Hyperexcitation of the glutamatergic neurons in lateral hypothalamus induced by chronic pain contributes to depression-like behavior and learning and memory impairment in male mice.

Chronic pain can induce mood disorders and cognitive dysfunctions, such as anxiety, depression, and learning and memory impairment in humans. However, the specific neural network involved in anxiety- and depression-like behaviors and learning and memory impairment caused by chronic pain remains poorly understood. In this study, behavioral test results showed that chronic pain induced anxiety- and depression-like behaviors, and learning and memory impairment in male mice. c-Fos immunofluorescence and fiber photometry recording showed that glutamatergic neurons in the LH of mice with chronic pain were selectively activated. Next, the glutamatergic neurons of LH in normal mice were activated using optogenetic and chemogenetic methods, which recapitulates some of the depressive-like behaviors, as well as memory impairment, but not anxiety-like behavior. Finally, inhibition of glutamatergic neurons in the LH of mice with chronic pain, effectively relieved anxiety- and depression-like behaviors and learning and memory impairment. Taken together, our findings suggest that hyperexcitation of glutamatergic neurons in the LH is involved in depression-like behavior and learning and memory impairment induced by chronic pain.