The human frontal cortex displays an accelerated phenotypic evolution in structural and functional complexity, and arguably contributes more than any other brain region to our cognitive and behavioral attributes. Consequently, the frontal cortex represents the most critical region in which to study the molecular and cellular bases of many psychiatric disorders. Our preliminary studies show that distinct areas of the human frontal cortex are distinguished from other cortical regions by the combinatorial expression of specific genes during the second trimester of gestation, and that microarray expression profiling can be used to identify further candidate genes for patterning of these areas. Our main hypothesis is that the patterning and development of the frontal cortex are associated with changes in the activity of genes, from embryonic stages to adolescence, and that these differentially expressed genes play critical roles in the formation and refinement of frontal cortical circuits. To identify such genes, we will use whole- genome exon microarrays and state-of-the-art bioinformatics to analyze temporal and spatial patterns of gene expression and alternative mRNA splicing in the developing human brain. Our studies will encompass all crucial stages of prenatal and postnatal development, including the first trimester, during which cortical neurons are generated;the second trimester, when cortical connections are starting to form;and the late fetal and early postnatal periods, when connections are organized to create functional circuits. Just as importantly, our studies will survey a comprehensive selection of brain regions for high spatial resolution of gene expression mapping, especially within the frontal lobe.

Public Health Relevance

The identification of genes involved in formation and maturation of the frontal cortex as outlined in this proposal will help in understanding normal human brain development and plasticity as well as the neurobiological foundations of disorders such as schizophrenia, autism, and language impairment. This research may further facilitate the identification of disease genes and the development of new therapeutic strategies for the treatment of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH081896-05
Application #
8489339
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2009-08-20
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,025,802
Indirect Cost
$405,982
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Vasung, Lana; Raguz, Marina; Kostovic, Ivica et al. (2017) Spatiotemporal Relationship of Brain Pathways during Human Fetal Development Using High-Angular Resolution Diffusion MR Imaging and Histology. Front Neurosci 11:348
Lennington, Jessica B; Coppola, Gianfilippo; Kataoka-Sasaki, Yuko et al. (2016) Transcriptome Analysis of the Human Striatum in Tourette Syndrome. Biol Psychiatry 79:372-382
Shibata, Mikihito; Gulden, Forrest O; Sestan, Nenad (2015) From trans to cis: transcriptional regulatory networks in neocortical development. Trends Genet 31:77-87
Ouyang, Austin; Jeon, Tina; Sunkin, Susan M et al. (2015) Spatial mapping of structural and connectional imaging data for the developing human brain with diffusion tensor imaging. Methods 73:27-37
Ercan-Sencicek, A Gulhan; Jambi, Samira; Franjic, Daniel et al. (2015) Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans. Eur J Hum Genet 23:165-72
Lin, Zhixiang; Sanders, Stephan J; Li, Mingfeng et al. (2015) A MARKOV RANDOM FIELD-BASED APPROACH TO CHARACTERIZING HUMAN BRAIN DEVELOPMENT USING SPATIAL-TEMPORAL TRANSCRIPTOME DATA. Ann Appl Stat 9:429-451
Caglayan, Ahmet Okay; Baranoski, Jacob F; Aktar, Fesih et al. (2014) Brain malformations associated with Knobloch syndrome--review of literature, expanding clinical spectrum, and identification of novel mutations. Pediatr Neurol 51:806-813.e8
Zhu, Ying; Li, Mingfeng; Sousa, André M M et al. (2014) XSAnno: a framework for building ortholog models in cross-species transcriptome comparisons. BMC Genomics 15:343
Carlyle, Becky C; Nairn, Angus C; Wang, Min et al. (2014) cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. Proc Natl Acad Sci U S A 111:5036-41
Bae, Byoung-Il; Tietjen, Ian; Atabay, Kutay D et al. (2014) Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning. Science 343:764-8

Showing the most recent 10 out of 30 publications