# Unlocking the postnatal human brain using activity augmented organoids

> **NIH NIH DP2** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $1,437,896

## Abstract

PROJECT SUMMARY
Understanding the principles that govern the development of the enormously complex human brain is a
fundamental goal in biology. Human pluripotent stem cells have proven to be a powerful tool in this effort as an
active field of researchers have leveraged this technology to define the factors required to trigger endogenous
genetic programs that ultimately give rise to diverse specialized brain cell types. One of the most exciting
recent applications of this technology is the generation of tri-dimensional (3D) brain cell cultures or "organoids,"
which enable neural progenitors to proliferate, differentiate, and self-organize into complex microphysiological
systems. Brain organoids have been shown to develop structural, transcriptional, and functional similarities up
to the mid-to-late gestation human brain with remarkably little external input. Currently they represent the
closest cellular model to native human brain tissue available. While an enormously powerful system for probing
mechanisms of prenatal development, efforts to access postnatal stages with brain organoids have been
frustrating. Numerous attempts to improve upon the maturation state of brain organoids have proved to be
incremental, inconclusive, or poorly reproduced. As a result, brain organoid systems remain largely
inappropriate for modeling advanced stages of development (e.g., postnatal brain). At the same time, these
prior studies underscore the momentum and unmet need to improve models of the human brain. Given the
potential for fundamental and clinical advances, breaking this developmental wall should be considered a top
priority in neuroscience research. My core hypothesis is that a major reason brain organoids fail to develop
past late gestational time points is because they lack developmental guidance from significant sources of
inputs. The primary objective of this proposal is to unlock advanced stages of human brain organoid
development by applying a multipronged approach to replace missing exogenous neural inputs in brain
organoids with synthetic "virtual" inputs and to determine the effects such manipulations have on development,
with an emphasis on the specification of diverse neuronal cell types and acquisition of advanced states of
activity. We will try several methods in parallel that activate cells and circuits over extended periods of time and
in different biologically-relevant ways. To achieve these goals, we will also develop new methods to enable the
repeated measurement of diverse neuronal activities that change dramatically over the course of human brain
development. Finally, we will leverage our insights to study pathogenic mechanisms in a disease model of
severe developmental delay and epilepsy in which neurotransmission is impaired. The tools and approaches
established here may be readily adapted to cell culture models of other organ systems for which neuronal
inputs are important. If successful, this New Innovator proposal will lead to g...

## Key facts

- **NIH application ID:** 10473206
- **Project number:** 1DP2MH132944-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Christopher D Makinson
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,437,896
- **Award type:** 1
- **Project period:** 2022-08-05 → 2025-08-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473206

## Citation

> US National Institutes of Health, RePORTER application 10473206, Unlocking the postnatal human brain using activity augmented organoids (1DP2MH132944-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10473206. Licensed CC0.

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