Sprouty2 in the Dorsal Hippocampus Regulates Neurogenesis and Stress Responsiveness in Rats
Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2015
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| Online Access: | http://hdl.handle.net/1721.1/97108 https://orcid.org/0000-0002-3854-5968 |
| _version_ | 1811091452764094464 |
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| author | Dow, Antonia L. Lin, Tiffany V. Chartoff, Elena H. Potter, David McPhie, Donna L. Van’t Veer, Ashlee V. Knoll, Allison T. Lee, Kristen N. Neve, Rachael L. Patel, Tarun B. Ongur, Dost Cohen, Bruce M. Carlezon, William A., Jr. |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Dow, Antonia L. Lin, Tiffany V. Chartoff, Elena H. Potter, David McPhie, Donna L. Van’t Veer, Ashlee V. Knoll, Allison T. Lee, Kristen N. Neve, Rachael L. Patel, Tarun B. Ongur, Dost Cohen, Bruce M. Carlezon, William A., Jr. |
| author_sort | Dow, Antonia L. |
| collection | MIT |
| description | Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP). Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals. In contrast, antidepressant treatments increase HIP neurogenesis, and their efficacy is eliminated by ablation of this process. These findings have led to the working hypothesis that HIP neurogenesis serves as a biomarker of neuroplasticity and stress resistance. Here we report that local alterations in the expression of Sprouty2 (SPRY2), an intracellular inhibitor of growth factor function, produces profound effects on both HIP neurogenesis and behaviors that reflect sensitivity to stressors. Viral vector-mediated disruption of endogenous Sprouty2 function (via a dominant negative construct) within the dorsal HIP of adult rats stimulates neurogenesis and produces signs of stress resilience including enhanced extinction of conditioned fear. Conversely, viral vector-mediated elevation of SPRY2 expression intensifies the behavioral consequences of stress. Studies of these manipulations in HIP primary cultures indicate that SPRY2 negatively regulates fibroblast growth factor-2 (FGF2), which has been previously shown to produce antidepressant- and anxiolytic-like effects via actions in the HIP. Our findings strengthen the relationship between HIP plasticity and stress responsiveness, and identify a specific intracellular pathway that could be targeted to study and treat stress-related disorders. |
| first_indexed | 2024-09-23T15:02:39Z |
| format | Article |
| id | mit-1721.1/97108 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:02:39Z |
| publishDate | 2015 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/971082022-10-02T00:13:12Z Sprouty2 in the Dorsal Hippocampus Regulates Neurogenesis and Stress Responsiveness in Rats Dow, Antonia L. Lin, Tiffany V. Chartoff, Elena H. Potter, David McPhie, Donna L. Van’t Veer, Ashlee V. Knoll, Allison T. Lee, Kristen N. Neve, Rachael L. Patel, Tarun B. Ongur, Dost Cohen, Bruce M. Carlezon, William A., Jr. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Neve, Rachael L. Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP). Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals. In contrast, antidepressant treatments increase HIP neurogenesis, and their efficacy is eliminated by ablation of this process. These findings have led to the working hypothesis that HIP neurogenesis serves as a biomarker of neuroplasticity and stress resistance. Here we report that local alterations in the expression of Sprouty2 (SPRY2), an intracellular inhibitor of growth factor function, produces profound effects on both HIP neurogenesis and behaviors that reflect sensitivity to stressors. Viral vector-mediated disruption of endogenous Sprouty2 function (via a dominant negative construct) within the dorsal HIP of adult rats stimulates neurogenesis and produces signs of stress resilience including enhanced extinction of conditioned fear. Conversely, viral vector-mediated elevation of SPRY2 expression intensifies the behavioral consequences of stress. Studies of these manipulations in HIP primary cultures indicate that SPRY2 negatively regulates fibroblast growth factor-2 (FGF2), which has been previously shown to produce antidepressant- and anxiolytic-like effects via actions in the HIP. Our findings strengthen the relationship between HIP plasticity and stress responsiveness, and identify a specific intracellular pathway that could be targeted to study and treat stress-related disorders. 2015-05-29T13:21:36Z 2015-05-29T13:21:36Z 2015-03 2014-09 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/97108 Dow, Antonia L., Tiffany V. Lin, Elena H. Chartoff, David Potter, Donna L. McPhie, Ashlee V. Van’t Veer, Allison T. Knoll, et al. “Sprouty2 in the Dorsal Hippocampus Regulates Neurogenesis and Stress Responsiveness in Rats.” Edited by Ulrike Schmidt. PLOS ONE 10, no. 3 (March 30, 2015): e0120693. https://orcid.org/0000-0002-3854-5968 en_US http://dx.doi.org/10.1371/journal.pone.0120693 PLOS ONE Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science Public Library of Science |
| spellingShingle | Dow, Antonia L. Lin, Tiffany V. Chartoff, Elena H. Potter, David McPhie, Donna L. Van’t Veer, Ashlee V. Knoll, Allison T. Lee, Kristen N. Neve, Rachael L. Patel, Tarun B. Ongur, Dost Cohen, Bruce M. Carlezon, William A., Jr. Sprouty2 in the Dorsal Hippocampus Regulates Neurogenesis and Stress Responsiveness in Rats |
| title | Sprouty2 in the Dorsal Hippocampus Regulates Neurogenesis and Stress Responsiveness in Rats |
| title_full | Sprouty2 in the Dorsal Hippocampus Regulates Neurogenesis and Stress Responsiveness in Rats |
| title_fullStr | Sprouty2 in the Dorsal Hippocampus Regulates Neurogenesis and Stress Responsiveness in Rats |
| title_full_unstemmed | Sprouty2 in the Dorsal Hippocampus Regulates Neurogenesis and Stress Responsiveness in Rats |
| title_short | Sprouty2 in the Dorsal Hippocampus Regulates Neurogenesis and Stress Responsiveness in Rats |
| title_sort | sprouty2 in the dorsal hippocampus regulates neurogenesis and stress responsiveness in rats |
| url | http://hdl.handle.net/1721.1/97108 https://orcid.org/0000-0002-3854-5968 |
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