# Developing 3D brain circuits on-a-chip for in vitro study of human cortico-striatal circuitry development and connectivity

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $195,933

## Abstract

Neural circuits are the underlying functional units of the human brain. By receiving glutamatergic (Glut)
inputs through cortico-striatal pathway, the striatum acts as an integrative hub to coordinate multiple higher-order
behavior and cognition. Dysfunction of the striatum and the associated neural circuitry development have been
implicated in the pathogenesis of multiple neurodevelopmental disorders e.g., schizophrenia. Despite the
functional importance, studies of such long-distance human cortical-subcortical network development and
connectivity have been significantly hindered due to lack of suitable microphysiological platforms. A major
unresolved hurdle in current human cells-based assays is that in vitro cultures weakly recapitulate the key biology
of neural microphysiological system, especially the long-distance projections in both two and three dimensions
(2D/3D). In this grant, we propose to fill this critical gap, by reconstructing human cortico-striatal circuits on-a-
chip to recapitulate and monitor long-range brain circuitry development and connectivity in vitro, in response to
PAR-20-082. We will reconstruct human cortico-striatal circuits by developing a novel 2D/3D microfluidic
microelectrode arrays (MEA) chip together with the co-culture of human pluripotent stem cells (hPSCs)-derived
region-specific neurons or brain organoids. Coupling with MEA allows us to monitor brain circuit dynamics in a
high-throughput manner. Further, our innovative implementation of microfluidic channels and arrays of surface
and probe electrodes in 3D configurations enables resemblance of 3D brain circuits for high-order brain function
studies. We hypothesize that human cortico-striatal circuits on a microfluidic-MEA chip can reconstitute striatal
synchrony, a key striatal physiology which is absent in unconnected striatal neurons, and the reconstructed 3D
neural circuits between cortical and striatal organoids can resemble high-order brain function e.g., brain waves
like in vivo. We will reconstruct human cortico-striatal circuits by using our novel microfluidic MEA chip together
with the co-culture of hPSCs-derived cortical and striatal neurons in Aim 1. We will monitor axon projections and
neural network dynamics during circuitry development and determine whether striatal synchrony is driven by
cortical Glut inputs by pharmacological manipulation of Glut transmission. In Aim 2, we will develop a 3D
microfluidic MEA chip with microchannels and microelectrodes integrated in 3D configurations. We will
reconstruct 3D cortico-striatal circuits by assembling cortical and striatal organoids on-a-chip. We expect 3D
brain circuits on-a-chip approach will resemble brain waves (a.k.a. large-scale neural oscillation) like human
brains. This proposal presents a novel approach to reconstitute well-defined long-range human circuit in vitro.
Our model can be benchmarked against existing human and rodent in vitro brain circuitry systems and exceed
state-of-the-art b...

## Key facts

- **NIH application ID:** 10878893
- **Project number:** 5R21MH132038-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Ziyuan Guo
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,933
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878893

## Citation

> US National Institutes of Health, RePORTER application 10878893, Developing 3D brain circuits on-a-chip for in vitro study of human cortico-striatal circuitry development and connectivity (5R21MH132038-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10878893. Licensed CC0.

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