Research Identifies Brain Circuit Linked to Anxiety and Depression

The study, led by Juan Lerma and his team at the Synaptic Physiology laboratory, part of the Institute for Neurosciences—a collaboration between the Spanish National Research Council (CSIC) and Miguel Hernández University (UMH) in Elche—was published in the journal iScience.

The research centered on the amygdala, a brain region involved in regulating emotions. The team discovered that a particular group of neurons in this area has a substantial impact on emotional and social behavior. Lerma noted that the researchers had previously established the amygdala's role in anxiety and fear, but this study identified a specific population of neurons whose imbalanced activity could trigger pathological behaviors.

Using genetically modified mice that exhibited elevated levels of the Grik4 gene, the researchers found that increased GluK4 glutamate receptors made certain neurons in the amygdala more excitable. This mouse model, developed in 2015, displays behaviors resembling anxiety and social withdrawal, traits often linked to conditions such as autism and schizophrenia.

In the basolateral amygdala, the team targeted neurons to normalize Grik4 gene activity, restoring communication with inhibitory neurons called regular firing neurons in the centrolateral amygdala. The results were striking, as Álvaro García, the study's first author, stated that this adjustment successfully reversed anxiety-related behaviors and social deficits.

To evaluate the effects, the team combined electrophysiological recordings with behavioral tests designed to measure anxiety, depression, and social interaction in rodents, assessing factors like exploration of open spaces and interest in unfamiliar mice.

The researchers employed genetic engineering techniques and modified viruses to selectively correct the neural imbalance in the basolateral amygdala, observing improvements in both brain activity and behavior.

Further investigations involved applying the same intervention to wild-type mice with elevated anxiety levels, yielding similar reductions in anxiety. Lerma expressed confidence that the identified mechanism is not restricted to the specific genetic model used in the study, suggesting it may indicate a general principle for emotional regulation in the brain.

While the intervention did not improve all symptoms—such as deficits in object recognition memory, indicating that other brain regions may contribute—the findings present a promising avenue for future therapies. The researchers concluded that targeting specific neural circuits could serve as an effective and localized strategy for treating affective disorders.

The study received funding from the Spanish State Research Agency (AEI) under the Spanish Ministry of Science, Innovation and Universities, along with support from the Severo Ochoa Excellence Program, the European Regional Development Fund (ERDF), and the Generalitat Valenciana through the PROMETEO and CIPROM programs.