Scientists Discover a Small Group of Brain Cells That Completely Reverse Anxiety and Depression in Mice

Anxiety can feel like a storm that starts deep inside the skull. For years, neuroscientists have known that the amygdala — an almond-shaped structure buried in the brain — helps whip that storm into motion. But what if calming a single group of neurons could quiet it down?

That’s what a team led by neuroscientist Juan Lerma at Spain’s Institute for Neurosciences has shown. In a study published in iScience in June 2025, his group identified a precise set of neurons in the amygdala whose overactivity can trigger anxiety, depression, and social withdrawal in mice — and whose restoration can erase those symptoms almost entirely.

“We already knew the amygdala was involved in anxiety and fear, but now we’ve identified a specific population of neurons whose imbalanced activity alone is sufficient to trigger pathological behaviors,” Lerma said in a press release.

The Anxious Amygdala

To explore how anxiety takes root, Lerma’s lab turned to a gene called Grik4, which encodes a receptor that excites neurons. Too much of this receptor, known as GluK4, makes brain cells overactive. Mice engineered to overexpress Grik4 became nervous and withdrawn, avoiding open spaces and shunning unfamiliar companions, the kind of behaviors eerily similar to anxiety and social withdrawal in humans.

Inside the amygdala, Lerma’s team found the trouble began in a network connecting two regions: the basolateral amygdala (BLA) and the centrolateral amygdala (CeL). The BLA acts like an emotional amplifier, sending signals to the CeL, where inhibitory neurons help modulate fear and stress. In the anxious mice, this communication broke down.

“We found that Grik4 overexpression in mice induces anxiety, social deficits, and amygdala output imbalance,” the study reports.

When Lerma’s team used genetic tools to normalize Grik4 levels only in the BLA, they saw something remarkable: neuronal balance returned — and so did normal behavior.

“That simple adjustment was enough to reverse anxiety-related and social deficit behaviors, which is remarkable,” said first author Álvaro García.

Behavioral tests backed it up. Mice that once huddled in dark corners began exploring open arenas. They socialized with unfamiliar mice. Their despair-like immobility in the “forced swim test” vanished. In essence, the scientists had dialed back the emotional storm of anxiety.

When Balance Breaks

The researchers pinpointed a specific group of neurons in the centrolateral amygdala, known as regular-firing neurons, as drivers of anxiety-like behavior in mice. These cells act as gatekeepers for emotional signals traveling through the amygdala. When BLA neurons went into overdrive, the regular-firing neurons became too excited, while their neighboring “late-firing” cells went quiet. That imbalance disrupted the network’s output, leading to anxiety and depression-like behaviors.

Normalizing Grik4 expression restored communication between the two groups, but only in the regular firing neurons. “Grik4 normalization in BLA restored activity in regular but not late-firing cells,” the researchers wrote in iScience. Yet this was enough to normalize behavior, suggesting that the regular-firing neurons wield outsized control over emotional regulation.

Lerma’s team also tried the same intervention in wild-type mice, normal animals (in the sense that they hadn’t been genetically modified) that naturally showed higher anxiety levels. The treatment lowered their anxiety, too.

“This validates our findings and gives us confidence that the mechanism we identified is not exclusive to a specific genetic model, but may represent a general principle for how these emotions are regulated in the brain,” Lerma said.

However, some symptoms didn’t budge. The mice still struggled with object recognition, hinting that memory-related deficits might stem from other regions like the hippocampus. That finding underscores how complex emotional disorders really are: no single brain area acts alone.

Rewiring the Emotions of the Future

Imbalances in glutamate signaling — the chemical pathway regulated by Grik4 — have been implicated in autism, schizophrenia, and bipolar disorder. Variations in the human version of this gene have turned up in studies of those conditions.

If future research confirms the same circuitry in humans, the discovery could open doors to highly localized treatments for affective disorders. Instead of bathing the brain in drugs that alter global neurotransmitter levels, scientists might one day target the precise neural circuits responsible for pathological anxiety and depression.

As the authors wrote, “The identification of such a critical role for a small population of neurons in the centrolateral amygdala circuitry… provides a new target for the therapy of affective disorders.”