Exploring cortical inhibitory circuit design in the human brain

PROJECT SUMMARY A basic understanding of human neural circuit design is essential to grasping neurological disease processes and developing targeted brain therapies. However, due to a shortfall of human experimental platforms, scientists have investigated neural circuits in model systems that lack the constituent cell types and

organizational principles of the human brain. As a result, we are left with a poor understanding of how human neural circuits are configured, impacted by disease processes, and targeted for therapeutic purposes. Here our laboratory will pursue innovative research approaches that specifically advance our knowledge of human

neural circuits. Using live brain specimens collected from neurosurgical procedures and CellREADR, a novel genetic tool for cellular access, we will investigate the cellular properties and circuit functional roles of human cortical interneurons. Cortical interneurons are the principal inhibitory cellular elements of neural circuits in

the cerebral cortex, and their dysfunction has been implicated in various brain disorders such as epilepsy, autism, and Alzheimer’s. While scientists have detailed interneuron form and function in laboratory mice, the cellular diversity, circuit functions, and pathophysiologies of human interneuron populations remain almost

entirely unknown. Here, using a range of anatomical, physiological, and transcriptomics methods in ex vivo human brain tissues, we will generate a multimodal phenotypic catalog of human interneurons and characterize their functional organization in neural circuits. These studies will advance generalizable strategies

for human cellular and circuit neuroscience, while furthermore yielding a fundamental understanding of human interneurons and human inhibitory circuit design.