisingly little is known about the biological processes that underlie the development of perisylvian cortical regions in humans, their asymmetry, and presence in other potential model organisms. This proposal is an extension of the Pi's Merit Award, in which we have worked successfully to identify key genes involved in human higher cognition by virtue of their asymmetric expression or enrichment in perisylvian cortex, including CNTNAP2 and other extracellular adhesion molecules that are also related to neuropsychlatric disease. In parallel, we have developed an entirely novel approach to elucidate the complex structure of the transcriptome, and successfully applied this to adult human brain. We propose to apply these methods in conjunction with NextGen sequencing to perform digital gene expression in anatomically defined interconnected human language cortex and its homologues in nonhuman primates. This work will put gene products in a clear functional context, enabling characterization of the set of genes most central to this aspect of human brain organization, rather than relying on less structured means of prioritizing genes for follow-up. Putative differentially expressed genes and key hub genes within the networks will be confirmed using qRT-PCR and In Situ hybridization. Cross species comparisons, in mice and non-human primate species will continue to be performed to investigate the evolutionary conservation of genes that are central hubs of the modules that are enriched in languagerelated cortex in adults, or asymmetrically expressed in the developing human cerebral cortex. This will provide insight into the potential role of these genes in the development and evolution of language and related human cognitive specializations and the relationship of these regions in lower species to homologous human structures. All of this will clearly inform the study of human neurodevelopmental disorders that are related to speech and language, such as autism or schizoprenia, as we and others have already demonstrated, and provide proper context for the use of animal models for these disorders.

Public Health Relevance

This work will identify some of the critical pathways involved in human higher cognitive functions, such as language and social cognition. This has great relevance to our understanding of neurodevelopmental disorders such as autism and schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Stein, Jason L; de la Torre-Ubieta, Luis; Tian, Yuan et al. (2014) A quantitative framework to evaluate modeling of cortical development by neural stem cells. Neuron 83:69-86
Geschwind, Daniel H; Rakic, Pasko (2013) Cortical evolution: judge the brain by its cover. Neuron 80:633-47
Parikshak, Neelroop N; Luo, Rui; Zhang, Alice et al. (2013) Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155:1008-21
Konopka, G; Wexler, E; Rosen, E et al. (2012) Modeling the functional genomics of autism using human neurons. Mol Psychiatry 17:202-14
Bernard, Amy; Lubbers, Laura S; Tanis, Keith Q et al. (2012) Transcriptional architecture of the primate neocortex. Neuron 73:1083-99
Voineagu, Irina; Wang, Xinchen; Johnston, Patrick et al. (2011) Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474:380-4
Mukamel, Zohar; Konopka, Genevieve; Wexler, Eric et al. (2011) Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk. J Neurosci 31:11437-42
Geschwind, Daniel H (2011) Genetics of autism spectrum disorders. Trends Cogn Sci 15:409-16
Konopka, Genevieve; Geschwind, Daniel H (2010) Human brain evolution: harnessing the genomics (r)evolution to link genes, cognition, and behavior. Neuron 68:231-44
Abrahams, Brett S; Geschwind, Daniel H (2010) Connecting genes to brain in the autism spectrum disorders. Arch Neurol 67:395-9

Showing the most recent 10 out of 20 publications