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April 18, 2018

CHOP: 'Antidepressive' behavior in new animal test offers hope for humans

Research Psychology
CHOP Children's Hospital Thom Carroll/PhillyVoice

The Smilow Center for Translational Research, left, and the Children's Hospital of Philadelphia's Buerger Center for Advanced Pediatric Care.

Stimulating the brain circuitry of mice in a newly targeted neural pathway creates "antidepressive" behavior that may prove valuable in future treatments for people dealing with clinical depression, according to researchers at the Children's Hospital of Philadelphia. 

In a study published this week in Nature Medicine, CHOP neurobiologists present evidence suggesting that a shift in focus on a mood-sensitive pathway of the brain produces results that show promise for improved mental health. 

“Major depressive disorder is a serious health problem worldwide. Existing treatments are helpful for many people, but also have a high rate of relapse and significant side effects,” study leader Amelia J. Eisch said. “Because scientists consider depression to be caused by malfunctions in brain circuitry, we suggest that ‘tuning’ a specific circuit could set the stage for a targeted treatment.”

The current study deviated from previous research in humans that directly stimulated the hippocampus, a brain region with strong links to mood and memory. Past studies found that humans experienced either no effect or their memory suffered as a result of such stimulation. 

In the CHOP study, researchers chose to stimulate a brain region upstream from the hippocampus, known as the entorhinal (Ent) cortex, and study both memory and mood effects in lab mice. Their choice was based on prior research that found stimulation of this part of the brain improved memory and learning in both animals and humans. 

The current study marked the first time researchers looked at whether stimulating the entorhinal cortex could affect mood. 

In mice, Ent "stimulation" was achieved through genetic engineering. Researchers suppressed a protein in the Ent-hippocampal pathway associated with stress and inhibited cell firing. With more Ent neurons firing, hippocampal neurons were produced at a faster rate.

The mice were put through a variety of behavioral tests to monitor their moods after stimulation. 

In a forced swim test, for example, a researcher observes how a mouse behaves after being placed in a beaker of water. Mice respond by moving until they become immobile and float. A shorter duration of immobility signifies antidepressive behavior. 

Feeding tests gauge how anxious a mouse is to approach a food pellet. When mice approach the pellet in a shorter timeframe, researchers see their pursuit of something pleasurable as showing more antidepressive behavior.

It was not immediately clear how these findings would translate into treatments for humans, where "stimulation" of the hippocampus is typically administered using electroconvulsive therapy (ECT) and similar methods. 

"We are strictly basic scientists at this point, but our ultimate goal is to improve the human condition," Eisch told PhillyVoice. "We imagine the benefit of our work is that it indicates the strength of focusing on particular cells rather than brain regions, which is what ECT and deep brain stimulation currently do."

The potential breakthrough in the current study is that it points toward a shift from "non-specific" regional targeting to cell- or circuit-specific interventions.

In theory, though still entirely speculative at this point, Eisch said that gene editing could play a factor in future treatments for clinical depression in people. 

"In the realm of not too far away, it's a neuroscientist's science fiction dream — non-invasive treatment with cell- or circuit-specific targeting, Eisch said. "Something taken orally or placed on the skin. There is no medication that one can take to drive gene-editing or manipulate genes right now. It's really speculative, but it's exciting speculative." 

Eisch said the goal is developing treatments that can help the broadest number of people and minimize the negative side effects and risks of current approaches. 

“This is a first step, so there is much research to be done to determine if we can translate this knowledge into practical, noninvasive treatments for people with depression,” Eisch said. “Existing brain stimulation therapies for depression are extremely helpful for many patients, but they don’t work for everyone, and they also have side effects such as memory loss and cognitive impairment. It is important to increase the number of tools available to treat depression, and find those with fewer side effects as well.”