Pancreatic insulin disruption triggers bipolar disorder-like behaviors in mice, study shows

Bipolar disorder is a psychiatric disorder characterized by alternating episodes of depression (i.e., low mood and a loss of interest in everyday activities) and mania (i.e., a state in which arousal and energy levels are abnormally high). On average, an estimated 1–2% of people worldwide are diagnosed with bipolar disorder at some point during their lives.

Bipolar disorder can be highly debilitating, particularly if left untreated. Understanding the neural and physiological processes that contribute to its emergence could thus be very valuable, as it could inform the development of new prevention and treatment strategies.

In addition to experiencing periodic changes in mood, individuals diagnosed with this disorder often exhibit some metabolic symptoms, including changes in their blood sugar levels. While some previous studies reported an association between blood sugar control mechanisms and bipolar disorder, the biological link between the two has not yet been uncovered.

Researchers at Tsinghua University, the Chinese Academy of Sciences and other institutes in China recently carried out a study aimed at further exploring the link between insulin secretion and bipolar disorder-like behaviors, particularly focusing on the expression of the gene RORβ.

Their findings, published in Nature Neuroscience, show that an overexpression of this gene in a subtype of pancreatic cells disrupts the release of insulin, which in turn prompts a feedback loop with a region of the brain known as the hippocampus, producing alternative depression-like and mania-like behaviors in mice.

“Individuals with neuropsychiatric disorders often show metabolic symptoms. However, the mechanisms underlying this co-occurrence remain unclear,” wrote Yao-Nan Liu, Qiu-Wen Weng and their colleagues in their paper. “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.”

As part of their study, the researchers first extracted stem cells from individuals diagnosed with bipolar disorder and used them to create pancreatic islets, clusters of cells in the pancreas that support the regulation of blood sugar in the human body. When they tested these islets’ release of insulin (i.e., a hormone that allows the body to use and store energy derived from food), they found that it was significantly disrupted as a result of an overexpression of the RORβ gene.

The researchers also carried out experiments involving mice that had an increased expression of RORβ in a subset of pancreatic cells known as β cells. The team observed the mice both during the day, when they are typically resting, and at night, when their activity levels are generally higher.

“Enhancing RORβ expression in mouse pancreatic β cells induced depression-related behaviors in the light phase and mania-like behaviors in the dark phase,” wrote the authors.

“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.”

Interestingly, the researchers observed that an overexpression of the RORβ gene in β pancreatic cells prompted bipolar-like behavioral patterns in mice. Specifically, the mice were found to be particularly low energy during the day and high-energy during the night. The team’s findings hint at the existence of a mechanism that links cells in the pancreas with activity in the hippocampus, a brain region that supports memory processes and some emotional behavior.

“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,” wrote the authors.

The recent work by Liu, Weng and their colleagues sheds new light on the connection between metabolic processes, particularly insulin release, and bipolar disorder. In the future, it could inspire other neuroscientists to probe the existence and neuro-physiological underpinnings of the pancreas-hippocampus feedback loop identified by the researchers.

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