• Hongxing Zhang, Dipesh Chaudhury, Alexander R Nectow, Allyson K Friedman, Song Zhang, Barbara Juarez, He Liu, Madeline L Pfau, Hossein Aleyasin, Cheng Jiang, Marshall Crumiller, Erin S Calipari, Stacy M Ku, Carole Morel, Nikos Tzavaras, Sarah E Montgomery, Michelle He, Stephen R Salton, Scott J Russo, Eric J Nestler, Jeffrey M Friedman, Jun-Li Cao, and Ming-Hu Han.
• Department of Pharmacological Sciences, Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
• Biol. Psychiatry. 2019 Feb 1; 85 (3): 226-236.

BackgroundHomeostatic plasticity in mesolimbic dopamine (DA) neurons plays an essential role in mediating resilience to social stress. Recent evidence implicates an association between stress resilience and projections from the locus coeruleus (LC) to the ventral tegmental area (VTA) (LC→VTA) DA system. However, the precise circuitry and molecular mechanisms of the homeostatic plasticity in mesolimbic DA neurons mediated by the LC→VTA circuitry, and its role in conferring resilience to social defeat stress, have not been described.MethodsIn a well-established chronic social defeat stress model of depression, using projection-specific electrophysiological recordings and optogenetic, pharmacological, and molecular profiling techniques, we investigated the functional role and molecular basis of an LC→VTA circuit in conferring resilience to social defeat stress.ResultsWe found that LC neurons projecting to the VTA exhibit enhanced firing activity in resilient, but not susceptible, mice. Optogenetically mimicking this firing adaptation in susceptible mice reverses their depression-related behaviors, and induces reversal of cellular hyperactivity and homeostatic plasticity in VTA DA neurons projecting to the nucleus accumbens. Circuit-specific molecular profiling studies reveal that α1- and β3-adrenergic receptors are highly expressed in VTA→nucleus accumbens DA neurons. Pharmacologically activating these receptors induces similar proresilient effects at the ion channel and cellular and behavioral levels, whereas antagonizing these receptors blocks the proresilient effect of optogenetic activation of LC→VTA circuit neurons in susceptible mice.ConclusionsThese findings reveal a key role of the LC→VTA circuit in mediating homeostatic plasticity in stress resilience and reveal α1- and β3-adrenergic receptors as new molecular targets for therapeutically promoting resilience.Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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