Researchers at NIEHS designed genetically modified mice that will help neurobiologists address one of the most fundamental questions in brain research — what are the identities and functions of different cell types in the brain? The new mouse lines will let scientists identify specific populations of brain cells and determine how they control behavior in an animal. The findings will advance our understanding of neurological disorders such as Alzheimer’s disease, drug addiction, and depression.
NIEHS scientist Patricia Jensen, Ph.D., is the corresponding author of the article that appeared June 14 in the journal Cell Reports, and an earlier, companion paper published in 2015 in the journal Development. Jensen said it took approximately six years to develop and characterize the seven mouse lines described in the papers.
Identifying distinct cell populations
The mouse lines allow researchers to identify distinct populations of brain cells, as defined by the expression of different genes during development, determine where these populations are located, and investigate their function.
The mouse lines described in the 2015 paper allow expression of fluorescent proteins to label and visualize cells, whereas the lines described in the later article allow researchers to noninvasively increase the activity of cells and observe the behavioral and physiological effects in freely moving animals. This control of cell activity is achieved by the expression of a mutated cell surface receptor called hM3Dq.
Developed by Bryan Roth, M.D., Ph.D., at the University of North Carolina at Chapel Hill, hM3Dq is most often introduced into brain cells by injecting them with engineered viruses. However, Jensen’s staff scientist, Nicholas Plummer, Ph.D., who shared first authorship on the Cell Reports paper with postdoctoral fellow Natale Sciolino, Ph.D., said that the viral injection procedure has drawbacks.
"Using viruses limits you to examining fairly compact populations of cells," Plummer said. "With our mouse lines, we can label and control the activity of widely dispersed cells, and we can activate them any time during development."
Jensen’s current research
Sciolino said the group is using the mouse lines to investigate the noradrenergic system, or the neurons that use the neurotransmitter norepinephrine, also called noradrenaline. She explained that the noradrenergic system is disrupted in a number of conditions, such as anxiety disorders, depression, Alzheimer’s disease, Parkinson’s disease, and drug addiction. The mouse lines will help researchers answer key questions about developmental and functional diversity within the noradrenergic system.
"For the first time, we’ll be able to manipulate small subsets of these neurons and ask which ones are important for anxiety-type or impulsive behaviors," Sciolino added.
While Jensen’s group is studying the nervous system, the mouse lines may be used in almost any type of cell, not just neurons. "A cardiologist who wants to study heart cells could use them or someone interested in diabetes could use them to study pancreatic beta cells," Jensen said. "The system can be used in virtually any cell that has the Gq-coupled signaling pathway."
Sciolino NR, Plummer NW, Chen YW, Alexander GM, Robertson SD, Dudek SM, McElligott ZA, Jensen P. 2016. Recombinase-dependent mouse lines for chemogenetic activation of genetically defined cell types. Cell Rep 15(11):2563−2573.
Plummer NW, Evsyukova IY, Robertson SD, de Marchena J, Tucker CJ, Jensen P. 2015. Expanding the power of recombinase-based labeling to uncover cellular diversity. Development. 15;142(24):4385−4393.