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 iPSC-derived pancreatic islets from individuals with bipolar disorder (BD) have insulin secretion deficits caused by increased expression of RORß, a susceptibility gene for BD. Enhancing RORß expression in mouse pancreatic ß-cells induced depression-related behaviors in the light phase and mania-like behaviors in the dark phase. Pancreatic RORß overexpression in the light phase reduced insulin release from islets, inducing hippocampal hyperactivity and depression-like behaviors. Further, this hippocampal hyperactivity in the light phase had the delayed effect of promoting insulin release in the dark phase, resulting 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. Overall design: The experimental conditions and variables under investigation included replicates. We utilized neurons and islet-like organoids derived from healthy controls who had no psychiatric disorders, serving as the control group.