| 研究課題/領域番号 |
23K14685
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| 研究種目 |
若手研究
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| 配分区分 | 基金 |
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| 審査区分 |
小区分51030:病態神経科学関連
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| 研究機関 | 筑波大学 |
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研究代表者 |
ROY Koustav 筑波大学, 国際統合睡眠医科学研究機構, 助教 (30893086)
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| 研究期間 (年度) |
2023-04-01 – 2026-03-31
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| 研究課題ステータス |
交付 (2024年度)
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| 配分額 *注記 |
4,680千円 (直接経費: 3,600千円、間接経費: 1,080千円)
2025年度: 1,560千円 (直接経費: 1,200千円、間接経費: 360千円)
2024年度: 1,820千円 (直接経費: 1,400千円、間接経費: 420千円)
2023年度: 1,300千円 (直接経費: 1,000千円、間接経費: 300千円)
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| キーワード | Schizophrenia / A2AR receptor / Nucleus accumbens (NAc) / Opto pharmacology / Optopharmacology / Adenosine |
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| 研究開始時の研究の概要 |
The current strategies to treat schizophrenia are very limited. Overactive mesolimbic dopaminergic activity is the probable reason for triggering psychosis in schizophrenia. Interestingly, D2R are co-expressed with A2AR in
the Nucleus accumbens, raising the idea of schizophrenia therapy based on an adenosine hypothesis.
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| 研究実績の概要 |
Adenosine A2A receptors (A2AR) and dopaminergic 2 receptors (D2R) interact in the nucleus accumbens (NAc) to regulate molecular signaling. Enhancing A2AR activation may counteract D2R hyperactivity in the MAP6KO psychosis model. To explore this, we developed an A2AR positive opto-allosteric modulator (optoA2AR PAM) that induced slow-wave sleep in freely moving wild type mice (Roy et al., Nature Communications 2024).
Behavioral analyses of male and female MAP6KO mice using the open field test and pre-pulse inhibition a dedicated assay for psychosis evaluation revealed significant behavioral alterations. To investigate dopaminergic dynamics in psychosis, we used fiber photometry in MAP6KO mice and observed a dramatic increase in dopamine levels, especially following behavioral stimuli like rewards or the introduction of a female mouse, highlighting a state of hyperarousal.
Direct infusion of A2AR PAM into the NAc or through intraperitoneal injection of psychotic mice, further confirmed significant SWS induction and a marked decrease in exploratory behavior. To explore the molecular basis of these observations, I performed spatial transcriptomics on MAP6KO and Wild Type mice across sleep and wakefulness. The analysis revealed a set of candidate genes potentially linked to psychosis-associated sleep disturbances and hyperarousal, providing valuable insights into the underlying mechanisms.
This project uncovers the complex interplay between dopaminergic and adenosinergic signaling in the NAc, offering potential therapeutic strategies for psychosis-related sleep disturbances.
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| 現在までの達成度 |
現在までの達成度
3: やや遅れている
理由
I have incorporated spatial transcriptomics (10X Genomics, Visium) alongside single-cell RNA transcriptomics as proposed, but completing the bioinformatics analysis for the large dataset requires more time. While we have shortlisted a few key genes potentially linked to psychosis-induced hyperarousal and insomnia, further analysis is needed. Additionally, we recently conducted dopamine dynamics measurements, which were not part of the original project plan. Additionally, we have recently acquired a pre-pulse inhibition (PPI) apparatus specifically for this project to evaluate psychotic behavior.
We have incorporated several new experiments and detailed bioinformatics analyses, which may cause a slight delay in the project timeline.
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| 今後の研究の推進方策 |
Although I have added several new experiments that were not included in the original project proposal, the overall objectives remain unchanged. Incorporating cutting-edge techniques such as spatial transcriptomics and fiber photometry for dopamine dynamics will enhance the project's depth and informativeness. Additionally, I plan to include AI-based behavioral analysis for psychotic mice using DeepLabCut. We have already utilized this software in other ongoing projects, and it will help identify subtle or previously unnoticed behavioral changes in psychotic mice, particularly after hyperadenosinergic stimulation.
Another experiment we plan to conduct is the chemogenetic activation of glial cells to induce adenosine levels. We have previously demonstrated that chemogenetic activation of astrocytes in the NAc significantly increases SWS and adenosine. Now, we aim to perform this experiment in MAP6KO mice to investigate whether hyperadenosinergic activity can restore psychotic behavior and normalize sleep architecture. We have already prepared the virus for DREADD (Designer Receptors Exclusively Activated by Designer Drugs) receptors to selectively activate the glial cells. Overall, I am confident in completing the proposed hypothesis without significant delays.
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