Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress
Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in fe...
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| Format: | Article |
| Language: | en_US |
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Society for Neuroscience
2017
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| Online Access: | http://hdl.handle.net/1721.1/110520 https://orcid.org/0000-0002-3854-5968 |
| _version_ | 1811078115330359296 |
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| author | Hodes, G. E. Pfau, M. L. Purushothaman, I. Ahn, H. F. Golden, S. A. Christoffel, D. J. Magida, J. Brancato, A. Takahashi, A. Flanigan, M. E. Menard, C. Aleyasin, H. Koo, J. W. Lorsch, Z. S. Feng, J. Heshmati, M. Wang, M. Turecki, G. Zhang, B. Shen, L. Nestler, E. J. Russo, S. J. Neve, Rachael L. |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Hodes, G. E. Pfau, M. L. Purushothaman, I. Ahn, H. F. Golden, S. A. Christoffel, D. J. Magida, J. Brancato, A. Takahashi, A. Flanigan, M. E. Menard, C. Aleyasin, H. Koo, J. W. Lorsch, Z. S. Feng, J. Heshmati, M. Wang, M. Turecki, G. Zhang, B. Shen, L. Nestler, E. J. Russo, S. J. Neve, Rachael L. |
| author_sort | Hodes, G. E. |
| collection | MIT |
| description | Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more susceptible to SCVS, whereas Dnmt3a knock-out in this region rendered females more resilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that a DNA methyltransferase in NAc contributes to sex differences in stress vulnerability. |
| first_indexed | 2024-09-23T10:53:38Z |
| format | Article |
| id | mit-1721.1/110520 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:53:38Z |
| publishDate | 2017 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/1105202022-09-30T23:48:46Z Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress Hodes, G. E. Pfau, M. L. Purushothaman, I. Ahn, H. F. Golden, S. A. Christoffel, D. J. Magida, J. Brancato, A. Takahashi, A. Flanigan, M. E. Menard, C. Aleyasin, H. Koo, J. W. Lorsch, Z. S. Feng, J. Heshmati, M. Wang, M. Turecki, G. Zhang, B. Shen, L. Nestler, E. J. Russo, S. J. Neve, Rachael L. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Neve, Rachael L. Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more susceptible to SCVS, whereas Dnmt3a knock-out in this region rendered females more resilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that a DNA methyltransferase in NAc contributes to sex differences in stress vulnerability. 2017-07-07T14:09:20Z 2017-07-07T14:09:20Z 2015-12 2015-10 Article http://purl.org/eprint/type/JournalArticle 0270-6474 1529-2401 http://hdl.handle.net/1721.1/110520 Hodes, G. E.; Pfau, M. L.; Purushothaman, I.; Ahn, H. F.; Golden, S. A.; Christoffel, D. J.; Magida, J. et al. “Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility Versus Resilience to Subchronic Variable Stress.” Journal of Neuroscience 35, 50 (December 2015): 16362–16376 © 2015 The Authors https://orcid.org/0000-0002-3854-5968 en_US http://dx.doi.org/10.1523/jneurosci.1392-15.2015 Journal of Neuroscience Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Society for Neuroscience Society for Neuroscience |
| spellingShingle | Hodes, G. E. Pfau, M. L. Purushothaman, I. Ahn, H. F. Golden, S. A. Christoffel, D. J. Magida, J. Brancato, A. Takahashi, A. Flanigan, M. E. Menard, C. Aleyasin, H. Koo, J. W. Lorsch, Z. S. Feng, J. Heshmati, M. Wang, M. Turecki, G. Zhang, B. Shen, L. Nestler, E. J. Russo, S. J. Neve, Rachael L. Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress |
| title | Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress |
| title_full | Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress |
| title_fullStr | Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress |
| title_full_unstemmed | Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress |
| title_short | Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress |
| title_sort | sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress |
| url | http://hdl.handle.net/1721.1/110520 https://orcid.org/0000-0002-3854-5968 |
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