The brain’s dorsal medial habenula (dMHb) may be responsible for an individual’s motivation to exercise and participate in other potentially rewarding activities, a finding that could lead to improved depression treatment.

A study of mice showed that the dMHb, which in mice has a structure similar to that in humans, controlled the animals’ desire to exercise. Those that were genetically engineered to block signals from the dMHb were more lethargic and ran significantly less than the unaltered mice. The altered mice also lost the desire for sweetened drinking water, which they preferred beforehand.

“These mice lost 2 kinds of pleasure, which are some of the best kinds of tests you can do to measure their mood,” principal investigator Eric E. Turner, MD, professor at the Center for Integrative Brain Research at Seattle Children’s Research Institute in Washington, told Medscape Medical News.

“We’re interested in this because when patients become depressed, they lose interest in exercise, their hobbies, and their usual rewarding activities,” said Dr. Turner, who is also a professor in the Department of Psychiatry and Behavioral Sciences at the University of Washington.

The investigators add that the findings could potentially help in the development of more targeted treatments for depression in the future.

“I think with the habenula, we’ve tapped into a specific circuit. And when you treat depression, you look for an entry point into that circuit where you can increase activity through a drug or deep brain stimulation,” said Dr. Turner.

“The habenula has some unique neurotransmitters. And neurotransmitters like dopamine or serotonin are really the places where you could possibly intervene to design new drugs.”

The study was published in the August 20 issue of the Journal of Neuroscience.

Primitive Part of Brain

Dr. Turner noted that the dMHb is a “primitive part of the brain that sits on top of the thalamus, which is the major relay station for traffic coming in and out of the brain.”

The habenula has been implicated in the regulation of learning, memory, maternal behaviors, sleep, stress, and even the behavioral effects of nicotine, the investigators write.

“However, most prior studies have disrupted habenula function with lesions of the entire nucleus or the fasciculus retroflexus…and thus have not allowed the specific functions of MHb and LHb [lateral habenula], or their subnuclei, to be discerned,” they add.
The current study was divided into parts. In the first part, a group of mice had neurons from the dMHb removed through “tissues-specific deletion of the transcription factor Pou4f1 (Brn3a),” report the investigators.

The second part of the study “used Cre recombinase-mediated expression of channelrhodopsin-2 and halorhodopsin to activate dMHb neurons or silence their output in freely moving mice, respectively,” write the researchers.

In other words, a different group of mice had their dMHb areas activated through optogenetics, a precise laser technology. Turning 1 or 2 response wheels with their paws allowed these mice to “choose” for themselves whether or not to activate this area of their brain through laser stimulation.

“Optogenetics is a method by which we make neurons sensitive to light, so they can be stimulated with an implanted optical fiber connected to a laser,” explained Dr. Turner.
Results from the first part of the study showed that the mice with the blocked dMHb signals exhibited significantly less wheel running activity at night vs the control mice (P = .0004). However, they showed normal levels of “basal locomotion” and only minor changes in their gait and balance.

“Without a functioning [dMHb], the mice became couch potatoes,” said Dr. Turner. “They were physically capable of running but appeared unmotivated to do it.”

The altered mice also showed a significant decrease in sucrose preference vs the control mice (P = .04), but no difference was evident in a forced swim test. The investigators note that both of these are common measures of “depression-related phenotypes in rodents.”

Future Role in Treating Depression

In the second part of the study, the optogenetic mice showed a significantly stronger preference for turning a response wheel that stimulated their dMHb vs the unaltered littermates, “demonstrating that this area of the brain is tied to rewarding behavior,” report the investigators.

“Optical activation of the dMHb in vivo supports intracranial self-stimulation, showing that dMHb activity is intrinsically reinforcing, whereas optical silencing of dMHb outputs is aversive,” they write.

They go on to note that deep brain stimulation of the habenula has been shown in past case reports to be effective in treating depression.

“Although to date this has been interpreted in the context of the LHb-negative motivational system, the findings presented here indicate that the potential role of dMHb activity in clinical depression…should also be considered,” write the researchers.

Dr. Turner admitted that working in the field of mental health can often be frustrating.
“We have not made a lot of progress in developing new treatments. I hope the more we can learn about how the brain functions, the more we can help people with all kinds of mental illness,” he said.

“As a basic scientist as well as a clinician, I believe that we need to really understand how some of this circuitry works at a more detailed level before we can jump ahead with clinical treatments that are not based on guesses but on a real understanding of the circuitry.”

J Neurosci. 2014;34:11366-11384.