The primary goal of this competitive grant renewal remains to identify genes and regulatory non-coding sequences that generate species-specific differences in development and organization of the cerebral cortex, particularly association areas, such as the prefrontal cortex. The prefrontal cortex is considered the crucible of human cognitive capacities with well-documented neuroanatomical connectivity and unique cellular features that are thought to be undermined in neuropsychiatric disorders and hijacked by drugs of abuse. We start with the assumption that basic principles of cortical development in all mammals are remarkably similar. It i, however, reasonable to expect important quantitative (e.g. the number of neurons, tempo and sequence of cellular events) and qualitative changes (e.g. the introduction of new neuronal subtypes, elaboration of synaptic connections and addition of functionally specialized cortical areas) since primates split from the rodent lineage about 100 million years ago. Thus, our strategy has been to study in parallel developmental events in the rodent (mouse), non-human primate (macaque) and human embryonic telencephalon by using the most advanced molecular and cell biological methods available, including comparative high-resolution mRNA-sequencing, in utero and ex utero gene manipulation (Loss or Gain of function) and heterologous transplantation of neural stem cells. We will complete and further augment our ongoing high-resolution mRNA-sequencing, confirm results by qRT-PCR, and gain further insight through bioinformatics network analysis in three species, which was initiated in the first cycle of this grant (Aim #1). Then, based on our discovery of several primate-specific cortical neuronal subtypes, we now plan to identify their genetic determinants by performing lineage analysis and use of ex-utero electroporation to overexpress and/or knockdown selected genes to examine their interactions and identify downstream transcription factors (Aim #2). Finally, we will proceed to the next stage f this research by identifying regulatory changes driving human and nonhuman primate-specific gene expression and binding sites on downstream targets followed by comparison of ChIP-seq data to differential gene expression (Aim #3). Although the proposed research is extremely time-consuming, logistically difficult and costly, it is realistic based on our published record and our progress, which shows that we succeeded to establish the unique facilities, master and modify essential methodology and already have obtained a substantial amount of feasibility data. We argue that abnormal genesis and initial formation of the evolutionarily novel, human- specific traits of the cerebral cortex ay be particularly vulnerable to genetic mutations and environmental influences each of which alone, or in combination, can give rise to elusive neuropsychiatric disorders and neuronal response to prenatal exposure to drugs of therapy and abuse.

Public Health Relevance

The proposed research is a continuation of the longitudinal studies of developmental molecular and cellular events that generate differences between cortical organization of humans, non-human primates and rodents. The expected set of unique data on the genetic origin and nature of species-specific differences are not onl of theoretical significance, but also of considerable clinical importance, as many of the newly evolved traits may be involved in neuropsychiatric disorders as well as in response to drugs used in therapy and abuse in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023999-09
Application #
9280884
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Wu, Da-Yu
Project Start
2007-12-01
Project End
2019-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
9
Fiscal Year
2017
Total Cost
$641,789
Indirect Cost
$232,066
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Hashimoto-Torii, Kazue; Sasaki, Masanori; Chang, Yu-Wen et al. (2018) Detection of local and remote cellular damage caused by spinal cord and peripheral nerve injury using a heat shock signaling reporter system. IBRO Rep 5:91-98
Memi, Fani; Zecevic, Nada; Radonji?, Nevena (2018) Multiple roles of Sonic Hedgehog in the developing human cortex are suggested by its widespread distribution. Brain Struct Funct 223:2361-2375
Bagasrawala, Inseyah; Memi, Fani; V Radonjic, Nevena et al. (2017) N-Methyl d-Aspartate Receptor Expression Patterns in the Human Fetal Cerebral Cortex. Cereb Cortex 27:5041-5053
Morozov, Yury M; Koch, Marco; Rakic, Pasko et al. (2017) Cannabinoid type 1 receptor-containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus. Mol Metab 6:374-381
Ortega, J Alberto; Sirois, Carissa L; Memi, Fani et al. (2017) Oxygen Levels Regulate the Development of Human Cortical Radial Glia Cells. Cereb Cortex 27:3736-3751
Ishii, Seiji; Torii, Masaaki; Son, Alexander I et al. (2017) Variations in brain defects result from cellular mosaicism in the activation of heat shock signalling. Nat Commun 8:15157
Torii, Masaaki; Sasaki, Masanori; Chang, Yu-Wen et al. (2017) Detection of vulnerable neurons damaged by environmental insults in utero. Proc Natl Acad Sci U S A 114:2367-2372
Bagasrawala, Inseyah; Zecevic, Nada; Radonji?, Nevena V (2016) N-Methyl D-Aspartate Receptor Antagonist Kynurenic Acid Affects Human Cortical Development. Front Neurosci 10:435
Morozov, Yury M; Sun, Yu-Yo; Kuan, Chia-Yi et al. (2016) Alteration of SLP2-like immunolabeling in mitochondria signifies early cellular damage in developing and adult mouse brain. Eur J Neurosci 43:245-57
Rash, Brian G; Ackman, James B; Rakic, Pasko (2016) Bidirectional radial Ca(2+) activity regulates neurogenesis and migration during early cortical column formation. Sci Adv 2:e1501733

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