Balancing the excitation and inhibition tightrope in depression

Isaac Newton famously showed that in physics, every action has an equal and opposite reaction. A similar push-and-pull of positive and negative inputs also exists in our brains. Brain cells can send out excitatory chemical signals, and they can also receive inhibitory chemical signals, putting the brakes on further signaling.

This delicate balance of excitation and inhibition allows our brains to function normally and to react to the world around us. A new study shows that the same neurons contribute excitatory and inhibitory chemical signals in a brain area linked with how we process disappointment, and that antidepressants might be able to change this delicate molecular dance and stop some of the negative thought cycles associated with depression. But while the work finds an association, it’s not yet proof that the balance of these chemicals holds the key to relieving depressive symptoms.

The study, published September 19 in Science, focuses on the lateral habenula. This tiny area makes up the “stalk” connecting the pineal gland to the rest of the brain. It receives inputs from areas of the brain important in reward and emotional processing, including the basal ganglia.  

Some areas of the brain appear to specialize in predicting rewards, showing increases in activity in response to enjoyable things such as food, sex or drugs. Activity in these areas lets us know when things are about to get good. But for every high there is a low. The lateral habenula is thought to play a role in how we process negative events: Getting a lemon on the slot machine again or the empty inbox on your dating site. Studies in monkeys and other animals have shown that increased activity in the habenula is linked to depressive behaviors, and treatment with antidepressants decreases this activity. In addition, a study in rats and a 2009 case study in a human patient showed that deep-brain stimulation in the lateral habenula could relieve symptoms of depression.

Steven Shabel, a neuroscientist at the University of California, San Diego, wanted to know how antidepressants might be changing the lateral habenula. He and his colleagues performed a series of experiments in rats and mice, targeting the neurons that send signals into the brain area. Shabel inserted light-activated protein channels into neurons heading from the reward-related areas of the basal ganglia toward the lateral habenula.  He then used a technique called electrophysiology to carefully impale single cells with a small glass pipette, gaining access to the electrically sensitive cell membrane. Shabel could then shine light onto the cell, activating the light-sensitive protein channel and causing electrically charged ions to rush into or out of the cell. The rush of ions causes chemical messengers to be released from one cell to another. With this access to the cell membrane, Shabel could hold the cell at different electrical potentials, keeping the electrical charge higher or lower than the electrical charge outside the cell. At different potentials, different amounts of ions go rushing in and out of the membrane, stimulating the release of different chemicals.

At some potentials, the cells released the excitatory signaling molecule glutamate. At others, he watched the same cell release the inhibitory signaling molecule GABA. Further studies confirmed that the same cell was releasing both excitatory and inhibitory signals into the lateral habenula.

The lateral habenula is dominated by excitatory activity, but there is a small amount of inhibitory activity that holds the excitation in check. The excitatory activity is particularly increased during times of disappointment. “The excitatory signals dominate,” Shabel notes. “The inhibitory signals appear to limit the excitation. We think in a live animal this might limit the disappointment signal.”

Other studies have shown that the small amount of inhibitory activity decreases even further in animal models of depression. Without that small inhibitory check, the excitation overwhelms the habenula, and may lead to constant feelings of disappointment. So Shabel and his colleagues wanted to see if antidepressant treatment might alter the balance of excitatory and inhibitory signals. They administered two weeks of antidepressants to normal mice and to a rat model of depression, and found that the inhibitory signals to the lateral habenula increased.

“It’s known that antidepressants can reduce people’s processing of negative events,” Shabel says. “So we think this might be one mechanism for how they do that.” If higher activity in the habenula is a sign of increased experience of negative events, increasing inhibition to that area could help combat some of the symptoms of depression. But Shabel cautions “there are a lot of experiments that still need to be done.”

Thomas Hahn, a computational neuroscientist at the Bernstein Center for Computational Neuroscience in Mannheim, Germany, notes that the methods were “expertly done.” But he cautions that while the study shows the signals coming into the lateral habenula from reward-related areas, it doesn’t show anything going out. Without data coming out of the habenula, Hahn notes, it’s impossible to tell how the inputs are affecting the area. “One should not forget that the lateral habenula gets numerous other inputs,” he says. “So it’s not clear that a bit more [inhibitory signaling] would do the job” of controlling all the inputs going in to the area.

And while the study shows that antidepressant treatment can change the excitatory and inhibitory balance, it does not show what effect this has on behavior. While the authors did use doses of antidepressants that have been effective in other animals and in other laboratories, they didn’t do any behavioral studies of depressive behavior to go with their studies of the habenula. Catherine Belzung, a neuroscientist at the University of Tours in France, says that while the paper is “certainly important,” without behavior or depression-related biomarkers, “the data presented are not causal.”

Shabel says his next goal is to “look at disappointment in rodents, to see if the pathway is affecting behavior. The idea is then to look at whether antidepressants do decrease the responses in the habenula, and how that affects the animal’s behavior.” If the behavioral studies are promising, he hopes that eventually scientists might find drugs that specifically alter activity in habenula to treat depression. But in the meantime, more studies are needed to understand the delicate chemical push and pull that underlies how we experience life’s disappointments.