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When alpha mice are trounced by weaklings, they spiral into depression

When two male mice meet in a confined space, the rules of engagement are clear: The lower ranking mouse must yield. But when these norms go out the window—say, when researchers rig such an encounter to favor the weakling—it sends the higher ranking male into a depressionlike spiral. That’s the conclusion of a new neuroimaging study that reveals how the mouse brain responds to an unexpected loss of social status, which has been shown to be a major risk factor for depression in humans, particularly men.

The new study’s approach is “clever and powerful,” says Neir Eshel, a neuroscientist and psychiatrist at Stanford University who wasn’t involved in the work. But he cautions more work is needed to extend the results to our own species.

Groups of mice live in hierarchies, both in the lab and the wild. In the lab, though, the highest ranking males form particularly despotic regimes. One or more dominant “alpha mice” will have privileged access to food and females. They can pee wherever they please, rather than in the designated corner reserved for commoners.

Hailan Hu, a neuroscientist at the Zhejiang University School of Medicine, wanted to know what would happen in the brains of these mousy muckety-mucks when their pecking order was upended. She and colleagues set up a battle of wills, designed to avoid any actual fighting or bloodshed. Ten times a day, over 4 days, the researchers put a dominant mouse nose-to-nose with a subordinate in a clear, narrow tube. Then they blocked the lower ranked rodent’s exit, leaving it no choice but to advance on its superior.

At first, the dominant mice resisted the upstarts and held their ground. But by the fourth day, they were retreating voluntarily from their opponents after only a few seconds. In doing so, the mouse kings also fell in social status and lost their high-ranking perks, including VIP access to a warm nest in the corner.

As the researchers threw the rodents’ social order into upheaval, the once-dominant mice began to exhibit symptoms of mouse depression. Their cravings for sugar water dwindled. In a widely used test of rodent “despair,” in which scientists drop mice in a tank of water to measure how long they fight to stay afloat, they gave up paddling sooner. 

Curious what the rodents’ brain activity might reveal, Hu and her colleagues turned to a technique called fiber photometry, a kind of brain-imaging and mind-control technique all in one. Researchers implanted an optical fiber in the rodents’ brains that can observe the fluorescent light cast by neurons that have been genetically modified to express fluorescent proteins when they’re active. The researchers could also shine light on specific neurons, turning up or down their activity.

The scientists homed in on a region near the brainstem called the lateral habenula (LHb). Some researchers call the equivalent region in human brains the “disappointment center.” It appears to be most active when life fails to meet our expectations—when you’re rejected for a job, say, or learn someone already ate the ice cream you left in the freezer. The region is often hyperactive in people with depression, Hu adds.

When the elite mice were forced to retreat, the scientists found, cells in their LHbs began to fire in a rapid bursting pattern, similar to patterns seen in human depression. If the scientists quieted this neural activity with the light, or if they administered a dose of the antidepressant drug ketamine, the rodents’ mood improved. What’s more, they regained their previous social status in their colony, the researchers reported earlier this week in Cell.

The results suggest that, at least in mice, treating depressive symptoms depends on interrupting a vicious cycle, Hu says. When we encounter a discrepancy between our expectations and reality—between defending one’s turf or losing ground, in the case of the dethroned mice—the mismatch whips up the LHb’s neurons into a frenzy. Next, the LHb blocks neural pathways involved in decision-making and emotional control, “weakening our grit” and making it even harder to meet our own expectations, Hu says. As frustrations and failures mount, activity keeps ramping up in the LHb. Over time, she says, the cycle begins to look a lot like depression.

That hypothesis makes intuitive sense, Eshel says. “When you’re pessimistic, you might act in a way that confirms what you already believe.” Still, figuring out whether the results apply to depression in people is “much trickier,” he says. For one thing, the rigged competition only works in males, because different social rules apply to female mice. Scientists are still searching for rodent analogs for social stress-induced depression in women. “There’s a big push to figure out what we can do in female mice,” given that women are twice as likely to be diagnosed with depression, he says.

Hu says her study does point to one potentially helpful takeaway for humans. “Try not to get too used to winning all the time.” After all, the higher your expectations, the harder you can fall.

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