Norepinephrine neurons in the locus coeruleus and the nucleus of the solitary tract drive different stress-related behavioral outputs in mice

Norepinephrine (NE) is one of the main neuromodulators that regulate the stress response. NE-expressing neurons in the locus coeruleus (LC) and the nucleus of the solitary tract (NTS) project to the corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) to regulate the hypothalamic-pituitary-adrenal (HPA) axis response to stress. NE neurons also project to other brain regions to regulate stress outputs, including throughout the limbic system and the medial prefrontal cortex. The NE circuits, therefore, are well-positioned to regulate an integrated stress response that coordinates the activation of the HPA axis with different behavioral responses appropriate to distinct stressors. Here, we show that chemogenetic activation of LC-NE neurons induces affective stress behaviors while activation of NTS-NE neurons stimulates sickness-like behaviors. Selective activation of NE neurons in the NTS caused an increase in immobility, a decrease in mechanical nociception threshold, and reduced exploratory, grooming, and feeding behaviors. Activation of LC-NE neurons, on the other hand, caused an increase in grooming and a decrease in exploratory behaviors, but no change in immobility. Stimulation of either the NTS-NE or LC-NE neurons elicited an increase in activation of the HPA axis. Taken together, our results show that the activation of NTS-NE and LC-NE neurons stimulates both redundant and distinct aspects of the stress response, perhaps via stimulation of both discreet and overlapping populations of PVN neurons. • Activation of PVN-projecting NE neurons causes immobility and increased grooming • Chemogenetic activation of LC NE neurons induces stress-like behaviors in mice • Chemogenetic activation of NTS NE neurons induces sickness-like behaviors in mice • Both LC and NTS NE neurons activate the HPA axis