Exendin-4 alleviates anxiety-like behaviors in chronic restraint stress mice via regulating BLA GLP-1R/BDNF signaling.

Clinical studies have suggested that exendin-4 (Ex-4) exhibits therapeutic potential for anxiety disorders, yet the molecular mechanisms underlying its efficacy remain largely unclear. Our study demonstrates that Ex-4 at specific doses ameliorates anxiety-like behaviors in mice. Mechanistically, Ex-4 could cross the blood-brain barrier and enter the central nervous system, where it exerts anxiolytic effects by activating glucagon-like peptide-1 receptor (GLP-1R) in the basolateral amygdala (BLA). Anterior dorsal bed nucleus of the stria terminalis (adBNST) as a downstream projection target of BLA neurons. Chemogenomic inhibition of the BLA-adBNST circuit induced anxiety-like phenotypes, which were rescued by Ex-4 treatment. Brain-derived neurotrophic factor (BDNF), a critical neurotrophin implicated in neuropsychiatric disorders including anxiety and depression, was functionally interrogated in this pathway. Furthermore, conditional knockdown of Bdnf in the BLA-adBNST circuit abolished the anxiolytic effects of Ex-4, indicating that the activation of GLP-1R in BLA neurons drives BDNF release into adBNST to mitigate anxiety. Taken together, these studies identify a central mechanism whereby Ex-4 attenuates anxiety-like behaviors by promoting BDNF release in the BLA-adBNST circuit.