A research team at the Institute for Neurosciences (IN), led by Juan Lerma, has discovered how a specific group of neurons in the amygdala -- a brain region associated with emotional processing -- plays a role in anxiety, depression, and alterations in social behavior. The findings, published in iScience, indicate that restoring the balance of neuronal excitability within a particular area of the amygdala can reverse these behavioral changes in mice.
Restoring Brain Balance to Reverse Anxiety
"We already understood that the amygdala was linked to anxiety and fear, but we have now pinpointed a specific population of neurons whose imbalanced activity alone can instigate pathological behaviors," explains Lerma. His team utilized a genetically modified mouse model that overexpresses the Grik4 gene, which enhances the production of GluK4-type glutamate receptors and increases neuronal excitability. These mice, developed by the same laboratory in 2015, exhibited anxiety and social withdrawal akin to symptoms observed in individuals with conditions such as autism or schizophrenia.
The researchers successfully normalized Grik4 expression specifically in neurons situated in the basolateral amygdala. This modification restored normal communication with a group of inhibitory neurons in the centrolateral amygdala referred to as "regular firing neurons." "That straightforward adjustment was sufficient to reverse anxiety-related and social deficit behaviors, which is extraordinary," states Álvaro García, the first author of the study.
The team evaluated the animals through electrophysiological recordings and behavioral tests aimed at measuring anxiety, depression, and social interaction. These assessments examine characteristics such as the preference for open versus enclosed spaces and interest in unfamiliar mice. By employing genetic engineering techniques and modified viruses, the scientists accurately rectified the dysfunction in the basolateral amygdala and monitored changes in both neuronal activity and overall behavior.
Widespread Effects Beyond Genetic Models
The researchers subsequently utilized the same methodology on normal (wild-type) mice that inherently exhibited elevated anxiety levels. The treatment also alleviated their anxiety. "This confirms our findings and instills confidence that the mechanism we have identified is not limited to a particular genetic model, but may signify a universal principle regarding the regulation of these emotions in the brain," Lerma observes.
Certain cognitive impairments, such as difficulties with object recognition memory, were not rectified, indicating that other areas, such as the hippocampus, may also contribute to these disorders. Nevertheless, the findings pave the way for promising new therapeutic approaches. "Focusing on these specific neural circuits could evolve into an effective and more targeted strategy for treating affective disorders," Lerma concludes.
This research received support 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.