Phosphodiesterase 4 inhibition after retrieval switches the memory fate favoring extinction instead of reconsolidation
Abstract Phosphodiesterase 4 (PDE4), an enzyme expressed in the dorsal hippocampus (DH), hydrolyzes the cAMP, limiting the PKA-induced CREB phosphorylation (pCREB) and BDNF expression. Depending on the brain region, PKA and pCREB mediate reconsolidation or extinction, whereas BDNF is mainly related...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-47717-1 |
| _version_ | 1797453261303709696 |
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| author | Jeferson Machado Batista Sohn Nathalie Carla Cardoso Ana Maria Raymundi Jos Prickaerts Cristina Aparecida Jark Stern |
| author_facet | Jeferson Machado Batista Sohn Nathalie Carla Cardoso Ana Maria Raymundi Jos Prickaerts Cristina Aparecida Jark Stern |
| author_sort | Jeferson Machado Batista Sohn |
| collection | DOAJ |
| description | Abstract Phosphodiesterase 4 (PDE4), an enzyme expressed in the dorsal hippocampus (DH), hydrolyzes the cAMP, limiting the PKA-induced CREB phosphorylation (pCREB) and BDNF expression. Depending on the brain region, PKA and pCREB mediate reconsolidation or extinction, whereas BDNF is mainly related to extinction facilitation. The mechanisms underpinning the switch between reconsolidation and extinction are relatively unknown. Here, we tested the hypothesis that PDE4 might control these processes. We showed in Wistar rats submitted to contextual fear conditioning that PDE4 inhibition with roflumilast (ROF) within the DH, after a short retrieval, did not change freezing behavior after one day (TestA1). After 10 days, the ROF-treated group significantly reduced the expression of freezing behavior. This effect depended on retrieval, Test A1 exposure, and reinstated after a remainder foot shock, suggesting an extinction facilitation. The ROF effect depended on PKA after retrieval or, protein synthesis after Test A1. After retrieval, ROF treatment did not change the pCREB/CREB ratio in the DH. It enhanced proBDNF expression without changing pre-proBDNF or mature BDNF in the DH after Test A1. The results suggest that the inhibition of PDE4 in the DH after a short retrieval changes the memory sensibility from reconsolidation to extinction via regulating proBDNF expression. |
| first_indexed | 2024-03-09T15:20:16Z |
| format | Article |
| id | doaj.art-2ee66150f7164e66aadfc86795d6c400 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:20:16Z |
| publishDate | 2023-11-01 |
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| series | Scientific Reports |
| spelling | doaj.art-2ee66150f7164e66aadfc86795d6c4002023-11-26T12:49:48ZengNature PortfolioScientific Reports2045-23222023-11-0113111110.1038/s41598-023-47717-1Phosphodiesterase 4 inhibition after retrieval switches the memory fate favoring extinction instead of reconsolidationJeferson Machado Batista Sohn0Nathalie Carla Cardoso1Ana Maria Raymundi2Jos Prickaerts3Cristina Aparecida Jark Stern4Department of Pharmacology, Federal University of ParanaDepartment of Pharmacology, Federal University of ParanaDepartment of Pharmacology, Federal University of ParanaDepartment of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, University of MaastrichtDepartment of Pharmacology, Federal University of ParanaAbstract Phosphodiesterase 4 (PDE4), an enzyme expressed in the dorsal hippocampus (DH), hydrolyzes the cAMP, limiting the PKA-induced CREB phosphorylation (pCREB) and BDNF expression. Depending on the brain region, PKA and pCREB mediate reconsolidation or extinction, whereas BDNF is mainly related to extinction facilitation. The mechanisms underpinning the switch between reconsolidation and extinction are relatively unknown. Here, we tested the hypothesis that PDE4 might control these processes. We showed in Wistar rats submitted to contextual fear conditioning that PDE4 inhibition with roflumilast (ROF) within the DH, after a short retrieval, did not change freezing behavior after one day (TestA1). After 10 days, the ROF-treated group significantly reduced the expression of freezing behavior. This effect depended on retrieval, Test A1 exposure, and reinstated after a remainder foot shock, suggesting an extinction facilitation. The ROF effect depended on PKA after retrieval or, protein synthesis after Test A1. After retrieval, ROF treatment did not change the pCREB/CREB ratio in the DH. It enhanced proBDNF expression without changing pre-proBDNF or mature BDNF in the DH after Test A1. The results suggest that the inhibition of PDE4 in the DH after a short retrieval changes the memory sensibility from reconsolidation to extinction via regulating proBDNF expression.https://doi.org/10.1038/s41598-023-47717-1 |
| spellingShingle | Jeferson Machado Batista Sohn Nathalie Carla Cardoso Ana Maria Raymundi Jos Prickaerts Cristina Aparecida Jark Stern Phosphodiesterase 4 inhibition after retrieval switches the memory fate favoring extinction instead of reconsolidation Scientific Reports |
| title | Phosphodiesterase 4 inhibition after retrieval switches the memory fate favoring extinction instead of reconsolidation |
| title_full | Phosphodiesterase 4 inhibition after retrieval switches the memory fate favoring extinction instead of reconsolidation |
| title_fullStr | Phosphodiesterase 4 inhibition after retrieval switches the memory fate favoring extinction instead of reconsolidation |
| title_full_unstemmed | Phosphodiesterase 4 inhibition after retrieval switches the memory fate favoring extinction instead of reconsolidation |
| title_short | Phosphodiesterase 4 inhibition after retrieval switches the memory fate favoring extinction instead of reconsolidation |
| title_sort | phosphodiesterase 4 inhibition after retrieval switches the memory fate favoring extinction instead of reconsolidation |
| url | https://doi.org/10.1038/s41598-023-47717-1 |
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