α1- and β3-Adrenergic Receptor–Mediated Mesolimbic Homeostatic Plasticity Confers Resilience to Social Stress in Susceptible Mice

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. NestlerJeffrey M. Friedman, Jun Li Cao, Ming Hu Han

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalBiological Psychiatry
DOIs
StateAccepted/In press - Jan 1 2018

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Dopaminergic Neurons
Adrenergic Agents
Ventral Tegmental Area
Optogenetics
Locus Coeruleus
Adrenergic Receptors
Depression
Neurons
Nucleus Accumbens
Ion Channels
Dopamine
Pharmacology

Keywords

  • Adrenergic receptors
  • Depression
  • Locus coeruleus
  • Nucleus accumbens
  • Resilience
  • Ventral tegmental area

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

α1- and β3-Adrenergic Receptor–Mediated Mesolimbic Homeostatic Plasticity Confers Resilience to Social Stress in Susceptible Mice. / Zhang, Hongxing; Chaudhury, Dipesh; Nectow, Alexander R.; Friedman, Allyson K.; Zhang, Song; Juarez, Barbara; Liu, He; Pfau, Madeline L.; Aleyasin, Hossein; Jiang, Cheng; Crumiller, Marshall; Calipari, Erin S.; Ku, Stacy M.; Morel, Carole; Tzavaras, Nikos; Montgomery, Sarah E.; He, Michelle; Salton, Stephen R.; Russo, Scott J.; Nestler, Eric J.; Friedman, Jeffrey M.; Cao, Jun Li; Han, Ming Hu.

In: Biological Psychiatry, 01.01.2018.

Research output: Contribution to journalArticle

Zhang, H, Chaudhury, D, Nectow, AR, Friedman, AK, Zhang, S, Juarez, B, Liu, H, Pfau, ML, Aleyasin, H, Jiang, C, Crumiller, M, Calipari, ES, Ku, SM, Morel, C, Tzavaras, N, Montgomery, SE, He, M, Salton, SR, Russo, SJ, Nestler, EJ, Friedman, JM, Cao, JL & Han, MH 2018, 'α1- and β3-Adrenergic Receptor–Mediated Mesolimbic Homeostatic Plasticity Confers Resilience to Social Stress in Susceptible Mice', Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2018.08.020
Zhang, Hongxing ; Chaudhury, Dipesh ; Nectow, Alexander R. ; Friedman, Allyson K. ; Zhang, Song ; Juarez, Barbara ; Liu, He ; Pfau, Madeline L. ; Aleyasin, Hossein ; Jiang, Cheng ; Crumiller, Marshall ; Calipari, Erin S. ; Ku, Stacy M. ; Morel, Carole ; Tzavaras, Nikos ; Montgomery, Sarah E. ; He, Michelle ; Salton, Stephen R. ; Russo, Scott J. ; Nestler, Eric J. ; Friedman, Jeffrey M. ; Cao, Jun Li ; Han, Ming Hu. / α1- and β3-Adrenergic Receptor–Mediated Mesolimbic Homeostatic Plasticity Confers Resilience to Social Stress in Susceptible Mice. In: Biological Psychiatry. 2018.
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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.",
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T1 - α1- and β3-Adrenergic Receptor–Mediated Mesolimbic Homeostatic Plasticity Confers Resilience to Social Stress in Susceptible Mice

AU - Zhang, Hongxing

AU - Chaudhury, Dipesh

AU - Nectow, Alexander R.

AU - Friedman, Allyson K.

AU - Zhang, Song

AU - Juarez, Barbara

AU - Liu, He

AU - Pfau, Madeline L.

AU - Aleyasin, Hossein

AU - Jiang, Cheng

AU - Crumiller, Marshall

AU - Calipari, Erin S.

AU - Ku, Stacy M.

AU - Morel, Carole

AU - Tzavaras, Nikos

AU - Montgomery, Sarah E.

AU - He, Michelle

AU - Salton, Stephen R.

AU - Russo, Scott J.

AU - Nestler, Eric J.

AU - Friedman, Jeffrey M.

AU - Cao, Jun Li

AU - Han, Ming Hu

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Adrenergic receptors

KW - Depression

KW - Locus coeruleus

KW - Nucleus accumbens

KW - Resilience

KW - Ventral tegmental area

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