Penn Vet researchers link inflammation and mania

People with schizophrenia and bipolar disorder often exhibit symptoms of mania, including impulsivity, risk-taking behaviors, and irritability.

Though scientists knew that the inflammatory response triggered by certain infections and immune disorders was somehow involved in these diseases, a team of Penn scientists wanted to find out what that link looked like in the body. Their work, which implicates a brain region called the dorsal raphe, suggests that new treatments for such neurological disorders could take a targeted approach to alleviate manic symptoms.

Tracy Bale, a professor of neuroscience in the School of Veterinary Medicine’s Department of Animal Biology and in the Perelman School of Medicine’s Department of Psychiatry, was the senior author of the study, which was published this week in the Journal of Neuroscience.

Bale and colleagues chose to focus their study on a brain region called the dorsal raphe, which produces serotonin, and is located close to circulating immune cells, making it potentially vulnerable to the effects of inflammation. Though serotonin, a neurotransmitter, is often associated with feelings of happiness and well-being, it also regulates behaviors characteristic of mania, including impulsivity, hedonism, and aggression.

“We compared the raphe with another important region, the prefrontal cortex—a region where serotonin acts, but is not produced—to see if the effects of neuroinflammation were specific to how the brain synthesizes this neurotransmitter,” Bale says.

The researchers performed tests on mice in which they could induce inflammation selectively in specific brain regions. Comparing mice with inflammation in the dorsal raphe to mice with inflammation in their prefrontal cortex, they found the mice with prefrontal cortex inflammation behaved similarly to normal mice, but those with dorsal raphe inflammation displayed more behaviors characteristic of mania.

For example, though mice generally prefer closed-in spaces, in a test where the mice were given the choice to explore either an open or narrow compartment, the raphe-inflamed mice chose the open compartment more frequently. In addition, in a test where mice were given the choice to move along an open, elevated platform or a closed, elevated platform, the mice with raphe inflammation spent a lot of time at the riskiest part of the maze—the far ends of the open platform.

Suspecting that the manic effects were a result of problems in serotonin regulation, Bale’s team tried to alleviate the symptoms by treating the mice with a selective serotonin reuptake inhibitor (SSRI)—a type of drug frequently prescribed to treat depression. The team found that a single treatment given right before testing made the mice with raphe neuroinflammation behave more like normal mice, restoring some of the risk-aversion behavior that most mice exhibit.

“Our findings suggest that the manic-like symptoms are caused by a loss of serotonin regulation,” Bale says. “Targeting treatments to the specific brain regions that are responsible could provide an effective approach in human diseases associated with mania, like schizophrenia and bipolar disorder.”

Mouse Maze