Researchers have found that by specifically targeting a central signaling pathway in the brain, they can improve the innate behavioral response to stress in mice. Stress-induced behaviors in rodents reflect many of the symptoms that affect people suffering from major depression and other clinical conditions associated with stress. The findings, published July 20th online in the journal Nature Neuroscience, suggest a new strategy for treating depression and other stress-associated disorders.

The study was led by James A. Bibb, Ph.D., at The University of Texas Southwestern Medical Center, who received NARSAD Young Investigator grants in 2000 and 2003, and lead author Florian Plattner, Ph.D. The scientific team also included Paul Greengard, Ph.D., a member of BBRF's Scientific Council and a 1992, 2002, and 2008 Distinguished Investigator; Eric J. Nestler, M.D., Ph.D., a Scientific Council Member and a 1996 Distinguished Investigator; 2006 Young Investigator Kanehiro Hayashi, Ph.D.; 2007 Young Investigator Eunice Y. Yuen, Ph.D.; 1999 and 2004 Young Investigator Zhen Yan, Ph.D.; and 1999 Independent Investigator and 2006 Distinguished Investigator Angus C. Nairn, Ph.D.

The team's findings are a result of a detailed investigation into a “signaling cascade,” called the cAMP/PKA pathway, which regulates a wide range of processes in the central nervous system. Disruption of the pathway has been linked with several mental disorders, including depression. Some existing antidepressant medications are known to boost cAMP signaling, but better understanding how this signaling network works could help researchers develop treatments that are more effective or cause fewer side effects.

In a series of experiments, the team discovered that a protein called PDE4, which reduces the level of cAMP in the brain, modulates behavioral responses to stress. Mice with increased levels of cAMP are more likely to struggle to escape an uncomfortable situation and less likely to exhibit signs of despair. They also interact more with other mice and are more likely to choose sugar water over plain water, suggesting a resistance to the loss of motivation to seek pleasure that is normally observed in mice subjected to stress.

The scientists found that preventing PDE4 from reducing cAMP levels made the animals’ behavior less reactive to both chronic and acute stress. In fact, they were able to restore a normal struggling response to acute stress by preventing activation of PDE4 in just one region of the animals’ brains, the ventral striatum. The ventral striatum is a component of the brain’s reward system.

Read the abstract.