New mouse models are key to designing better therapeutic interventions for people at risk for addiction.
Addiction’s toll on people, and their families and communities, continues to rise in the U.S. Preventing and treating addiction depends on scientific understanding of the genetic and biological risk factors, but these are complicated by environmental and social factors that can’t be replicated in a lab for study.
Mice, on the other hand, exhibit a range of behaviors and physiological traits that replicate those of the human population with regard to addictive substances. Jackson Laboratory (JAX) researchers including Associate Professor use mouse models to research genetically based behavior and behavioral abnormalities such as addiction.
“Understanding the factors that influence vulnerability to addiction, and developing effective therapies, requires identifying the genes and pathways involved in the process of addiction,” Kumar says.
Kumar has two new grants from the National Institute on Drug Abuse for innovative approaches to using mouse models to understand addiction.
The first is a five-year grant totaling $4,151,622 from the National Institute on Drug Abuse to create dozens of new mouse models for addiction. The work will yield both datasets and mouse resources that will be available to the worldwide addiction research community to discover novel therapeutics for addiction.
Under the grant, Kumar will take advantage of an existing large-scale initiative at JAX. The NIH Knockout Mouse Project 2 (KOMP2), an international initiative to develop an encyclopedia of deletions for every gene in the mouse genome, and to characterize them in high-throughput assays. Kumar has identified KOMP2 strains with phenotypes that might make them vulnerable to addiction, and will characterize new mouse models of addiction. These new strains can then be utilized by the wider addiction research community in mechanistic studies and therapeutic interventions. “The goal is to give the addiction research community new mouse models that can be used to better understand the neurobiology of addiction and to model treatment,” Kumar says.
Kumar will be collaborating with , a computer scientist and JAX associate professor, who will conduct integrated analysis of the mouse data combined with human data from the addiction research community. Brian J. Nieman, Ph.D., an associate professor at the Hospital for Sick Children in Toronto, will analyze brain structure data in the KOMP2-produced mutant mice.
The second NIDA grant is an award to study the effects of a specific gene (Cyfip2), which the Kumar lab had previously identified as a regulator of responses to cocaine. The team had developed new mouse models with variations in the gene under a 2020 exploratory NIDA grant, which has now been extended for three years for a total of $1,165,683. In this project Kumar will collaborate with Stone Chen, Ph.D., an assistant professor at Iowa State University and an expert in Cyfip2 structure and biochemistry.
The researchers will test reward behavior in these models, including their response to cocaine and voluntary self-administration of cocaine, and correlate that behavior with measurements of their brains’ biochemical interactions. The goal is to identify the important signaling pathways for addiction behaviors.
Kumar is now recruiting for a research assistant and a postdoctoral associate in the molecular genetics of addiction and, with JAX Associate Professor Kristen O’Connell, Ph.D., a postdoctoral associate in the neurocircuitry of addiction.
Establishment and Characterization of Novel Mutant Mouse Models for the Addiction Research Community, National Institute on Drug Abuse, Grant Number 1U01DA051235-01A1
Dissection of Addiction-Relevant Signal Integration by Cyfip2 through Precise Genome Engineering, National Institute on Drug Abuse, Grant Number 4R33DA050837-02