Seattle Children’s researchers are illuminating the huge role a tiny part of the brain may play in depression and moods.

In 2014, Dr. Eric Turner ’s team found that a tiny part of the brain – the dorsal medial habenula (dMHb) – helps regulate moods and controls the motivation to exercise and engage in pleasurable activities in mice, and thus potentially in people.

New Insights into Depression

The dMHb is part of the habenula, which is located in the brain stem. Researchers have long suspected that the dMHb and other habenula components play an important role in everything from moods to stress to sleep. But the dMHb has been nearly impossible to study because it is very small (about a fifth of a millimeter across in mice) and hard to manipulate without interfering with neighboring brain regions.

Turner’s team used innovative tools – including mice whose neurons can be activated by lasers – to pinpoint the dMHb’s function and show how it may contribute to depression.

“It shows how much we can learn about mental illness by investigating parts of the brain that have been overlooked or too hard to study,” Turner says.

Game-changing mice

In the past, researchers could only use crude techniques to wipe out the dMHb.

“Older approaches either eliminated the entire habenula or cut its output circuit. The habenula is a complex area, so you never really knew what specific region was causing your results,” Turner says.

Dr. Yun-Wei (Toni) Hsu, a postdoctoral fellow in Turner’s lab, solved this by genetically engineering mice without a dMHb.

In the first part of their latest study, Turner’s team showed that mice without a dMHb lost interest in things they would normally enjoy. The mice lost their preference for sugar-sweetened water. In collaboration with Dr. Horacio de la Iglesia at the University of Washington, the team also tested the mice’s inclination to use a running wheel, an activity they usually seem to love. Mice lacking the dorsal medial habenula were far less interested in running than the control mice.

“We’d never seen anything like it – mice usually run on their exercise wheels like crazy as soon as it gets dark, but the modified mice preferred to lay around,” Hsu says. “Without a functioning dMHb, they were just like patients with depression.”

Laser-activated neurons
New Insights into Depression

Turner’s lab used another innovative tool to pinpoint the dMHb’s role: optogenetic mice that let researchers activate parts of the brain using tiny lasers.

Researchers use viruses or genetic engineering to insert light-sensitive proteins into neurons in these mice. Those neurons can then be turned on and off with pulses of light that are delivered through fiber-optic cables. Researchers can then observe how turning the light on changes a mouse’s behavior.

Investigators at the Allen Institute for Brain Science created the mice. Turner’s lab was among the first to test them and Hsu engineered a version where dMHb activity can be isolated and controlled.

During the second part of the dMHb study, Turner’s lab placed these mice in a cage with two response wheels. The mice could turn one wheel with their paws to trigger a laser that activated the dMHb. Nothing happened when they turned the other wheel. The mice strongly preferred the dMHb wheel and turned it over and over again.

“We think this shows that dMHb activity enhances your mood and maybe protects you from depression,” Turner says.

The results were published in the Journal of Neuroscience.

Depression treatments

Turner is a practicing psychiatrist, and the habenula research is the latest step in his quest to understand how depression stops patients from enjoying things they used to love and makes them too lethargic to exercise.

“Exercise is one of the best treatments for depression, but it can be impossible for patients to find the drive to get up and move,” Turner says.

One of his next goals is to see if drug treatment or electrical stimulation can boost dMHb activity and restore lab mice’s desire to exercise.

“We have a long way to go before this could work in people,” Turner says, “but it might be possible to develop treatments that activate the dMHb and help people get back to enjoying their lives.”

It might be possible to develop treatments that activate the dorsal medial habenula and help people get back to enjoying their lives.
Dr. Eric Turner