Emory researchers have identified molecular mechanisms that regulate motivation and persistence in mice. Their findings could have implications for intervention in conditions characterized by behavioral inflexibility, such as drug abuse and depression.
Scientists showedÂ that by manipulating a particular growth factor in one region of the brain, they couldÂ tune up or down a mouseâ€™s tendency to persist in seeking a reward. In humans, this region of the brain is located just behind the eyes and is called the medial orbitofrontal cortex or mOFC.
â€œWhen we make decisions, we often need to gauge the value of a reward before we can see it — for example, will lunch at a certain restaurant be better than lunch at another, or worth the cost,â€ says Shannon Gourley, PhD, assistant professor of pediatrics and psychiatry at Emory University School of Medicine. â€œWe think the mOFC is important for calculating value, particularly when we have to imagine the reward, as opposed to having it right in front of us.â€
The results were published WednesdayÂ inÂ Journal of Neuroscience.
Being able to appropriately determine the value of a perceived reward is critical in goal-directed decision making, a component of drug-seeking and addiction-related behaviors. While scientists already suspected that the medial orbitofrontal cortex was important for this type of learning and decision-making, the specific genes and growth factors were not as well-understood.
The researchers focused on brain-derived neurotrophic factor (BDNF), a protein that supports the survival and growth of neurons in the brain. BDNF is known to play key roles in long-term potentiation and neuronal remodeling, both important in learning and memory tasks. Variations in the human gene that encodes BDNF have been linked with several psychiatric disorders.
â€œWe might imagine that the effects of gene variants on the medial orbitofrontal cortex in particular could contribute to disorders in which we fail to appropriately gauge the value of food or drugs — leading to, for example, uncontrolled food seeking or addiction,â€ Gourley says.
The researchers tested the importance of BDNF in the medial orbitofrontal cortex in a variety of ways, including a combination of surgical, behavioral, and pharmacological manipulations. A test the researchers relied on to gauge motivation and persistence in mice was the â€œoutcome devaluation task.â€
â€œIt would be as if you were given a big piece of cake,â€ Gourley explains, â€œthen someone asked you if you wanted to pay $10 for another big piece of cake. Most likely, you would decline, but mice with the Bdnf gene cut selectively out of the medial orbitofrontal cortex still worked for the food reward, even though it had little value.â€
Mice were food restricted throughout the test and asked to make a particular response (poking their noses into a window) that would result in a food reward over the course of several sessions. After these training sessions, mice were given free access to the reward prior to the test. Mice that had this region selectively activated with drugs displayed increased sensitivity to this task, while Bdnf knockdown in other mice blocked this effect.
Behavioral tests using mice, as well as several biochemical assays, were conducted at Yerkes National Primate Research Center. Additional biochemical assays were done in collaboration with Jane Taylor, PhD at Yale University. Neuroscience graduate student Kelsey Zimmermann and research specialistÂ Amanda Allen wereÂ co-authors. Allen was a co-author of this article.
Also at Emory, Keqiang Ye and colleagues have discovered compounds that can mimic the signals supplied by BDNF and thus have positive effects in several animal models of neurological disease. BDNF is also thought to be important for the effects of aerobic exercise and hypoxia on neurons.
This work was supported by National Institute on Drug Abuse (DA011717, DA027844), the National Institute of Mental Health (MH101477), the Childrenâ€™s Center for Neuroscience Research (Emory), and the Connecticut Department of Mental HealthÂ and Addiction Services (Yale). The Emory Viral Vector Core is supported by National Institute of NeurologicalÂ Disorders and Stroke (P30NS055077).