| Project/Area Number |
16K18393
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Research Collaborator |
Kaibuchi Kozo
Nagai Taku
Amano Mutsuki
Nishioka Tomoki
Kuroda Keisuke
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | ドーパミン / リン酸化 / プロテオミクス解析 / 情動 / 報酬 / 記憶・学習 / 転写因子 / 遺伝子発現 / 学習・記憶 / 細胞種特異的 / MAPK / 学習 / 記憶 / 情動記憶 |
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| Outline of Final Research Achievements |
How dopamine regulates reward-related learning and memory through gene expression is poorly understood. Here, to identify the relevant transcriptional factors, we performed proteomic analysis using affinity beads coated with CREB-binding protein (CBP), a transcriptional coactivator involved in reward-related behavior. We identified more than 100 CBP-interacting proteins, including Neuronal Per-Arnt-Sim domain protein 4 (Npas4). We also found that MAPK phosphorylated Npas4 downstream of PKA, increasing Npas4-CBP interaction and the transcriptional activity of Npas4 at the brain-derived neurotrophic factor (BDNF) promoter. Deletion of Npas4 in the D1R-expressing MSNs impaired cocaine-induced place preference, which was rescued by Npas4-WT but not by a phospho-deficient Npas4 mutant. These observations suggest that MAPK phosphorylates Npas4 in D1R-MSNs and increases its transcriptional activity to enhance reward-related learning and memory.
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| Academic Significance and Societal Importance of the Research Achievements |
ドーパミンの下流で働くリン酸化酵素により、リン酸化される主要な転写因子が明らかになり、ドーパミンによる遺伝子発現の制御機構、並びに、情動記憶形成の制御機構の一端が解明された。これらの成果は、基礎神経科学において重要というだけでなく、統合失調症やうつ病、薬物依存症、パーキンソン病などの精神・神経疾患の病因・病態解明や診断・治療法の確立等の医学分野に貢献する可能性が高い。
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