Josh Huang, PhD
Cold Spring Harbor Laboratories
Cold Spring Harbor, New York
Toward a Genetic Dissection of the GABA Inhibitory System in the Mouse Brain
Dr. Huang got to know Jeff Hall and Kalpana White while working in the Rosbash lab. During his tenure at Brandeis from 1989 to 1994, his work focused on the contribution of a variety of genes involved in circadian rhythms (day/night sleep cycles).
A major challenge in modern neuroscience is to understand how behaviors emerge from the underlying neural networks and their cellular constituents. To take on this challenge, a productive approach aims to establish causal links between patterns of activity in specific groups of neurons (for example, cell types) and the computation of neural circuits that guides behavior. At the core of this approach is the identification and precise and flexible manipulation of distinct cell types, the functional units of neural circuits. However, the diversity and heterogeneity of neuron types in mammalian brains have been major road blocks. For example, GABAergic interneurons are crucial in establishing the functional balance, complexity, and computational architecture of neural circuits, but the heterogeneity of GABAergic cell types has been exceedingly difficult to penetrate by conventional anatomical and physiological techniques. Genetic strategies hold the promise to “de-convolute” this complexity because they tap into the intrinsic gene regulatory mechanism and logic that generate and maintain the heterogeneity of the GABAergic system.
The Huang lab uses cell type specific promoters and Cre/LoxP recombination-regulated gene expression to establish “genetic access” to all major classes GABAergic neurons. Using bacterial artificial chromosome (BAC) engineering technology, the Huang lab is generating more than twenty knockin “driver lines” expressing Cre or the inducible CreER in specific GABAergic cell types. In addition, they are constructing a new generation of Cre-activated “reporter” mice and, in particular, Cre-activated viruses to achieve high-level expression of fluorescent proteins (FPs) and “molecular switches”(MSs, such as ligand- or light-induced ion channels) in vivo. These genetic strategies will allow researchers to: 1) visualize the morphology and connectivity of GABA interneurons with synapse resolution (genetic neuroanatomy); 2) visualize the activity and activity-history of interneurons (genetic neurophysiology); 3) manipulate the firing and synaptic transmission of defined classes of cells at physiological time scales (genetic manipulation). Using this approach, the Huang lab has imaged the structural dynamics of a major class of GABA interneurons in vivo and manipulated their firing activity.
The genome-wide mapping of the transcriptome onto the mouse brain (that is, the Allen Brain Atlas) provides unprecedented opportunity to discover and define cell types by gene expression. The genetic access to specific cell types through Cre driver mice combined with efficient and flexible delivery of an array of conditional viruses to visualize and manipulate these cell types will herald a new era for studying the organization and function of complex neural circuits.