LAUSR

Melanin‐concentrating hormone (MCH) neurons within the hypothalamus are heterogeneous and can coexpress additional neuropeptides and transmitters. The majority of MCH neurons express vesicular transporters to package glutamate for synaptic release, and MCH neurons can directly innervate downstream neurons via glutamate release. Although glutamatergic signalling from MCH neurons may support physiological and behavioural roles that are independent of MCH (e.g., in glucose homeostasis and nutrient‐sensing), it can also mediate similar roles to MCH in the regulation of energy balance. In addition to energy balance, the MCH system has also been implicated in mood disorders, as MCH receptor antagonists have anxiolytic and anti‐depressive effects. However, the contribution of glutamatergic signalling from MCH neurons to mood‐related functions have not been investigated. We crossed Mch‐cre mice with floxed‐Vglut2 mice to delete the expression of the vesicular glutamate transporter 2 (Vglut2) and disable glutamatergic signalling specifically from MCH neurons. The resulting Mch‐Vglut2‐KO mice showed Vglut2 deletion from over 75% of MCH neurons, and although we did not observe changes in depressive‐like behaviours, we found that Mch‐Vglut2‐KO mice displayed anxiety‐like behaviours. Mch‐Vglut2‐KO mice showed reduced exploratory activity when placed in a new cage and were quicker to consume food placed in the centre of a novel open arena. These findings showed that Vglut2 deletion from MCH neurons resulted in anxiolytic actions and suggested that the anxiogenic effects of glutamate are similar to those of the MCH peptide. Taken together, these findings suggest that glutamate and MCH may synergize to regulate and promote anxiety‐like behaviour.