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Thalamus-cortex interactions drive cell type-specific cortical development in human pluripotent stem cell-derived

Masatoshi Nishimura1, Shota Adachi1, Tomoki Kodera1

  • 1Laboratory of Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|November 17, 2025
PubMed
Summary
This summary is machine-generated.

The thalamus guides human cortical development by promoting gene expression, circuit formation, and cell-type-specific neural activity. This study used human thalamocortical assembloids to reveal these crucial thalamus-dependent developmental mechanisms.

Keywords:
cell typehuman brainneural assembloidneural circuitsynchronization

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Stem Cell Biology

Background:

  • The human embryonic brain is inaccessible, limiting understanding of thalamus-cortex interactions in cortical development.
  • Thalamic influence on human cortical circuit formation and function is largely unknown.

Purpose of the Study:

  • To investigate thalamus-dependent gene expression, circuit organization, and neural activity during human corticogenesis.
  • To model thalamus-cortex interactions using human thalamocortical assembloids (hThCAs).

Main Methods:

  • Generation of human cortical organoids (hCOs) and thalamic organoids from induced pluripotent stem cells.
  • Fusion of hCOs and thalamic organoids to create hThCAs, enabling study of reciprocal connections.
  • Transcriptomic, histological, and calcium imaging analyses to assess cortical development and neural activity.

Main Results:

  • hThCAs successfully reconstructed reciprocal thalamus-cortex axonal projections and synaptic connections.
  • Thalamic input accelerated cortical maturation, upregulating genes for axon development and subplate/cortical plate identity.
  • Wave-like neural activity originated in the thalamus and propagated to the cortex, inducing cell type-specific synchronous activity in hThCAs.

Conclusions:

  • Diffusible thalamic cues enhance progenitor expansion, while long-range input organizes cell type-specific synchronous activity.
  • Thalamus-dependent mechanisms drive the acquisition of mature, cell type-specific cortical phenotypes.
  • hThCAs provide a model to study how regional interactions shape human cortical development and circuit specification.