Development a translatable visual discrimination test in rodents to apply for drug discovery and development

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H04031
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Nagoya University
• Principal Investigator: Yamada Kiyofumi 名古屋大学, 医学部附属病院, 教授 (30303639)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: タッチパネル式視覚弁別試験 / 統合失調症 / 動物モデル / DISC1 / Npas4 / MHC1

Outline of Final Research Achievements

Cognitive function in mouse models of schizophrenia was evaluated by a touchscreen-based visual discrimination (VD) test, a rational assay that can be performed by rodents and humans, in order to provide translational validity. Genetic mouse models of schizophrenia, including mouse carrying DISC1 deletion, schizophrenia-associated RELN or ARHGAP10 gene mutation, all exhibited impairments in the VD test, which was accompanied by an increase in c-Fos expression in the prefrontal cortex and dorsomedial striatum. We also demonstrated that mitogen-activated protein kinase signaling in the dopamine D1 receptor expressing-medium spiny neurons of the nucleus accumbens plays an important role in stimulus-reward learning. Through the comprehensive behavioral and neurochemical analyses of genetic mouse models of neuropsychiatric disorders we have identified several new targets for novel drug discovery and development.

Free Research Field

神経精神薬理学

Academic Significance and Societal Importance of the Research Achievements

本研究において視覚弁別機能に関連する神経回路の一端が解明できたことにより、高次脳機能の理解が大きく進んだと考えられる。さらに、統合失調症の情動認知機能障害に関わる分子としてDISC1, リーリンおよびARHGAP10を同定した。これらの研究成果は、これまで治療困難であった統合失調症の新規治療薬や予防薬の開発に繋がるものと期待できる。実際、患者型遺伝子変異を有する動物モデルの研究から、ドーパミンD2受容体などの従来の創薬標的とは異なる新しい創薬標的候補分子を同定した。
以上、本研究成果は脳科学研究の発展に寄与するだけでなく、精神疾患の病態解明や新規治療薬の開発への応用展開が可能である。