α1- and β3-Adrenergic Receptor–Mediated Mesolimbic Homeostatic Plasticity Confers Resilience to Social Stress in Susceptible Mice
Open accessAbstract
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 α 1- and β 3-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 α 1- and β 3-adrenergic receptors as new molecular targets for therapeutically promoting resilience.
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Several brain regions that innervate bone marrow have been linked to stress responses, reward processing and the pathogenesis of depression and anxiety disorders.
“Notably, several of these bone marrow-innervating brain regions have been implicated in stress responses, reward processing and the pathogenesis of depression and anxiety disorders.”
From Central regulation of stress-evoked peripheral immune responses (2023) · cites this paper as [45]
The Discussion (page unavailable) identifies the locus coeruleus–ventral tegmental area–nucleus accumbens circuit as a stress-resilience pathway, and the paper studies it in a model of depression. Our copy does not establish that these regions innervate bone marrow or directly link the circuit to the pathogenesis of anxiety disorders; its reference list alone does not establish those parts of the claim. (LLM, conf=0.83)
Experimental — accuracy not yet measuredStress activates locus coeruleus neurons in resilient mice and promotes resilience to social avoidance.
“whereas it activates LC neurons in resilient mice to promote resilience to social avoidance behaviour44–46.”
From Central regulation of stress-evoked peripheral immune responses (2023) · cites this paper as [45]
Activation of α1 and β3 adrenergic receptors balances Ih and K+ currents to reverse hyperactivity of nucleus accumbens projecting ventral tegmental area neurons.
“Activation of these receptors balances Ih and K+ currents to reverse the hyperactivity of NAc projecting VTA neurons [38].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [38]
Repeated activation of ventral tegmental area projecting locus coeruleus neurons promotes chronic social defeat stress resilience through α1 and β3 adrenergic receptors on ventral tegmental area dopamine neurons.
“Repeated activation of VTA projecting LC neurons promotes CSDS-resilience through α1 and β3 adrenergic receptors on VTA dopamine neurons [38].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [38]
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Self-citation
- Authors
- Zhang, H., Chaudhury, D., Nectow, A. R., Friedman, A. K., Zhang, S., Juarez, B., Liu, H., Pfau, M. L., Aleyasin, H., Jiang, C., Crumiller, M., Calipari, E. S., Ku, S. M., Morel, C., Tzavaras, N., Montgomery, S. E., He, M., Salton, S. R., Russo, S. J., Nestler, E. J., Friedman, J. M., Cao, J.-L., & Han, M.-H.
- Affiliations
- Xuzhou Medical College (CN)
- New York University Abu Dhabi (AE)
- Howard Hughes Medical Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- University of Washington (US)
- Rockefeller University (US)
- Corresponding author
- Cao, Jun-Li
- Han, Ming-Hu
- ORCID
- Zhang, Hongxing
- Chaudhury, Dipesh
- Nectow, Alexander R.
- Friedman, Allyson K.
- Zhang, Song
- Juarez, Barbara
- Liu, He
- Aleyasin, Hossein
- Jiang, Cheng
- Calipari, Erin S.
- 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
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 85
- Issue
- 3
- Pages
- 226-236
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC6800029
- OpenAlex
- W2890059556
- Cited by
- 88
- References
- 52
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 17 · 2023: 8 · 2022: 12 · 2021: 12 · 2020: 5 · 2019: 11 · 2017: 1
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01 MH092306, MH051399)
- National Natural Science Foundation of China (NSFC81230025, 81720108013, NSFC81200862, 81771453)
- Jiangsu Province Natural Science Foundation (BK20171158)
- Xuzhou Medical University (D2018010)
- National Research Service (F31 AA022862, T32 MH 087004, MH096464)
- Jiangsu Provincial Special Program of Medical Science (BL2014029)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- homeostatic plasticity, social defeat stress, locus coeruleus, ventral tegmental area, mesolimbic dopamine neurons, nucleus accumbens, alpha1-adrenoceptors, beta3-adrenergic receptor, chronic social defeat, depression, optogenetic manipulation
- MeSH terms
- Animals, Behavior, Animal, Homeostasis, Locus Coeruleus, Male, Neural Pathways, Neuronal Plasticity, Stress, Psychological, Ventral Tegmental Area, Receptors, Adrenergic, alpha-1, Receptors, Adrenergic, beta-3, Mice, Resilience, Psychological, Adrenergic alpha-1 Receptor Agonists, Adrenergic beta-3 Receptor Agonists, Adrenergic alpha-1 Receptor Antagonists, Adrenergic beta-3 Receptor Antagonists, Dopaminergic Neurons
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