A Distinct Metabolically Defined Central Nucleus Circuit Bidirectionally Controls Anxiety-Related Behaviors

摘要

Anxiety disorders are debilitating psychiatric diseases that affect similar to 16% of the world's population. Although it has been proposed that the central nucleus of the amygdala (CeA) plays a role in anxiety, the molecular and circuit mechanisms through which CeA neurons modulate anxiety-related behaviors are largely uncharacterized. Soluble epoxide hydrolase (sEH) is a key enzyme in the metabolism of polyunsaturated fatty acids (PUFAs), and has been shown to play a role in psychiatric disorders. Here, we reported that sEH was enriched in neurons in the CeA and regulated anxiety-related behaviors in adult male mice. Deletion of sEH in CeA neurons but not astrocytes induced anxiety-like behaviors. Mechanistic studies indicated that sEH was required for maintaining the the excitability of sEH positive neurons (sEH(CeA) neurons) in the CeA. Using chemogenetic manipulations, we found that sEH(CeA) neurons bidirectionally regulated anxiety-related behaviors. Notably, we identified that sEH(CeA) neurons directly projected to the bed nucleus of the stria terminalis (BNST; sEH(CeA-BNST)). Optogenetic activation and inhibition of the sEH(CeA-BNST) pathway produced anxiolytic and anxiogenic effects, respectively. In summary, our studies reveal a set of molecular and circuit mechanisms of sEH(CeA) neurons underlying anxiety.

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