Discovering the rules of neocortical development

We make and use advanced molecular and imaging tools to understand how the cerebral cortex is built. Using this information, we hope to uncover the causes of intellectual disability in neurodevelopmental disorders.

How does the brain work?

Our perspective is that the best way to figure out how the brain works, and how to possibly repair it when it doesn’t work, is to understand how it comes together in the first place. If the playbook followed during early brain development can be learned, if we can determine how genetic, cellular and environmental cues combine to produce the functional circuits that govern brain function, we will have the tools to understand how our cognitive abilities evolved and how they might be rescued when affected by neurodevelopmental or neurodegenerative changes.

Our Projects:

Neurogenesis and neural precursor diversity

The neurons and glial cells of the brain are all produced from proliferative stem and progenitor cells that arise in different locations and at different times in development. In the cerebral cortex, most cell production occurs prenatally from neural precursors that line the lateral ventricles. Recent advances have enabled the study of these cells at single cell resolution, and this has uncovered the existence of several different types of precursor cells all generating neurons at the same time during development. Our goal is to develop molecular tools to visualize and follow these precursor groups over time to test the hypothesis that their variety is key for generating the cellular and functional complexity of the mammalian cerebral cortex.  

One approach we have used is to classify cells in the developing brain with single cell RNA sequencing (scRNA-Seq) and to combine cells with similar gene expression profiles into groups.

TSNE plot of scRNA-Seq data from fetal mouse neocortex

The gene expression signatures of these cells are then used to design genetic tools (plasmids) in the lab that will specifically target those same cells in vivo. This strategy allows us to confirm that the cells in different scRNA-Seq groups are indeed separate types of cells in the brain. Because the plasmids also express a fluorescent marker protein that labels both the cells and their progeny, we can follow their lineages over time and use electrophysiological, anatomical and optogenetic methods to discover how the neurons they produce become functional members of cortical circuits.   

Down syndrome and brain development

Down syndrome (DS), or trisomy 21, is caused by triplication of human chromosome 21 and occurs in ~1:700 live births. People with DS experience a wide range of changes in their bodies including cognitive, motor, digestive, cardiac, sleep and speech deficits. While some people with Down syndrome lead happy and active lives, others can be severely disabled. We are very interested in the underlying causes of this diversity and hope that by better understanding how trisomy 21 influences brain development – both before and after birth – approaches can be developed to improve the quality of life and independence for people with DS.

Our work on this subject uses experimental platforms ranging from mouse models, human stem cell cultures and samples from human postmortem brains. Thus far, our work has discovered that neural precursor proliferation is altered in DS and that some neurons don’t survive well compared to typically developing brains. Experiments using human brain samples and mouse models, conducted with the Sestan Lab at Yale University, suggested that oligodendrocytes, the glial cells that makes the insulating myelin or white matter in the brain, are not able to mature properly and that this reduces the speed at which neuronal signals are transmitted in the brain.  We are testing this hypothesis in mouse models and we are using induced pluripotent stem cells (hiPSCs) from people with DS to more closely examine human oligodendrocytes with trisomy 21. Once the mechanisms underlying the slower maturation of oligodendrocytes are found, our goal is to use pharmacological tools to rescue this deficit. Working with clinical colleagues at Children’s National, we are working to generate multiple lines of trisomy 21 iPSCs from children across the range of cognitive abilities to uncover the cellular and molecular reasons for their differences in intellectual functioning.