In order to understand how the brain works, it is crucial to better understand its complexity and more specifically: how that complexity arises. One way to achieve this goal is to study complexity in terms of its core components: neuronal cell types and the rules that govern how individual cell types come together during development in the process of brain assembly. The neocortex is the brain structure involved in higher level executive function and decision-making. It is composed of two main cell classes: 1) long range principal cells that have stereotyped projections depending on the cortical layer in which they reside as well as 2) locally-projecting inhibitory interneurons distributed throughout the cortex. This second class of cell, cortical interneurons is perhaps the most diverse neuronal population in the entire brain and plays a vital role in local information processing and the computational power of the brain as a whole.
My lab is interested in how different cortical interneuron subtypes arise, migrate into the cortex, and wire themselves into the cortex. We are also interested in how defects in specific interneuron subtypes can contribute to disease, especially mental illness. Our general approach is to start with undifferentiated stem cells that we convert into interneurons and then introduce them into embryonic mouse brain so that they can recapitulate normal development and maturation. This approach allows us the flexibility to a priori alter individual molecular components – gain-of-function as well as genetic loss-of-function by CRISPR – in order to study their downstream effects on interneuron microcircuit assembly.
Specifically, we are interested in understanding the molecular underpinnings of microcircuit assembly during three distinct phases developmentally: i) lineage specification that produces broad subclasses of interneurons; ii) arealization – interneurons arise from a distal progenitor region and through a poorly understood process, migrate to different regions of the cortex and settle throughout the cortical layers; iii) synaptic specificity – interneuron subtypes form characteristic synapses onto other cortical neurons in order to establish stereotyped microcircuits throughout the brain. As we gain a better understanding of how different interneurons develop and integrate, we will be able to produce highly specific interneuron subtypes from stem cells, which we can use to model and study neuropsychiatric disease mechanisms.