Environmental Enrichment Produces a Behavioral Phenotype Mediated by Low Cyclic Adenosine Monophosphate Response Element Binding (CREB) Activity in the Nucleus Accumbens

Thomas Green, Imran N. Alibhai, C. Nathaniel Roybal, Catharine A. Winstanley, David E H Theobald, Shari G. Birnbaum, Ami R. Graham, Stephen Unterberg, Danielle L. Graham, Vincent Vialou, Caroline E. Bass, Ernest F. Terwilliger, Michael T. Bardo, Eric J. Nestler

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

Background: Previous research has shown that rats reared in an enriched condition (EC) are more sensitive to the acute effects of amphetamine than rats reared in an isolated condition (IC); yet, EC rats self-administer less amphetamine than IC rats. The present study used cocaine to further explore this environmental enrichment behavioral phenotype, as well as the underlying molecular mechanisms involved. Methods: Enriched condition and IC rats were studied in a broad battery of behavioral tests, including cocaine conditioned place preference (CPP) and self-administration and several measures of anxiety- and depression-related behavior. The involvement of the transcription factor, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), in mediating EC versus IC differences was investigated. Results: Enriched condition rats exhibited less cocaine self-administration, despite showing enhanced cocaine CPP. Enriched condition rats also displayed less depression-like behavior but higher levels of anxiety-like behavior. This behavioral phenotype is consistent with low CREB activity in the nucleus accumbens, a key brain reward region. Indeed, EC rats have less phospho-CREB (the transcriptionally active form of the protein) in the nucleus accumbens than IC rats, and a selective knockdown of CREB in this brain region of normally reared rats, by use of a novel viral vector expressing a short hairpin RNA (shRNA) directed against CREB, reproduced the EC behavioral phenotype. Conclusions: These studies identify a potential molecular mechanism for how rearing environment-a nonpharmacological, nonsurgical manipulation-can modify a wide range of complex emotional behaviors.

Original languageEnglish (US)
Pages (from-to)28-35
Number of pages8
JournalBiological Psychiatry
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

Fingerprint

Nucleus Accumbens
Response Elements
Cyclic AMP
Phenotype
Cocaine
Self Administration
Amphetamine
Anxiety
Depression
Brain
Reward
Small Interfering RNA
Carrier Proteins
Transcription Factors

Keywords

  • Addiction
  • anxiety
  • craving
  • depression
  • differential rearing
  • drug abuse
  • drug addiction
  • forced swim test
  • incentive sensitization
  • relapse
  • salience

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Environmental Enrichment Produces a Behavioral Phenotype Mediated by Low Cyclic Adenosine Monophosphate Response Element Binding (CREB) Activity in the Nucleus Accumbens. / Green, Thomas; Alibhai, Imran N.; Roybal, C. Nathaniel; Winstanley, Catharine A.; Theobald, David E H; Birnbaum, Shari G.; Graham, Ami R.; Unterberg, Stephen; Graham, Danielle L.; Vialou, Vincent; Bass, Caroline E.; Terwilliger, Ernest F.; Bardo, Michael T.; Nestler, Eric J.

In: Biological Psychiatry, Vol. 67, No. 1, 01.01.2010, p. 28-35.

Research output: Contribution to journalArticle

Green, T, Alibhai, IN, Roybal, CN, Winstanley, CA, Theobald, DEH, Birnbaum, SG, Graham, AR, Unterberg, S, Graham, DL, Vialou, V, Bass, CE, Terwilliger, EF, Bardo, MT & Nestler, EJ 2010, 'Environmental Enrichment Produces a Behavioral Phenotype Mediated by Low Cyclic Adenosine Monophosphate Response Element Binding (CREB) Activity in the Nucleus Accumbens', Biological Psychiatry, vol. 67, no. 1, pp. 28-35. https://doi.org/10.1016/j.biopsych.2009.06.022
Green, Thomas ; Alibhai, Imran N. ; Roybal, C. Nathaniel ; Winstanley, Catharine A. ; Theobald, David E H ; Birnbaum, Shari G. ; Graham, Ami R. ; Unterberg, Stephen ; Graham, Danielle L. ; Vialou, Vincent ; Bass, Caroline E. ; Terwilliger, Ernest F. ; Bardo, Michael T. ; Nestler, Eric J. / Environmental Enrichment Produces a Behavioral Phenotype Mediated by Low Cyclic Adenosine Monophosphate Response Element Binding (CREB) Activity in the Nucleus Accumbens. In: Biological Psychiatry. 2010 ; Vol. 67, No. 1. pp. 28-35.
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abstract = "Background: Previous research has shown that rats reared in an enriched condition (EC) are more sensitive to the acute effects of amphetamine than rats reared in an isolated condition (IC); yet, EC rats self-administer less amphetamine than IC rats. The present study used cocaine to further explore this environmental enrichment behavioral phenotype, as well as the underlying molecular mechanisms involved. Methods: Enriched condition and IC rats were studied in a broad battery of behavioral tests, including cocaine conditioned place preference (CPP) and self-administration and several measures of anxiety- and depression-related behavior. The involvement of the transcription factor, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), in mediating EC versus IC differences was investigated. Results: Enriched condition rats exhibited less cocaine self-administration, despite showing enhanced cocaine CPP. Enriched condition rats also displayed less depression-like behavior but higher levels of anxiety-like behavior. This behavioral phenotype is consistent with low CREB activity in the nucleus accumbens, a key brain reward region. Indeed, EC rats have less phospho-CREB (the transcriptionally active form of the protein) in the nucleus accumbens than IC rats, and a selective knockdown of CREB in this brain region of normally reared rats, by use of a novel viral vector expressing a short hairpin RNA (shRNA) directed against CREB, reproduced the EC behavioral phenotype. Conclusions: These studies identify a potential molecular mechanism for how rearing environment-a nonpharmacological, nonsurgical manipulation-can modify a wide range of complex emotional behaviors.",
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AU - Alibhai, Imran N.

AU - Roybal, C. Nathaniel

AU - Winstanley, Catharine A.

AU - Theobald, David E H

AU - Birnbaum, Shari G.

AU - Graham, Ami R.

AU - Unterberg, Stephen

AU - Graham, Danielle L.

AU - Vialou, Vincent

AU - Bass, Caroline E.

AU - Terwilliger, Ernest F.

AU - Bardo, Michael T.

AU - Nestler, Eric J.

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KW - craving

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KW - salience

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