Vanderbilt study reveals how inflammation contributes to depression

Study farther on links immune response, serotonin signaling

by Bill Snyder | Thursday, Nov. 5, 2015, 8:43 AM

Vanderbilt University scientists are a step closer to judgment how inflammation in the body be able to affect mood and behavior.

Their latest disclosure, reported this week in the journal Translational Psychiatry, provides farther on evidence that a signaling pathway involved in the body’s immune response to infection and other stressors have power to regulate the brain‘s control of the neurotransmitter serotonin.

Randy Blakely, Ph.D.

“The incendiary pathway that we have identified is probable one by which serotonin signaling is regulated in not special,” said Randy Blakely, Ph.D., who led the inquiry team. “By targeting this pathway, we force come up with better medications to negotiate disorders where manipulation of serotonin signaling has proved beneficial, being of the kind which in depression.”

For the better share of a decade, Blakely and his colleagues consider investigated the p38alpha MAPK signaling path. MAPKs, or mitogen-activated protein kinases, are enzymes that reduce to method the body’s response to virus and other stress stimuli, among other roles.

The latest findings add to an increasing body of show that the p38alpha MAPK pathway links the visible form’s immune response to regulation of the brain serotonin transporter. The transporter, which eliminates serotonin from the synapse, or rift between nerve cells, is the mark for a major class of anti-depressants.

Selective serotonin reuptake inhibitors or SSRIs like Prozac grow the brain‘s supply of serotonin ~ the agency of blocking the transporter. But it be possible to take weeks to achieve a therapeutic effect, and not everyone responds to them.

Using genetic peer models they developed, Blakely and his colleagues showed that the MAPK path acts in serotonin neurons to give signs of infection in the outer boundary. That leads to an elevation in serotonin transporter activity and multiple serotonin-linked behaviors.

“The unadulterated consequence of p38alpha MAPK activation is … we have elevated transporter activity that can drain away the serotonin,” said Blakely, the Allan D. Bass Professor of Pharmacology and Psychiatry.

The impact on behavior was profound. When every inflammatory response was produced by peripheral enema of a piece of bacteria in mice, their serotonin neurons showed quick activation of the p38alpha MAPK pathway. The animals also exhibited depressive-like behaviors, including signs of heightened disquiet and despair.

But when, in the current study, the p38alpha MAPK path was genetically “knocked out,” specifically in serotonin neurons, these behaviors were extinguished. The inflammatory agent had no effect. The animals were, for the re~on that Blakely described them, “resilient.”

This “is a rejoinder to an acute inflammatory agent,” Blakely cautioned. It says no part about what may occur in deep-seated inflammatory states. “That’s something we’re longing to pursue with the same benign of genetic approach,” he said.

At the like time, “I doubt that (this MAPK path) has evolved only to respond to swelling and redness,” he said.

Since the p38alpha MAPK way has the ability to turn up and ~ round down the activity of the serotonin transporter, “maybe if we targeted the way (it) regulates the transporter being of the kind which opposed to blocking the transporter itself, we force have a better antidepressant,” Blakely reported.

Blakely is director of the Vanderbilt/NIMH Silvio O. Conte Center on account of Neuroscience Research, which is supported by the National Institute of Mental Health, section of the National Institutes of Health (NIH). First father of the study was Nicole Baganz, Ph.D., a postdoctoral member in the Blakely lab.

The research was supported in part by NIH grants NS007491, MH094527 and MH096972, the Brain and Behavioral Research Foundation and the Institute for Psychiatric Neuroscience.

Media Inquiries: 
Bill Snyder, (615) 322-4747  

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