Specific chemogenetic activation of norepinephrine neurons in the locus coeruleus causes stress-like behaviors in mice

Norepinephrine (NE) is one of the main neurotransmitters involved with the stress response. NE neurons in the locus coeruleus (LC) send efferent projections to the corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) to influence the neuroendocrine stress response. NE neurons also project to several additional brain regions including the limbic system and the cortex. Therefore, the NE circuits are specially positioned to regulate an integrated stress response. Study o bjective: This study aimed to investigate the participation of norepinephrine in the behavioral and endocrine responses to stress. Hypothesis: We hypothesized that the activation of NE neurons in the LC would cause stress-like behaviors in mice and that norepinephrine would depolarize CRH neurons in the PVN. Methods: In the present study we administered a DREADD-Gq-inducing virus to the LC of male and female DBH-CRE mice and investigated the effects of chemogenetic activation of LC-NE neurons. In addition, we employed transgenic mice with the expression of a fluorescent reporter in CRH neurons (CRH-ires-CRE +/- ; Ai14-TdTomato +/- ) to examine the effects of norepinephrine on CRH neurons in the PVN using whole-cell patch-clamp electrophysiology. Data: Virus administration induced the expression of DREADD/mCherry in the LC, and these neurons were mostly colocalized with tyrosine hydroxylase, which indicates that DREADD expression was restricted to catecholaminergic neurons in the LC. Specific activation of LC-NE neurons with deschloroclozapine, a DREADD agonist, caused an increased release of corticosterone to the blood, an increase in grooming behaviors, and decreased walking, rearing and food intake behaviors, with no change in immobility, i.e. a stress-like response. In addition, we showed that NE causes a depolarization on the majority of PVN-CRH neurons (11/19), although hyperpolarizations were also observed (4/19). We did not observe sexual dimorphism in behavior, the glucocorticoid release or the activity of CRH-PVN neurons in this study. Summary of Results: Activation of LC-NE neurons caused increased glucocorticoid release, increased grooming and decreased exploration. NE depolarized CRH-PVN neurons. Conclusion: Taken together this data indicates that the activation of NE neurons in the LC triggers a stress-like behavioral response and that NE depolarizes PVN-CRH neurons. This suggests that activation of NE-LC neurons causes the release of NE to the PVN and other nuclei, initiating the behavioral and endocrine components of the stress response. Supported by NIH (R01 MH119283); U.S. Department of Veterans Affairs (Merit Review BX005118). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.