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CREB regulation of nucleus accumbens excitability mediates social isolation–induced behavioral deficits

Nature Neuroscience volume 12, pages 200–209 (2009)Cite this article

Abstract

Here, we characterized behavioral abnormalities induced by prolonged social isolation in adult rodents. Social isolation induced both anxiety- and anhedonia-like symptoms and decreased cAMP response element–binding protein (CREB) activity in the nucleus accumbens shell (NAcSh). All of these abnormalities were reversed by chronic, but not acute, antidepressant treatment. However, although the anxiety phenotype and its reversal by antidepressant treatment were CREB-dependent, the anhedonia-like symptoms were not mediated by CREB in NAcSh. We found that decreased CREB activity in NAcSh correlated with increased expression of certain K+ channels and reduced electrical excitability of NAcSh neurons, which was sufficient to induce anxiety-like behaviors and was reversed by chronic antidepressant treatment. Together, our results describe a model that distinguishes anxiety- and depression-like behavioral phenotypes, establish a selective role of decreased CREB activity in NAcSh in anxiety-like behavior, and provide a mechanism by which antidepressant treatment alleviates anxiety symptoms after social isolation.

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Figure 1: Social isolation induces behavioral deficits.
Figure 2: Social isolation and imipramine modulate CREB activity in the NAcSh.
Figure 3: Increasing CREB activity in NAcSh of socially isolated animals reverses the anxiety-like behavior, but not the reward-related deficits, induced by social isolation.
Figure 4: Patterns of gene regulation in the NAcSh of socially isolated versus double-housed animals.
Figure 5: Effect of social isolation in NAcSh on resting membrane potential (RMP), neuronal excitability and current-voltage relationship.

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Acknowledgements

This work was supported by grants from the National Institute of Mental Health (E.J.N.) and National Alliance of Research for Schizophrenia and Depression (M.-H.H.).

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Author notes

  1. Deanna L Wallace, Danielle L Graham & Thomas A Green

    Present address: Present addresses: Helen Willis Neuroscience Institute, University of California Berkeley, 132 Barker Hall, Berkeley, California 94720, USA (D.L.W.), Merck Laboratories, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA (D.L.G.), and Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 East Clay Street, Richmond, Virginia 23298, USA (T.A.G.).,

  2. Deanna L Wallace and Ming-Hu Han: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390-9070, Texas, USA

    Deanna L Wallace, Ming-Hu Han, Danielle L Graham, Thomas A Green, Vincent Vialou, Jun-Li Cao, Anne Kirk, Sumana Chakravarty, Arvind Kumar, Vaishnav Krishnan, Don C Cooper, Colleen A McClung & Eric J Nestler

  2. Fishberg Department of Neuroscience, Mount Sinai School of Medicine, One Gustav L. Levy Place Box 1065, New York, 10029, 02115, New York, USA

    Vincent Vialou & Eric J Nestler

  3. Department of Psychology, Florida State University, 1107 W. Call Street, Tallahassee, 32306-4301, Florida, USA

    Sergio D Iñiguez & Carlos A Bolaños

  4. Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, 02178, Massachusetts, USA

    Rachael L Neve

  5. Institut des Neurosciences Cellulaires et Intégratives, UMR7168, CNRS and University Louis Pasteur, 21 Rue Descartes, Strasbourg, 67084, France

    Michel Barrot

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Contributions

D.L.W. conducted the behavioral, immunohistochemical, cell counting and RT-PCR experiments, surgeries and tissue collection, and wrote the manuscript. M.-H.H. conducted the electrophysiology experiments and contributed to the preparation of the manuscript. D.L.G., T.A.G. and V.V. assisted with surgeries, tissue collection and RT-PCR experiments. S.D.I. assisted with behavioral and electrophysiology experiments. J.-L.C. and D.C.C. assisted with electrophysiology experiments. A. Kirk assisted with the behavioral experiments, immunohistochemistry and surgeries. S.C., A. Kumar and R.L.N. prepared the viral constructs. V.K. and C.A.B. assisted with behavioral experiments. M.B. assisted with behavioral experiments and preparation of the manuscript. C.A.M. conducted microarray experiments and their analysis, and E.J.N. oversaw the design and execution of the overall project and writing of the manuscript.

Corresponding author

Correspondence to Eric J Nestler.

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Wallace, D., Han, MH., Graham, D. et al. CREB regulation of nucleus accumbens excitability mediates social isolation–induced behavioral deficits. Nat Neurosci 12, 200–209 (2009). https://doi.org/10.1038/nn.2257

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