A hidden brain energy signal drives depression and anxiety

To better understand how ATP functions in this area, the team examined signaling patterns in the hippocampus and how they changed under stress. The hippocampus has long been associated with mood disorders, in part because it is sensitive to prolonged stress and is involved in shaping emotional behavior. disruptions in this region can affect how the brain processes stress, which may set the stage for depression or anxiety.

Stress, ATP Loss, and the Role of Connexin 43

The researchers found that male mice prone to developing depressive- and anxiety-like behaviors after long-term stress had lower levels of ATP. These mice also produced less of a key protein required for ATP release (connexin 43). Connexin 43 forms channels that allow ATP to move between certain cells, making it an important part of how the brain maintains healthy energy and signaling levels.

To test whether reduced ATP release contributed to mood-related symptoms, the team genetically decreased or removed connexin 43 in cells that normally release ATP. This experiment was done in another group of mice that had not been exposed to prolonged stress. Even without a stressful environment, lowering connexin 43 triggered depressive- and anxiety-like behaviors and reduced ATP levels. This finding suggested that disruptions in ATP release alone could influence emotional behavior.

When the researchers restored connexin 43 in the hippocampus of stressed mice, ATP levels returned to normal and the animals showed noticeable improvements in their behavior. This recovery helped reinforce the idea that ATP signaling plays a central role in regulating mood.

A Shared Biological Pathway for Depression and Anxiety

Gao explains, "This is the first direct evidence that deficient ATP release in [a region of the] hippocampus drives both depressive- and anxiety-like behaviors, revealing a shared molecular pathway [for these conditions]." Identifying such a pathway is important, as depression and anxiety often occur together and can be difficult to treat simultaneously with existing therapies.

Gao notes that the link between connexin 43 and ATP release highlights a possible target for future treatments. By improving or restoring ATP signaling, scientists may eventually be able to develop interventions that address both conditions at once. The research team also plans to include both male and female mice in upcoming studies to determine whether these mechanisms operate similarly across sexes, which could broaden the relevance of their findings.