Stressor-specific dynamic patterns of noradrenaline release in the paraventricular nucleus of the hypothalamus in freely moving mice
An organism is constantly challenged with various stressors. These stress signals ultimately converge on the hypothalamic paraventricular nucleus (PVN), where they are integrated by corticotropin-releasing hormone (CRH)-producing neurons that are primarily involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline (NA), among others, is recognized as the major transmitter that regulates the PVN-CRH neurons, and thereby is involved in the regulation of the HPA axis as well as the autonomic outflow. Previous studies have demonstrated that stress increases NA release within the PVN1 and that NA activates CRH neurons2. However, NA release patterns from the axon terminals in the PVN upon stress exposure have not yet been studied, because continuous monitoring of transmitter release became possible only recently. In the present study, we aimed to monitor stressor-dependent NA release patterns in the PVN. To continuously monitor NA release in freely moving mice, a fluorescent NA sensor (GRABNA)3,4 was expressed in the PVN, and the emitted signals were recorded via fibre photometry. Following stress exposure, NA release took place over distinct timescales ranging from seconds to hours. For example, a pulsatile NA release was observed in seconds in response to an acute nociceptive stressor. In contrast, sustained physical stressors, such as tail suspension and restraint, induced much more prolonged NA release that persists throughout the stress exposure period over tens of minutes. Intraperitoneal administration of lipopolysaccharide produced a gradual increase in NA release that persisted for several hours. These findings demonstrate that NA is released into the PVN in a stress-specific manner. In addition, elevated NA release was associated with increased behavioural activity, characteristic of each stressor. Together, these findings provide a framework for understanding how the temporal dynamics of NA release in the PVN encode diverse stress signals, and regulate neuroendocrine outputs.