“He who thus considers things in their first growth and origin … will obtain the clearest view of them.” (Politics by Aristotle, 350 BCE)

In the last several years, our understanding of the biological causes of neurodevelopmental disorders (NDDs) has accelerated dramatically, driven by advances in human genomics. However, finding cures has been challenging, largely because studies of postmortem human brain provide only a static view of neurodevelopmental events, and to date, brain imaging approaches have allowed for a low-resolution understanding of brain functionality. In addition, large structural rearrangements and polygenic states associated with NDDs pathogenesis cannot be engineered into animal models, and therapeutics that show promise in commonly used research animals fail to reproduce the predicted beneficial effects when tested in humans with mental disease.

Unlocking the incredible complexity of the human brain is only possible when its emergent properties can be direcly perturbed in experimental systems amenable to manipulation, phenotyping and high-throughput analysis.

The goal of our lab is to improve emerging brain-region specific models of the human brain, including pluripotent stem cell derived 3D organoids and human chimeric mice, and to combine them with large-scale single-cell omics technologies to:

  1. study how cell-cell interactions affect the establishment of functional circuits during human brain development;
  2. investigate how perturbation of neuronal activity affects cell-cell and cell-extracellular matrix interactions in distinct neural subtypes;
  3. understand how cell-type-specific cellular programs that control activity-dependent cell-cell interactions are disrupted in NDDs; and
  4. explore the potential neurodevelopmental origins of neurodegenerative disorders focusing on the selective vulnerability of distinct neural cell types.
Cryosection of a 2 month human brain organoid fixed one week after BrdU administration. BrdU green, Ki67 pink counterstained with DAPI. (Image by Giorgia Quadrato)