In the present study, we found that chronic HFD treatment leads to desensitization of AgRP neurons in response to hunger, downregulation of GABAAR-α5 signaling, and upregulation of 5-HT3R within the post-synaptic MC4RdBNST neurons, rendering abnormal hyperactivity of MC4RdBNST neurons with an overall effect on promoting HFD-mediated anxiety and depression (Fig. 6w). Here, AGRP is linked to depressive symptom measurement.