Restoring neuron balance in the amygdala reverses anxiety in mice

The Synaptic Physiology laboratory, led by Juan Lerma at the Institute for Neurosciences (IN), a joint center of the Spanish National Research Council (CSIC) and Miguel Hernández University (UMH) of Elche, has discovered that a specific group of neurons in the amygdala, a brain region involved in emotion regulation, plays a key role in the emergence of conditions such as anxiety, depression, and altered social behavior. This study, published in iScience, shows that restoring the neuronal excitability balance in a specific area of the amygdala is enough to reverse these behaviors in mice.

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.”

Juan Lerma, Institute for Neurosciences (IN), a joint center of the Spanish National Research Council (CSIC)

His team utilized a genetically modified mouse model to overexpress the Grik4 gene, thereby increasing the number of GluK4-type glutamate receptors and raising neuronal excitability. These animals, developed by the same lab in 2015, show anxiety and social withdrawal behaviors very similar to those observed in individuals with disorders such as autism or schizophrenia.

The researchers normalized the gene’s expression specifically in neurons of the basolateral amygdala, which restored communication with another group of inhibitory neurons in the centrolateral amygdala known as ‘regular firing neurons’. “That simple adjustment was enough to reverse anxiety-related and social deficit behaviors, which is remarkable”, says Álvaro García, first author of the study.

The animals were evaluated using electrophysiological techniques and behavioral tests that measure anxiety, depression, and social interaction in rodents, based on their preference for exploring open spaces or their interest in unfamiliar mice. Then, using genetic engineering and modified viruses, the scientists selectively corrected the alteration in the basolateral amygdala and observed changes in both neuronal activity and the animals’ behavior.

They also applied the same procedure to wild-type mice that displayed intrinsic anxiety, and it was also effective in reducing their anxiety. “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 adds.

Some behavioral deficits, such as object recognition memory, were not resolved, suggesting that other brain areas, such as the hippocampus, may also be involved in these disorders and remain uncorrected. The study opens the door to new therapeutic possibilities: “Targeting these specific neural circuits could become an effective and more localized strategy to treat affective disorders”, the researcher concludes.

This work was possible thanks to funding from the Spanish State Research Agency (AEI) – Spanish Ministry of Science, Innovation and Universities, the Severo Ochoa Excellence Program for Research Centers at the Institute for Neurosciences CSIC-UMH, the European Regional Development Fund (ERDF), and the Generalitat Valenciana through the PROMETEO and CIPROM programs.