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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Nestler, E.J. et al. Neurobiology of depression. Neuron 34, 13–25 (2002).
Barrot, M. et al. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc. Natl. Acad. Sci. USA 99, 11435–11440 (2002).
Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006).
Mendelson, S.D. & McEwen, B.S. Autoradiographic analyses of the effects of restraint-induced stress on 5-HT1A, 5-HT1C and 5-HT2 receptors in the dorsal hippocampus of male and female rats. Neuroendocrinology 54, 454–461 (1991).
Hall, F.S. Social deprivation of neonatal, adolescent, and adult rats has distinct neurochemical and behavioral consequences. Crit. Rev. Neurobiol. 12, 129–162 (1998).
Grippo, A.J., Cushing, B.S. & Carter, C.S. Depression-like behavior and stressor-induced neuroendocrine activation in female prairie voles exposed to chronic social isolation. Psychosom. Med. 69, 149–157 (2007).
Costello, J. & Kendrick, K. Grief and older people: the making or breaking of emotional bonds following partner loss in later life. J. Adv. Nurs. 32, 1374–1382 (2000).
Heinrich, L.M. & Gullone, E. The clinical significance of loneliness: a literature review. Clin. Psychol. Rev. 26, 695–718 (2006).
Ahmed, S.H., Stinus, L., Le Moal, M. & Cador, M. Social deprivation enhances the vulnerability of male Wistar rats to stressor- and amphetamine-induced behavioral sensitization. Psychopharmacology (Berl.) 117, 116–124 (1995).
Barrot, M. et al. Regulation of anxiety and initiation of sexual behavior by CREB in the nucleus accumbens. Proc. Natl. Acad. Sci. USA 102, 8357–8362 (2005).
Ehlers, C.L., Walker, B.M., Pian, J.P., Roth, J.L. & Slawecki, C.J. Increased alcohol drinking in isolate-housed alcohol-preferring rats. Behav. Neurosci. 121, 111–119 (2007).
Deroche, V., Piazza, P.V., Le Moal, M. & Simon, H. Social isolation-induced enhancement of the psychomotor effects of morphine depends on corticosterone secretion. Brain Res. 640, 136–139 (1994).
Greco, A.M., Gambardella, P., Sticchi, R., D'Aponte, D. & De Franciscis, P. Chronic administration of imipramine antagonizes deranged circadian rhythm phases in individually housed rats. Physiol. Behav. 48, 67–72 (1990).
Stranahan, A.M., Khalil, D. & Gould, E. Social isolation delays the positive effects of running on adult neurogenesis. Nat. Neurosci. 9, 526–533 (2006).
Blendy, J.A. The role of CREB in depression and antidepressant treatment. Biol. Psychiatry 59, 1144–1150 (2006).
Newton, S.S. et al. Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect. J. Neurosci. 22, 10883–10890 (2002).
Pliakas, A.M. et al. Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. J. Neurosci. 21, 7397–7403 (2001).
Carlezon, W.A., Jr. et al. Regulation of cocaine reward by CREB. Science 282, 2272–2275 (1998).
Pandey, S.C. et al. CREB gene transcription factors: role in molecular mechanisms of alcohol and drug addiction. Alcohol. Clin. Exp. Res. 29, 176–184 (2005).
Carlezon, W.A., Jr ., Duman, R.S. & Nestler, E.J. The many faces of CREB. Trends Neurosci. 28, 436–445 (2005).
de Jong, T.R., Veening, J.G., Waldinger, M.D., Cools, A.R. & Olivier, B. Serotonin and the neurobiology of the ejaculatory threshold. Neurosci. Biobehav. Rev. 30, 893–907 (2006).
Ferguson, J.M. The effects of antidepressants on sexual functioning in depressed patients: a review. J. Clin. Psychiatry 62 Suppl 3: 22–34 (2001).
Rothschild, A.J. Sexual side effects of antidepressants. J. Clin. Psychiatry 61 Suppl11: 28–36 (2000).
Bolanos, C.A., Barrot, M., Berton, O., Wallace-Black, D. & Nestler, E.J. Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood. Biol. Psychiatry 54, 1317–1329 (2003).
Yirmiya, R. Endotoxin produces a depressive-like episode in rats. Brain Res. 711, 163–174 (1996).
Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).
Balfour, M.E., Yu, L. & Coolen, L.M. Sexual behavior and sex-associated environmental cues activate the mesolimbic system in male rats. Neuropsychopharmacology 29, 718–730 (2004).
Hull, E.M. & Dominguez, J.M. Sexual behavior in male rodents. Horm. Behav. 52, 45–55 (2007).
Meisel, R.L. & Mullins, A.J. Sexual experience in female rodents: cellular mechanisms and functional consequences. Brain Res. 1126, 56–65 (2006).
Conti, A.C. & Blendy, J.A. Regulation of antidepressant activity by cAMP response element binding proteins. Mol. Neurobiol. 30, 143–155 (2004).
Tsankova, N., Renthal, W., Kumar, A. & Nestler, E.J. Epigenetic regulation in psychiatric disorders. Nat. Rev. Neurosci. 8, 355–367 (2007).
Kumar, A. et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48, 303–314 (2005).
McClung, C.A. & Nestler, E.J. Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Nat. Neurosci. 6, 1208–1215 (2003).
Dong, Y. et al. CREB modulates excitability of nucleus accumbens neurons. Nat. Neurosci. 9, 475–477 (2006).
Duman, R.S. & Monteggia, L.M. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 1116–1127 (2006).
Berton, O. & Nestler, E.J. New approaches to antidepressant drug discovery: beyond monoamines. Nat. Rev. Neurosci. 7, 137–151 (2006).
Dulawa, S.C. & Hen, R. Recent advances in animal models of chronic antidepressant effects: the novelty-induced hypophagia test. Neurosci. Biobehav. Rev. 29, 771–783 (2005).
Nibuya, M., Nestler, E.J. & Duman, R.S. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J. Neurosci. 16, 2365–2372 (1996).
Chen, A.C., Shirayama, Y., Shin, K.H., Neve, R.L. & Duman, R.S. Expression of the cAMP response element–binding protein (CREB) in hippocampus produces an antidepressant effect. Biol. Psychiatry 49, 753–762 (2001).
Pandey, S.C. The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol addiction. Pharmacol. Ther. 104, 47–58 (2004).
Bell, T.J. et al. Cytoplasmic BK(Ca) channel intron-containing mRNAs contribute to the intrinsic excitability of hippocampal neurons. Proc. Natl. Acad. Sci. USA 105, 1901–1906 (2008).
Salkoff, L., Butler, A., Ferreira, G., Santi, C. & Wei, A. High-conductance potassium channels of the SLO family. Nat. Rev. Neurosci. 7, 921–931 (2006).
Brown, E.S., Rush, A.J. & McEwen, B.S. Hippocampal remodeling and damage by corticosteroids: implications for mood disorders. Neuropsychopharmacology 21, 474–484 (1999).
Thome, J. et al. cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J. Neurosci. 20, 4030–4036 (2000).
Warner-Schmidt, J.L. & Duman, R.S. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 16, 239–249 (2006).
Impey, S. et al. Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat. Neurosci. 1, 595–601 (1998).
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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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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