Rhodes Probes Causal Mechanisms of Voluntary Behaviors

To the casual observer, a dedicated jogger out for his daily run may not seem to have much in common with a destitute alcoholic he sprints past on a city street. But for Beckman Institute researcher Justin Rhodes, the two would share more than the same piece of pavement for a fleeting second.

Rhodes' research as part of the NeuroTech group seeks to find the causal mechanisms that underlie motivational behaviors. One of his research projects was among the first to find that motivation for beneficial behaviors such as exercise and motivation for detrimental behaviors like alcoholism and drug addiction could have the same neurological bases.

"One conclusion that's fairly novel is this finding that motivation for exercise involves the same circuits, the same chemicals, that have been implicated in drug addiction," Rhodes said. "There seems to be quite a big overlap between the pathways, the neurobiology, and underlying motivation for drugs versus motivation for something that's beneficial like exercise."

The research projects Rhodes is involved in are many and varied, but almost all of them investigate how biology and environment affect voluntary behavior. Part of that research could eventually give hope to people who are battling alcohol and drug addiction.

In order to do that Rhodes, an Assistant Professor of Psychology at the University of Illinois, is building a model he hopes will add to our knowledge not only in those areas but in many other future scientific pursuits. He is creating multi-generational mice models that can be bred for specific research projects, from studies involving genetics to those centering on his own interests of drug addiction and alcoholism.

"Any mechanism in a mouse is almost always going to occur in a human," Rhodes said. "Their biology and genes are similar."

Those similarities mean mice models are useful in a wide range of research topics and provide a solid platform for repeatable testing and for gathering data.

"Mice are a tremendous resource because all the individuals within a strain are all genetically identical," Rhodes said. "The advantage of that is we can keep these strains for many, many years and they are genetically the same.

"That means I can be studying these mice today, someone can be studying these mice in Germany or wherever, and we're accumulating defined information about this genotype which can be put in a database."

"There seems to be quite a big overlap between the pathways, the neurobiology, and underlying motivation for drugs versus motivation for something that's beneficial like exercise."
- Justin Rhodes

One example is a project Rhodes was involved in that used different genotypes of mice and measured them for how much alcohol they drank. The study, the results of which were published in a 2006 paper in Gene, Brains, and Behavior, measured the alcohol intake and compared it with other data in the literature.

"The animals that tend to drink alcohol also show very low withdrawal from alcohol, which is exactly what you find in humans," Rhodes said. "Individuals who tend to have low alcohol withdrawal or resistance to hangovers, who are less sensitive to the effects of alcohol, are more prone to addiction. Among humans this is true, and it's paralleled what we've found in these mice."

The fact that the study confirmed findings from human studies demonstrated the validity of the mice model for researching different addictive behaviors.

"What we're doing with the mice is, you really have a defined genotype, so you can have multiple different genotypes that drink for different reasons," Rhodes said.

Model Useful for Drug Testing

The model is also useful in testing new compounds. The search for pharmaceutical treatments for alcoholism has produced drugs like Naltrexone and Acamprosate. Rhodes collaborated on a project that used specific mice models to screen new compounds for their effectiveness in reducing high levels of drinking and for identifying genetic and neurobiological mechanisms involved in that behavior. Their work has been described in a paper, Acute effects of Naltrexone and GBR 12909 on ethanol drinking-in-the-dark in C57BL/6J mice, that was published earlier this year.

Rhodes said developing a model that is specific to certain patterns of alcoholism is one way to advance drug treatments for addictive behavior.

"The fact is we don't really know what the difference is between the circuits in the brain that are involved in that compulsive, obsessive motivation for drugs from just the regular circuits that are activated when you're hungry, when you want food, or you want to exercise," Rhodes said. "Maybe there is no difference, and that is going to be a big problem for developing new (treatment) drugs. The only way you can develop drugs is if you are able to target the pathology. You can't just interfere with regular motivation for everything; you have to be somewhat specific."

That specificity is just one of the reasons Rhodes believes his mice model can be useful as a research tool and for applications such as the testing of new drugs. The study involving GBR12909, a new compound that blocks the dopamine up transporter protein involved in addiction, is an example. The compound was effective with mice just as it was in human trials, but also showed the same non-specific reward blocking properties of other drug treatments because it reduced the mice's desire for the reward of sugar water.

"It turns out that GBR12909 reduces drinking for alcohol but it also reduces the drinking for sugar water," Rhodes said. "So it seems that whatever mechanism that the dopamine transporter is playing in drinking is fairly non-specific and it's also playing a role in other kinds of rewards."

Again, the study validated Rhodes' mice model by confirming the results that had been found in human patients.

"This is very, very translational," Rhodes said of his research. "It's developing a model for drug testing. It's a nice model for that because it's simple in the sense that it doesn't take a long time to do, it's a high throughput screening. When you're doing screening for drugs you may have a hundred different drugs, so if you have an involved animal model that takes weeks to do it's not efficient. This particular technique is very simple."

Exercise Affecting Learning and Memory

Rhodes also studies exercise in his models toward gaining a better understanding of human learning and memory. He said that science in recent years has added greatly to our knowledge about the cognitive benefits of exercise, but that causal mechanisms for those benefits are still unknown. Rhodes said mice models have shown that exercise produces a tremendous activation of the hippocampus area of the brain that's known to play a role in learning and memory.

"One thing we know is that exercise produces new neurons in that area of the brain," Rhodes said. "Now we know that there are areas of the brain that continuously generate new neurons throughout adulthood and one of those areas is the hippocampus. It turns out that exercise produces a tremendous increase in the number of new neurons that are found in that area."

Rhodes is beginning a collaboration that will test whether the cognitive benefits of exercise such as improved memory are a function of the production of new neurons, or due to some other neural factor like increased vascular flow. The different genotypes in the mice model could provide answers to the question.

"If we can find that some mice get greater benefit than the others and find out which genes allow them to get greater benefit from exercise, then we can study the mechanism of how exercise promotes new learning," Rhodes said.

Rhodes said he has half a dozen different projects under way, but is most focused on building his mice model, studying the significance of new neurons, and continuing the translational research involving learning and memory, exercise, and addictions. He collaborates across campus and hopes to someday include imaging techniques and collaborations with physicists and engineers in his projects.

"The Beckman Institute is the center for collaborative research," Rhodes said. "Everything I do is collaborative research, so I'm situated in a place where I can talk to chemists, or people like Bill Greenough, or David Clayton, or Art Kramer, where we can meet and talk and plan.

"Plus, the facilities here are great. But mainly what drew me was the intellectual collaboration. Illinois is just a tremendous resource with all the expertise here."