In humans, the medial orbitofrontal cortex (mOFC) is thought to be important for determining the value of a perceived reward. Through manipulation of a growth factor in the mOFC, Emory scientists were able to modulate a mouseâ€™s tendency to persist in reward seeking. Image from O’Doherty et al, PLOS Biology (2006).
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€
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.
Decision-making time in mice. Further progress along these lines may lead to a clinical trial.
New research in mice strengthens a potential strategy for treating fragile X syndrome, the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorder.
The results, published April 23 inÂ Cell Reports, suggest that a drug strategy targeting a form of the enzyme PI3 (phosphoinositide-3) kinase could improve learning and behavioral flexibility in people with fragile X syndrome. The PI3 kinase strategy represents an alternative to one based on drugs targeting mGluR5 glutamate receptors, which have had difficulty showing benefits in clinical trials.
Research led by Emory scientistsÂ Gary Bassell, PhD and Christina Gross, PhD had previously found that the p110Î² form of PI3 kinase is overactivated in the brain in a mouse fragile X model, and in blood cells from human patients with fragile X syndrome.
Now they have shown that dialing back PI3 kinase overactivation by using genetic tools can alleviate some of the cognitive deficits and behavioral alterations observed in the mouse model. Drugs that target the p110Î² form of PI3 kinase are already in clinical trials for cancer.
The researchers examined neurons in the orbitofrontal cortex, a region of the brain thought to be important for â€œlinking reward to hedonic experience.â€ It was known that stimulants such as cocaine can cause the loss of dendritic spines: small protrusions that are critical for communication and interaction between neurons.
â€œTo make an analogy, itâ€™s like a tree losing some of its leaves,â€ Gourley writes. â€œLaurenâ€™s work shows for the first time that if cocaine is given in adolescence, it can cause the loss of dendrite arbors â€“ as if entire branches are being cut from the tree.â€
The mice are exposed to cocaine over the course of five days in early adolescence, and then their behavior is studied in adulthood. This level of cocaine exposure leads to impairments in instrumental task reversal, a test where mice need to change their habits (which chamber they poke their noses into) to continue receiving food pellets.
How can we study depression and antidepressants in animals? They canâ€™t talk and tell us how theyâ€™re feeling. Previously, researchers have used the model of â€œbehavioral despair,â€ with examples of the forced swimming test or the tail suspension test.
Several psychiatrists have been arguing that a new framework is needed, which better simulates aspects of depression in humans, such as the variety of behavioral changes and the several week time period needed for antidepressants to function. This new framework could help illuminate how depression develops, and lead to new antidepressants that are effective for more people.
Shannon Gourley, who recently joined the Emory-Childrenâ€™s Pediatric Research Center has been taking the approach of examining the lack of motivation and self-defeating behavior that are integral parts of depression.
The Pediatric Research Center is an effort led by Emory University and Childrenâ€™s Healthcare of Atlanta, including partnerships with the Georgia Institute of Technology and Morehouse School of Medicine.
Note: Gretchen Neigh in psychiatry/physiology has been doing work with a similar theme, looking at the effects of adolescent social stress in animal models.
Gourley, neuroscience graduate student Andrew Swanson and their colleagues at Yale, where Gourley was a postdoc with Jane Taylor and Tony Koleske, have a new paper in PNAS on this topic. In particular, they dissect how chronic stress â€“ or exposure to the stress hormone corticosterone â€“ can produce loss of motivation and impaired decision making.
First, the researchers found that exposing rodents to corticosterone shut off a growth factor called BDNF (brain-derived neurotrophic factor) in the frontal cortex, a region of the brain important for planning and goal-directed behavior. BDNF nourishes neurons and helps keep them alive.
To confirm that BDNF was important in this region of the brain, researchers selectively silenced the gene for BDNF only in the frontal cortex. Both mice exposed to stress hormones and the BDNF-altered mice showed reduced motivation to earn food rewards. Mice would ordinarily press a lever dozens of times to get a food pellet, but the BDNF-altered animals would stop trying earlier â€“ the â€œbreak pointâ€ is 2/3 as high.
â€œDepression is a leading cause of unemployment because people are unable to break out of self-defeating behavioral patterns and to muster the motivation to engage with the world. If we can better understand how to treat these symptoms, we can effect better outcomes for individuals suffering from depression,â€ Gourley says. â€œThe BDNF deficiency alone could account for the loss of motivation that individuals with depression suffer.â€
However, she reports her team was surprised that the loss of BDNF could not account for another aspect of depression: cyclical self-defeating behavior. They modeled this by asking whether mice continue to press a lever for a food reward even when the reward is no longer available.
â€œWhen we made the discovery that reduced BDNF could not account for all of the depression symptoms that we study, we took a step back and looked at the stress response system,â€ Gourley says.
Stress hormone exposure impairs the ability of mice to switch away from fruitless behaviors, but loss of BDNF in the frontal cortex does not. Here, the stress response system itself was the culprit. When her team temporarily blocked the ability of mice to shut off their stress response systems using the drug mifepristone, mice had impaired decision-making. However, their motivation to obtain rewards was not altered. When the drug wore off, they returned to normal.
Gourley says the implication is that effective antidepressants need to be able to attack not one, but two physiological systems: they need to increase levels of BDNF, and they need to help the stress system recover so that it can shut itself off better. A classic trycyclic antidepressant, amitriptyline, can do both and was effective in treating both the motivation and decision making parts of depression in animal models.
The use of tricyclic antidepressants is limited because of side effects and overdose potential. In addition, another challenge in treating depression is that current antidepressants only begin to work after several weeks or months of treatment. This is thought to be because it takes several weeks for these drugsâ€”which act only indirectly on BDNFâ€”to restore BDNF levels back to normal.
She and her team also showed that a drug called riluzole, which acts indirectly but rapidly on BDNF systems, has antidepressant effects in the animal models. Riluzole is currently in use to treat ALS, and reportedly has antidepressant effects in humans. Clinical trials with riluzole in the context of depression are underway.