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

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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Authors

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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