By Peter Jurich, Waisman Science Writer
Research has shown voluntary running is an activity most commonly associated with the reversal of negative impacts of aging and neurodegeneration, but little is understood about why that is.
A new study led by Waisman researcher Yu Gao, PhD, and professor Xinyu Zhao, PhD, together with collaborators Daifeng Wang, PhD, and Qiang Chang, PhD, of the Waisman Center, University of Wisconsin-Madison, provides the first genome-wide investigation of running-induced neurogenesis, or the production of new neurons, in the adult hippocampus — an area of the brain associated with memory and emotional responsiveness. The paper, “RGS6 mediates effects of voluntary running on adult hippocampal neurogenesis,” was published in the journal Cell Reports in early August 2020.
“The main discovery is that genes corresponding to more mature neurons are expressed earlier in new neurons of running mice,” Zhao says. In particular, the researchers identified the regulator of G protein signaling 6 (RGS6) gene as the underlying mediator of the impacts of running on adult neurogenesis. In this case, the expression of the RGS6 gene is increased in running mice — as opposed to the sedentary mice also involved in the study — and Zhao says this upregulation promotes neuronal maturation.
“RGS6 is an intracellular protein that inhibits the action of GABA-B receptor signaling,” Zhao says “GABA-B receptor activation inhibits adult neurogenesis. Therefore, RGS6 activates adult neurogenesis.” In mouse models, the findings indicate unique changes in gene expression and dynamic patterns in the new neurons of running mice that were not present in the new neurons of sedentary mice. Zhao says that the dynamic patterns in gene expression were also impacted by how long the mice ran.
To perform the study, Gao and Zhao used a new genetic mouse line that allowed them to isolate translating messenger RNA, or mRNA, from the small number of adult-born neurons of mice with either a freely moving or a locked running wheel in their cage. (The group with the locked wheel became the sedentary group.) Using this cutting edge method called cell type-specific RiboTag-seq, Zhao says, they were then able to isolate mRNA only expressed in adult-born new neurons for analysis.
The findings from the study may provide important insight into future treatments for individuals with reduced neurogenesis and subsequent decline in cognitive function. This is the case for some developmental disabilities and neurodegenerative disorders such as autism and Alzheimer’s disease. As Zhao says, “This study unveils changes in gene expression in new neurons in response to running, which may reveal novel targets for treatment for diseases related to impaired learning.”
Other scientists who contributed to the study include Minjie Shen, PhD, Qiping Dong, PhD, Brian Eisinger, PhD, Sudharsan Kannan, graduate student Sahar Javadi, and undergraduate students Johnson Hoang and Jyotsna Pandey at UW-Madison Waisman Center; and Jose Gonzalez, PhD, and Linda Overstreet-Wadiche, PhD, at University of Alabama-Birmingham.
This work was supported by grants from the National Institutes of Health, the American Epilepsy Society, UW Vilas Trust, and the Wisconsin Alumni Research Foundation.