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Genetic identification of a population of noradrenergic neurons implicated in attenuation of stress-related responses

Abstract

Noradrenergic signaling plays a well-established role in promoting the stress response. Here we identify a subpopulation of noradrenergic neurons, defined by developmental expression of Hoxb1, that has a unique role in modulating stress-related behavior. Using an intersectional chemogenetic strategy, in combination with behavioral and physiological analyses, we show that activation of Hoxb1-noradrenergic (Hoxb1-NE) neurons decreases anxiety-like behavior and promotes an active coping strategy in response to acute stressors. In addition, we use cerebral blood volume-weighted functional magnetic resonance imaging to show that chemoactivation of Hoxb1-NE neurons results in reduced activity in stress-related brain regions, including the bed nucleus of the stria terminalis, amygdala, and locus coeruleus. Thus, the actions of Hoxb1-NE neurons are distinct from the well-documented functions of the locus coeruleus in promoting the stress response, demonstrating that the noradrenergic system contains multiple functionally distinct subpopulations.

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Acknowledgements

Valuable support was provided by the NIEHS Comparative Medicine Branch, Biostatistics and Computational Biology Branch, Neurobehavioral Core and Fluorescence Microscopy and Imaging Core. We thank the NIDA Drug Supply Program for providing the CNO. This research was supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences (ZIA-ES102805 to P.J. and ZIA-ES090089-21 to J.L.Y.), and the Extramural Research Programs of the National Institute of Mental Health (R01MH111429, R41MH113252, R21MH106939) and National Institute of Neurological Disorders and Stroke (R01NS091236) to Y.Y.I.S.

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Y.W.C. and P.J. conceived, designed, and supervised the project. The behavioral and physiological tests were performed by Y.W.C. and G.J., and analyzed by Y.W.C. The fMRI experiments and analyses were performed by M.D. and E.A.O. under the guidance of Y.Y.I.S.; Q.C. performed the electrophysiological recordings under the guidance of J.L.Y.; Immunohistochemistry, in situ hybridization, and image acquisition was performed by K.G.S, G.J., D.M., and N.W.P.; Cell counts were performed by D.M. and G.J.; Y.W.C. and P.J. wrote the manuscript with input from co-authors.

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Correspondence to Patricia Jensen.

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Chen, YW., Das, M., Oyarzabal, E.A. et al. Genetic identification of a population of noradrenergic neurons implicated in attenuation of stress-related responses. Mol Psychiatry 24, 710–725 (2019). https://doi.org/10.1038/s41380-018-0245-8

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