Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell
The transcription factor ΔFosB and the brain-enriched calcium/calmodulin-dependent protein kinase II (CaMKIIα) are induced in the nucleus accumbens (NAc) by chronic exposure to cocaine or other psychostimulant drugs of abuse, in which the two proteins mediate sensitized drug responses. Although ΔFos...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Society for Neuroscience
2013
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| Online Access: | http://hdl.handle.net/1721.1/81336 https://orcid.org/0000-0002-3854-5968 |
| _version_ | 1826216710427901952 |
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| author | Neve, Rachael L. Robison, Alfred J. Vialou, Vincent Mazei-Robison, Michelle S. Feng, Jian Kourrich, Said Collins, Miles Wee, Sunmee Koob, George Turecki, Gustavo Thomas, Mark Nestler, Eric J. |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Neve, Rachael L. Robison, Alfred J. Vialou, Vincent Mazei-Robison, Michelle S. Feng, Jian Kourrich, Said Collins, Miles Wee, Sunmee Koob, George Turecki, Gustavo Thomas, Mark Nestler, Eric J. |
| author_sort | Neve, Rachael L. |
| collection | MIT |
| description | The transcription factor ΔFosB and the brain-enriched calcium/calmodulin-dependent protein kinase II (CaMKIIα) are induced in the nucleus accumbens (NAc) by chronic exposure to cocaine or other psychostimulant drugs of abuse, in which the two proteins mediate sensitized drug responses. Although ΔFosB and CaMKIIα both regulate AMPA glutamate receptor expression and function in NAc, dendritic spine formation on NAc medium spiny neurons (MSNs), and locomotor sensitization to cocaine, no direct link between these molecules has to date been explored. Here, we demonstrate that ΔFosB is phosphorylated by CaMKIIα at the protein-stabilizing Ser27 and that CaMKII is required for the cocaine-mediated accumulation of ΔFosB in rat NAc. Conversely, we show that ΔFosB is both necessary and sufficient for cocaine induction of CaMKIIα gene expression in vivo, an effect selective for D[subscript 1]-type MSNs in the NAc shell subregion. Furthermore, induction of dendritic spines on NAc MSNs and increased behavioral responsiveness to cocaine after NAc overexpression of ΔFosB are both CaMKII dependent. Importantly, we demonstrate for the first time induction of ΔFosB and CaMKII in the NAc of human cocaine addicts, suggesting possible targets for future therapeutic intervention. These data establish that ΔFosB and CaMKII engage in a cell-type- and brain-region-specific positive feedforward loop as a key mechanism for regulating the reward circuitry of the brain in response to chronic cocaine. |
| first_indexed | 2024-09-23T16:52:10Z |
| format | Article |
| id | mit-1721.1/81336 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:52:10Z |
| publishDate | 2013 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/813362022-09-29T22:01:32Z Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell Neve, Rachael L. Robison, Alfred J. Vialou, Vincent Mazei-Robison, Michelle S. Feng, Jian Kourrich, Said Collins, Miles Wee, Sunmee Koob, George Turecki, Gustavo Thomas, Mark Nestler, Eric J. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Neve, Rachael L. The transcription factor ΔFosB and the brain-enriched calcium/calmodulin-dependent protein kinase II (CaMKIIα) are induced in the nucleus accumbens (NAc) by chronic exposure to cocaine or other psychostimulant drugs of abuse, in which the two proteins mediate sensitized drug responses. Although ΔFosB and CaMKIIα both regulate AMPA glutamate receptor expression and function in NAc, dendritic spine formation on NAc medium spiny neurons (MSNs), and locomotor sensitization to cocaine, no direct link between these molecules has to date been explored. Here, we demonstrate that ΔFosB is phosphorylated by CaMKIIα at the protein-stabilizing Ser27 and that CaMKII is required for the cocaine-mediated accumulation of ΔFosB in rat NAc. Conversely, we show that ΔFosB is both necessary and sufficient for cocaine induction of CaMKIIα gene expression in vivo, an effect selective for D[subscript 1]-type MSNs in the NAc shell subregion. Furthermore, induction of dendritic spines on NAc MSNs and increased behavioral responsiveness to cocaine after NAc overexpression of ΔFosB are both CaMKII dependent. Importantly, we demonstrate for the first time induction of ΔFosB and CaMKII in the NAc of human cocaine addicts, suggesting possible targets for future therapeutic intervention. These data establish that ΔFosB and CaMKII engage in a cell-type- and brain-region-specific positive feedforward loop as a key mechanism for regulating the reward circuitry of the brain in response to chronic cocaine. 2013-10-07T12:10:06Z 2013-10-07T12:10:06Z 2013-03 2012-12 Article http://purl.org/eprint/type/JournalArticle 0270-6474 1529-2401 http://hdl.handle.net/1721.1/81336 Robison, A. J., V. Vialou, M. Mazei-Robison, J. Feng, S. Kourrich, M. Collins, S. Wee, et al. “Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving FosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell.” Journal of Neuroscience 33, no. 10 (March 6, 2013): 4295-4307. https://orcid.org/0000-0002-3854-5968 en_US http://dx.doi.org/10.1523/jneurosci.5192-12.2013 Journal of Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Society for Neuroscience Society for Neuroscience |
| spellingShingle | Neve, Rachael L. Robison, Alfred J. Vialou, Vincent Mazei-Robison, Michelle S. Feng, Jian Kourrich, Said Collins, Miles Wee, Sunmee Koob, George Turecki, Gustavo Thomas, Mark Nestler, Eric J. Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell |
| title | Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell |
| title_full | Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell |
| title_fullStr | Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell |
| title_full_unstemmed | Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell |
| title_short | Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell |
| title_sort | behavioral and structural responses to chronic cocaine require a feedforward loop involving δfosb and calcium calmodulin dependent protein kinase ii in the nucleus accumbens shell |
| url | http://hdl.handle.net/1721.1/81336 https://orcid.org/0000-0002-3854-5968 |
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