CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli
Open accessAbstract
The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed.
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CREB is induced in the NAc by natural rewards such as sucrose, and reduces an animal's sensitivity to the rewarding effects of sucrose.
“CREB is also induced in the NAc by natural rewards (such as sucrose), and similarly reduces an animal's sensitivity to the rewarding effects of sucrose [89].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [89]
Increased CREB activity in the NAc is negatively related to behavioral responses to cocaine, opiates, and alcohol in numerous experimental systems.
“in numerous experimental systems, increased CREB activity in the NAc is negatively related to behavioral responses to cocaine, opiates, and alcohol [86,88-90].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [89]
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- Authors
- Barrot, M., Olivier, J. D. A., Perrotti, L. I., DiLeone, R. J., Berton, O., Eisch, A. J., Impey, S., Storm, D. R., Neve, R. L., Yin, J. C., Zachariou, V., & Nestler, E. J.
- Affiliations
- Harvard University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2002-08-06
- Volume
- 99
- Issue
- 17
- Pages
- 11435-11440
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC123274
- OpenAlex
- W2149823377
- Cited by
- 508
- References
- 51
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 10 · 2023: 7 · 2022: 14 · 2021: 10 · 2020: 24 · 2019: 23 · 2018: 14 · 2017: 16 · 2016: 15 · 2015: 15 · 2014: 27 · 2013: 18 · 2012: 49
- FWCI
- 9.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- HAL (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- CREB, nucleus accumbens shell, morphine reward, sucrose preference, stress response, nociception, emotional stimuli, transcriptional regulation, addiction, mood disorders, drugs of abuse
- MeSH terms
- Animals, Anxiety, Avoidance Learning, beta-Galactosidase, Conditioning, Psychological, Emotions, Mice, Transgenic, Nucleus Accumbens, Pain, Stereotaxic Techniques, Transcription, Genetic, Cyclic AMP Response Element-Binding Protein, Genes, Reporter, Substance-Related Disorders, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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