| Abstrakt: |
Neuronal activity is modulated not only by inputs from other neurons but also by various factors, such as bioactive substances. Noradrenergic (NA) neurons in the locus coeruleus (LC-NA neurons) are involved in diverse physiological functions, including sleep/wakefulness and stress responses. Previous studies have identified various substances and receptors that modulate LC-NA neuronal activity through techniques including electrophysiology, calcium imaging, and single-cell RNA sequencing. However, many substances with unknown physiological significance have been overlooked. Here, we established an efficient screening method for identifying substances that modulate LC-NA neuronal activity through intracellular calcium ([Ca2+]i) imaging using brain slices. Using both sexes of mice, we screened 53 bioactive substances, and identified five novel substances: gastrin-releasing peptide, neuromedin U, and angiotensin II, which increase [Ca2+]i, and pancreatic polypeptide and prostaglandin D2, which decrease [Ca2+]i. Among them, neuromedin U induced the greatest response in female mice. In terms of the duration of [Ca2+]i change, we focused on prostaglandin E2 (PGE2), since it induces a long-lasting decrease in [Ca2+]i via the EP3 receptor. Conditional knock-out of the receptor in LC-NA neurons resulted in increased depression-like behavior, prolonged wakefulness in the dark period, and increased [Ca2+]i after stress exposure. Our results demonstrate the effectiveness of our screening method for identifying substances that modulate a specific neuronal population in an unbiased manner and suggest that stress-induced prostaglandin E2 can suppress LC-NA neuronal activity to moderate the behavioral response to stressors. Our screening method will contribute to uncovering previously unknown physiological functions of uncharacterized bioactive substances in specific neuronal populations. [ABSTRACT FROM AUTHOR] |
