A pancreas-hippocampus feedback mechanism regulates circadian changes in depression-related behaviors

Individuals with neuropsychiatric disorders often show metabolic symptoms. However, the mechanisms underlying this co-occurrence remain unclear. Here we show that induced pluripotent stem cell-derived pancreatic islets from individuals with bipolar disorder have insulin secretion deficits caused by increased expression of RORβ, a susceptibility gene for bipolar disorder. Enhancing RORβ expression in mouse pancreatic β cells induced depression-related behaviors in the light phase and mania-like behaviors in the dark phase. Pancreatic RORβ overexpression in the light phase reduced insulin release from islets, inducing hippocampal hyperactivity and depression-like behaviors. Furthermore, this hippocampal hyperactivity in the light phase had the delayed effect of promoting insulin release in the dark phase, resulting in mania-like behaviors and hippocampal neuronal hypoactivity. Our results in mice point to a pancreas-hippocampus feedback mechanism by which metabolic and circadian factors cooperate to generate behavioral fluctuations and which may play a role in bipolar disorder.