# Sliced human neocortical organoids for modeling cortical laminar and columnar organization and function

> **NIH NIH RF1** · UNIVERSITY OF PENNSYLVANIA · 2020 · $1,733,095

## Abstract

SUMMARY
The modular organization of the cerebral cortex is defined by anatomically and functionally segregated cortical
columns, as well as layer-specific anatomical and functional connections that span multiple columns.
Dysregulation of the developmental processes governing cortical formation can result in dysmorphic features
that have been implicated in numerous neurological and psychiatric disorders. Understanding the basic
principles of cortical development has largely relied on animal models but recent advances in 3D organoid
cultures using human induced pluripotent stem cells (hiPSCs) have provided unprecedented opportunities to
study the intrinsic properties of human neural stem cells and neural progenitors that give rise to highly
organized structures in the central nervous system. To date, hiPSC-based cortical organoid models have
captured the molecular and cellular dynamics in early stages of fetal human brain development but diffusion
limits within the culture system have prevented modeling of later stages of human prenatal and perinatal
development. To better model these later stages of human brain development that give rise to laminar and
columnar organization, we have developed a sliced organoid culture platform that allows for continuous
neurogenesis and the emergence of hallmark features of human cortical anatomy. In this project we will further
characterize and validate this strategy (Aim 1) using single-cell RNA-sequencing, immunohistology,
electrophysiology and electron microscopy. We will also fuse dorsal and ventral forebrain organoids to allow for
the integration of constituent cell types in the cerebral cortex arising from distinct lineages. We will perform
anatomical and functional mapping of the circuitry using virus-based trans-synaptic tracing, calcium imaging,
and electrophysiology, as well as pharmacological and genetic perturbations to probe the functional
implications of laminar (Aim 2) and columnar (Aim 3) organization. Finally, we will perform clonal lineage-
tracing to test the hypothesis that functional cortical columns arise from distinct progenitors and radial
migration of daughter cells (Aim 3). In sum, these experiments will lead to a human stem cell-based model to
understand the human-specific molecular and cellular processes that govern cerebral cortex development and
the emergence of functional and anatomical specificity in cortical modules.

## Key facts

- **NIH application ID:** 10049693
- **Project number:** 1RF1MH123979-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Guo-li Ming
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,733,095
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049693

## Citation

> US National Institutes of Health, RePORTER application 10049693, Sliced human neocortical organoids for modeling cortical laminar and columnar organization and function (1RF1MH123979-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10049693. Licensed CC0.

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