Hongxing Zhang1, Dipesh Chaudhury2, Alexander R Nectow3, Allyson K Friedman4, Song Zhang1, Barbara Juarez5, He Liu6, Madeline L Pfau7, Hossein Aleyasin8, Cheng Jiang7, Marshall Crumiller9, Erin S Calipari7, Stacy M Ku10, Carole Morel4, Nikos Tzavaras11, Sarah E Montgomery4, Michelle He4, Stephen R Salton7, Scott J Russo8, Eric J Nestler7, Jeffrey M Friedman3, Jun-Li Cao12, Ming-Hu Han13. 1. 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. 2. Department of Pharmacological Sciences, Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates. 3. Laboratory of Molecular Genetics, The Rockefeller University, New York, New York; Howard Hughes Medical Institute, Chevy Chase, Maryland. 4. Department of Pharmacological Sciences, Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York. 5. Department of Pharmacological Sciences, Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York; Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pharmacology, University of Washington, Seattle, Washington. 6. 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; Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates. 7. Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 8. Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Center for Affective Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 9. Laboratory of Biophysics, The Rockefeller University, New York, New York. 10. Department of Pharmacological Sciences, Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York; Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 11. Microscopy CORE, Icahn School of Medicine at Mount Sinai, New York, New York. 12. 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; Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. Electronic address: caojl0310@aliyun.com. 13. Department of Pharmacological Sciences, Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York; Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Center for Affective Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: ming-hu.han@mssm.edu.
Abstract
BACKGROUND: Homeostatic 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. METHODS: In 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. RESULTS: We 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. CONCLUSIONS: These 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.
BACKGROUND: Homeostatic 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. METHODS: In 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. RESULTS: We 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. CONCLUSIONS: These 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.
Authors: Jun-Li Cao; Herbert E Covington; Allyson K Friedman; Matthew B Wilkinson; Jessica J Walsh; Donald C Cooper; Eric J Nestler; Ming-Hu Han Journal: J Neurosci Date: 2010-12-08 Impact factor: 6.167
Authors: Joseph P Doyle; Joseph D Dougherty; Myriam Heiman; Eric F Schmidt; Tanya R Stevens; Guojun Ma; Sujata Bupp; Prerana Shrestha; Rajiv D Shah; Martin L Doughty; Shiaoching Gong; Paul Greengard; Nathaniel Heintz Journal: Cell Date: 2008-11-14 Impact factor: 41.582
Authors: Olivier Berton; Colleen A McClung; Ralph J Dileone; Vaishnav Krishnan; William Renthal; Scott J Russo; Danielle Graham; Nadia M Tsankova; Carlos A Bolanos; Maribel Rios; Lisa M Monteggia; David W Self; Eric J Nestler Journal: Science Date: 2006-02-10 Impact factor: 47.728
Authors: Christoph Naegeli; Thomas Zeffiro; Marco Piccirelli; Assia Jaillard; Anina Weilenmann; Katayun Hassanpour; Matthis Schick; Michael Rufer; Scott P Orr; Christoph Mueller-Pfeiffer Journal: Biol Psychiatry Date: 2017-09-07 Impact factor: 13.382
Authors: Matthew E Carter; Ofer Yizhar; Sachiko Chikahisa; Hieu Nguyen; Antoine Adamantidis; Seiji Nishino; Karl Deisseroth; Luis de Lecea Journal: Nat Neurosci Date: 2010-10-31 Impact factor: 24.884
Authors: Sylvia Klineova; Rachel Brandstadter; Michelle T Fabian; Ilana Katz Sand; Stephen Krieger; Victoria M Leavitt; Christina Lewis; Claire S Riley; Fred Lublin; Aaron E Miller; James F Sumowski Journal: Mult Scler Date: 2019-06-07 Impact factor: 6.312