Pancreas ↔ hippocampus: day-night mood "pendulum" found

Researchers have described a new feedback loop between the pancreas and the hippocampus that regulates circadian variations in behavior associated with depression and mania. In people with bipolar disorder, iPSC-pancreatic islets showed a defect in insulin secretion associated with increased expression of the RORβ gene. And artificially enhancing RORβ in mouse β cells induced “depressive” responses during the day and “mania-like” responses at night, via shifts in insulin and hippocampal neuronal activity. The authors propose a “pancreas↔hippocampus” model in which metabolism and the circadian clock work together to sway behavior. The study is published in the journal Nature Neuroscience.

Background

In bipolar disorder (BD), metabolic disturbances are very common - insulin resistance, diabetes, fluctuations in appetite and body weight. At the same time, BD is characterized by daily fluctuations in sleep, energy and mood. The connection is noticeable, but a mechanism that directly connects metabolism and the brain "on the clock" has long been lacking.

• Insulin affects the brain. Insulin receptors are found in the hippocampus; the hormone can alter neuronal excitability and synaptic plasticity. However, it remained unclear whether the rhythm of insulin secretion from the pancreas itself could “pump” mood along a circadian cycle.
• The hippocampus is not just about memory. In addition to memory, it is involved in regulating emotions and stress. Imbalances in its network activity have been linked to depressive and manic states, but the source of the peripheral “metabolic drive” for these shifts was not obvious.
• Clock and the transcription factor RORβ. Circadian genes coordinate rhythms in tissues. RORβ is a “clock” transcription factor; its role in pancreatic β-cells and possible influence on behavior via insulin are largely unknown.
• Main gap. Not shown:
  1. that a defect in β-cells (and not just in the brain) can cause day-night shifts in emotional behavior;
  2. that there is a feedback loop between the pancreas and the hippocampus (pancreas → insulin → hippocampus → response → subsequent insulin secretion).

The idea of the work

• To test whether a proportion of patients with bipolar disorder have cellular evidence of defective insulin secretion (on iPSC islets).
• To model in mice a selective enhancement of RORβ in β cells to see if this would induce predictable diurnal shifts in insulin, alter hippocampal excitability, and lead to depressive/manic-like behavioral phenotypes.
• To test the idea of a bidirectional “pancreas ↔ hippocampus” circuit that could explain the diurnal mood swings in bipolar disorder.

In other words, the authors close the gap between clinical observations (metabolic comorbidities and circadian disturbances in bipolar disorder) and a specific mechanism whereby insulin rhythms from the pancreas are able to restructure hippocampal activity and, as a consequence, behavior.

What exactly did they do?

• In cell models (iPSC islets) from patients with bipolar disorder, insulin deficiency and its association with increased RORβ were found.
• In mice, a local increase in RORβ in β cells during the day reduced insulin release → hippocampal hyperactivity and depressive-like behavior; this shift had a delayed effect at night - insulin increased, hippocampal neurons "quieted down", manic-like reactions appeared.
• The result is a two-way loop: the pancreas tunes the hippocampus through insulin, and the state of the hippocampus changes subsequent insulin secretion, setting a day-night inversion of behavior.

Why is this important?

The connection between psychiatry and metabolism has long been noted: insulin resistance and diabetes are more common in bipolar disorder, and circadian rhythm disorders are one of the “faces” of the disease. The new work suggests a mechanistic link – the hormone insulin and the clock that synchronizes the periphery and the brain. This helps explain why some patients experience mood “waves” depending on the time of day.

How does this fit into known biology?

• Insulin and memory. Insulin receptors are present in the hippocampus; insulin signaling is involved in plasticity and memory encoding. Metabolic disorders affect hippocampal circuits and cognition.
• Circadian factors and mood. A number of “clock” transcription factors have already been linked to diurnal fluctuations in affect; the fact that the circuit also involves a peripheral hormone adds to the overall picture.
• Parallel findings: Related models have manipulated insulin secretion (e.g., via Syt7) and found similar day-night fluctuations in emotional behavior—indirect support for the mood “metabolic lever.”

What it doesn't mean

• This is preclinical: cell models and mice. It is too early to talk about “treating bipolar disorder with insulin” or “RORβ inhibitors/agonists” in humans. Confirmation is needed in patients: do bipolar disorder subgroups have stable insulin rhythm disturbances that correlate with hippocampal activity and daily mood swings?

Possible practical implications (if the hypothesis holds up to scrutiny)

• Timing of therapy. Consider time of day when prescribing medications and behavioral interventions; adjust sleep-light-nutrition as part of treatment.
• Metabolic screening in bipolar disorder: insulin resistance and disrupted eating/sleep rhythms are potential targets for affect stabilization.

Conclusion

The Nature Neuroscience paper offers a bold idea: insulin from the pancreas and neurons in the hippocampus form a feedback loop that swings mood hourly. If the circuit is confirmed in humans, it could explain some of the metabolic comorbidities in bipolar disorder and suggest new application areas, from therapy timing to targets in the metabolism↔brain axis.