Inhibition of c-Jun in AgRP neurons mediates chronic stress-induced anxiety-like behaviors and colitis susceptibility

ABSTRACT Psychiatric disorders, such as anxiety, are frequently associated with inflammatory bowel diseases (IBD), however, the neural mechanisms are unknown. Here, we showed that hypothalamic agouti-related protein (AgRP) neuronal activity was suppressed under chronic restraint stress (CRS), a condition known to induce anxiety-like behaviors and increase colitis susceptibility. Consistently, chemogenic activation (inhibition) of AgRP neurons reversed (mimicked) CRS-induced anxiety-like behaviors and colitis susceptibility. Furthermore, CRS inhibited AgRP neuronal activity by suppressing the expression of c-Jun. As expected, overexpression of c-Jun in these neurons protected against the CRS-induced these effects and knockdown of c-Jun in AgRP neurons ( c-Jun ΔAgRP ) promoted anxiety-like behaviors and colitis. Moreover, relieving the anxiety with cyamemazine (an anxiolytic drug) alleviated colitis susceptibility in c-Jun ΔAgRP mice. Finally, according to a proteomic analysis, the levels of the secreted protein thrombospondin 1 (THBS1) were negatively associated with the increased anxiety-like behaviors and colitis susceptibility, supplementing recombinant THBS1 rescued colitis in c-Jun ΔAgRP mice. Taken together, these results reveal a critical role of hypothalamic AgRP neuron-derived c-Jun in orchestrating chronic stress-induced anxiety-like behaviors and colitis susceptibility. These results provide a new perspective for understanding the neuronal mechanisms and potential therapeutic target for the comorbidity of psychiatric disorders, such as anxiety, and IBD.