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

Autor: Erin S. Calipari, Song Zhang, Madeline L. Pfau, Hossein Aleyasin, Ming-Hu Han, Allyson K. Friedman, He Liu, Jeffrey M. Friedman, Nikos Tzavaras, Marshall Crumiller, Stephen R.J. Salton, Stacy M. Ku, Michelle He, Hongxing Zhang, Sarah E. Montgomery, Alexander R. Nectow, Jun Li Cao, Cheng Jiang, Barbara Juarez, Scott J. Russo, Eric J. Nestler, Dipesh Chaudhury, Carole Morel
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Adrenergic receptor
Adrenergic beta-3 Receptor Agonists
Nucleus accumbens
Optogenetics
Biology
Article
Social defeat
Mice
03 medical and health sciences
0302 clinical medicine
Receptors
Adrenergic
alpha-1
Homeostatic plasticity
Neural Pathways
medicine
Animals
Homeostasis
Biological Psychiatry
Social stress
Neuronal Plasticity
Behavior
Animal
Dopaminergic Neurons
musculoskeletal
neural
and ocular physiology
Ventral Tegmental Area
Resilience
Psychological
Ventral tegmental area
030104 developmental biology
medicine.anatomical_structure
nervous system
Receptors
Adrenergic
beta-3
Adrenergic alpha-1 Receptor Antagonists
Locus coeruleus
Locus Coeruleus
Adrenergic alpha-1 Receptor Agonists
Adrenergic beta-3 Receptor Antagonists
Neuroscience
Stress
Psychological
030217 neurology & neurosurgery
Zdroj: Biological Psychiatry. 85:226-236
ISSN: 0006-3223
Popis: 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.
Databáze: OpenAIRE
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