Rats have a long and storied history as an important animal model for research, especially in the study of behavior. The University of Chicago has particularly strong historical ties to this field. John B. Watson, PhD 1903, considered the father of behaviorism — a philosophy that psychology should be based on observation and experiment to understand behavior — helped transform psychology into a science.
But in recent decades, the use of rats has given way to mice because of dramatic innovations in the manipulation of mouse genomes. This shift has affected certain research fields, particularly the study of drug abuse and addiction, where behavioral tasks are often too complex for mice to perform. That’s led to a slowdown in research aimed at revealing the genetics thought underlie drug abuse-related behaviors.
To address this issue, the National Institute on Drug Abuse (NIDA) has awarded the University of Chicago a $12 million, five year grant to establish a national Center of Excellence to study drug abuse-associated behaviors by conducting research with rats. Led by Abraham Palmer, PhD, associate professor of human genetics, the NIDA Center for Genome-Wide Association Studies in Outbred Rats will combine complex behavioral studies with recent technological advances in rat genetics to help scientists shed light on the genes behind drug addiction.
“The odds of permanently recovering from drug addiction are low and there is currently very little understanding of why that is,” Palmer said. “With an animal system, we have a powerful advantage in that once we’ve found a genetic location or pathway, we can easily manipulate the gene and measure the resulting effects. The use of rats is critical because many of the behaviors we will study have proven difficult or impossible to adapt for mice.”
A rat revival
To shed light on the genetics behind complex traits such as drug abuse behavior, the researchers will utilize genome-wide association studies (GWAS) – an examination of the entire genomes of different individuals to reveal genetic variants linked with particular traits. Research groups around the country will perform experiments exploring separate behaviors, and send samples to UChicago for genetic analysis. This allows the center to study the genetics of multiple aspects of drug abuse efficiently and at a much more rapid pace than previously possible.
While most animal studies use almost genetically identical subjects, GWAS studies require large numbers of unrelated individuals. The center will support a comprehensive breeding program that provides researchers with a unique population of rats that have been bred to maintain as much genetic diversity as possible. Studies will be performed on both male and female rats to explore the relationship between gender, drug abuse behavior and genetics (Palmer recently spoke with the New York Times on this issue).
“This center is the culmination of several years of work in applying GWAS studies in animals toward drug abuse behavior,” Palmer said. “We are investigating fundamental processes to all stages in the hope that identifying the genes and molecular events involved in addiction gives us the opportunity to intervene through novel therapeutics.”
Once fully established, the center will enable future research toward the genetic underpinnings of other medically important traits. The center will also serve as a resource to foster the training of students who are interested in drug abuse research, provide seed funding for select research projects and engage in public education and outreach activities. It also includes funding from the NIH Big Data to Knowledge program to create a traveling “big data” museum exhibit about the biomedical sciences.
Dr. Palmer will operate the center in collaboration with research groups at the University of Michigan, University at Buffalo, University of Tennessee Health Science Center and the Medical College of Wisconsin.
Four initial projects are being supported by the center:
Genetic Studies of Incentive Salience (University of Michigan)
Principal Investigator: Terry Robinson, PhD, Shelly Flagel, PhD
This research project will investigate the genetic basis for differences in reward-seeking behavior. Some animals attribute importance to cues that predict the delivery of rewards. Such reward-associated cues are believed to influence the risk for relapse in recovering drug abusers. The genetic causes for this predisposition will be studied. This research project will also look for a genetic explanation for why some animals are more drawn to novel or unfamiliar environments. The response to novelty is also strongly implicated in drug abuse related-behaviors.
Socially-acquired nicotine self-administration (University of Tennessee Health Science Center)
Principal Investigator: Hao Chen, PhD
This research project will examine genetic influences on nicotine self-administration in rats. Adolescent rats typically have a strong aversion to nicotine, but will voluntarily consume nicotine if they’re exposed to another rat that appears to be doing the same thing. This social component parallels key features of how humans acquire smoking behavior. The relationships between social and emotional traits and the acquisition of nicotine self-administration will be studied to identify the genetic mechanisms that underlie this form of social learning. The project will also explore nicotine withdrawal and smoking-relapse.
Association between behavioral regulation and cocaine cue preference (University at Buffalo)
Principal Investigator: Jerry Richards, PhD
This research project will explore the link between addiction and various behaviors, such as response to novelty, sustained attention and reaction time. It also looks at preference for a large, delayed reward compared to smaller immediate reward, as well why some animals strongly react to cues that have been associated with cocaine. How these behaviors are related to each other and drug abuse will be investigated, as well as their genetic underpinnings.
Analysis – Integration of Genome-Wide Association Study (GWAS) and eQTL Data (University of Chicago)
Principal Investigator: Abraham Palmer, PhD
This research project will receive DNA samples for each of the other projects and will produce genetic data using next-generation sequencing technology. Using GWAS, the relationship between specific genes and each of the behaviors will be investigated. The heritability of these behavioral traits will also be examined.
For more information visit: www.ratgenes.org
About the National Institute on Drug Abuse (NIDA): NIDA is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports most of the world’s research on the health aspects of drug abuse and addiction. The Institute carries out a large variety of programs to inform policy and improve practice.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.