Our research group is interested in the genetic and cellular mechanisms of the development and function of the brain's inhibitory system. We apply advanced mouse genetics in combination with electrophysiology and modern molecular methods.
The group has four major research interests:
Genetic mechanisms controlling the emergence of higher cognitive function
Ever wondered why it might be a bad idea to lend your car to a teenager? Why do many forms of neuropsychiatric disorders including schizophrenia, depression and bipolar-disorder have late onsets, typically in the late teens to early twenties? The goal of our lab is to study the cellular changes that occur around or just after sexual maturation and which genetic programs control these changes. We are currently studying a few promising candidate genes and performing functional single-cell RNA-sequencing to identify novel genetic programs.
Neural diversity - disorders
Psychiatric disorders remain a large unmet medical need in society. Recent advances in human genetics have led to a massive increase in our understanding of their genetic structure and often polygenic origin but it has rarely led to “actionable” results. We are investigating how to leverage new-found knowledge of cellular diversity in understanding complex disorders. Combining single-cell RNA-sequencing data with large scale human genetics, we are investigating the cellular origin of polygenic heritability of a number of disorders. We are also developing algorithms that leverage single-cell resolution in case/control differences in gene expression.
Neural diversity – function
Since the days of Ramon y Cajal we have known that the inhibitory system exhibits a stunning diversity. A major research effort has gone into characterizing the morphology, marker expression and electrophysiological properties of interneurons (see Rudy et al 2011). With modern genetics we are starting to get a molecular handle on this diversity in order to functionally target individual cell classes with agents, revealing their connectivity and either driving their activity or silencing them. We have recently identified a number of novel classes of interneurons and are studying their role in the local and long-range circuitry as well as developing and applying pharmacogenetic tools to study their role in behavioral paradigms.
Neural diversity - stability
Knowing the transcriptional state of cells gives many clues to how cell classes are related to each other. But even with state of the art techniques, the data remains as “snapshots” of individual cells and does not tell us how these profiles can change over time. We are interested in what aspects of cell transcription and function are stable over time and which parameter are variable in response to the environment of the cells.