# Origin of Cortical Species-specific Distinctions

> **NIH NIH R37** · YALE UNIVERSITY · 2021 · $750,994

## Abstract

Project Summary
 The principal goal of this new grant cycle is to uncover the origin and nature of uniqueness
of the cerebral cortex of the human, and non-human primates (NHP), particularly the association
areas such as the prefrontal cortex, that underlie the highest level of our cognitive capacities
and are thought to be undermined in neuropsychiatric disorders including drug abuse. Although
basic principles of cortical development in all mammals are similar, there are important
quantitative and qualitative evolutionary innovations that were introduced in primates since their
split from the rodent lineage about 60 million years ago. Thus, our strategy will be to study in
parallel the developmental events in the NHP (macaque) and human skin-cell-derived iPSC
cortex-mimicking cultures by using the most advanced molecular and cell biological methods
available, including comparative high resolution single-cell mRNA sequencing, advanced
confocal and light-sheet imaging, and in utero and ex utero functional manipulation of neural
stem cells. We will complete and further augment our ongoing high-resolution single-cell mRNA
sequencing and gain insight through bioinformatic gene network analysis in three species:
macaque, human, and mouse. We will first investigate the genetic determinants of primate-
specific stem cell subtypes, using gene clustering analysis at the transcriptome level, and
determine how this impacts the cortical expansion process through functional studies (Aim #1).
As a next step, we will examine genes and regulatory elements involved in emergence of areal
and laminar specific distinction in monkey embryonic cortex and human iPSC 3D cortex
mimicking cultures, generated from skin fibroblasts, to identify unique signatures of human and
nonhuman primate-specific gene expression in evolutionarily new cortical areas such as
prefrontal cortex (Aim #2). Finally, we will examine how cortical neuropil and the growth and
patterning of white matter contribute to cortical area differences and drive primate-specific
cortical gyrification (Aim #3). Although the proposed research is time-consuming, logistically
difficult and costly, it is essential if we are to understand the biological basis of our humanity and
the pathogenesis of some high order cognitive disorders, including drug abuse. We have
established primate precisely timed breeding facilities at Yale, as well as mastered and modified
essential methodology and already have obtained a substantial amount of high impact
information which alone, or in combination, can give insight into elusive neuropsychiatric
disorders and neuronal susceptibility to prenatal exposure to drugs of therapy and abuse.

## Key facts

- **NIH application ID:** 10135898
- **Project number:** 5R37DA023999-12
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** PASKO RAKIC
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $750,994
- **Award type:** 5
- **Project period:** 2008-09-30 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135898

## Citation

> US National Institutes of Health, RePORTER application 10135898, Origin of Cortical Species-specific Distinctions (5R37DA023999-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10135898. Licensed CC0.

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