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【主权项】
1. 一种产生诱导型应激动物模型的方法，所述方法包括遗传修饰非人脊椎动物以表达 可以在下丘脑-垂体-肾上腺轴细胞中通过光激活的一种或多种蛋白，其中可以通过光激 活的蛋白能够诱导 (i) 从下丘脑前区的室旁核中的神经元释放促皮质素释放激素（CRH)和/或精氨 酸-加压素（AVP); (ii) 从垂体前叶中的促肾上腺皮质激素细胞释放促肾上腺皮质激素（ACTH);和/或 (iii) 从肾上腺皮质中的细胞释放糖皮质激素。2. 权利要求1的方法，其中可以通过光激活的蛋白选自光激活腺苷酸环化酶（PAC)、 channelrhodopsin 1和 channelrhodopsin 2〇3. 权利要求1或2的方法，其中所述非人脊椎动物为鱼。4. 权利要求3的方法，其中所述鱼选自斑马鱼和青鏘。5. 通过权利要求1-4中任一项的方法获得的应激动物模型。6. 权利要求5的动物模型在筛选用于预防、改善或治疗应激和/或应激相关疾病的化 合物中的用途。7. -种筛选用于预防、改善和/或治疗应激和/或应激相关疾病的化合物的方法，所述 方法包括 (a) 向权利要求5的动物模型给予受试化合物； (b) 在步骤（a)之前、与步骤（a)同时和/或在步骤（a)之后在所述动物模型中诱导应 激；以及 (c) 分析步骤（b)中诱导的应激应答， 其中与不存在受试化合物的情况下观察到的应激应答相比，在存在受试化合物的情况 下于（c)中观察到的减少的应激应答指示化合物适合作为预防、改善和/或治疗应激和/ 或应激相关疾病的化合物。8. 权利要求7的方法，其中在步骤（b)中通过将所述动物暴露于光来诱导应激。9. 权利要求1-4中任一项的方法，权利要求5的动物，权利要求6的用途或者权利要求 7或8的方法，其中所述应激为慢性应激。10. -种分析鱼中的应激行为的方法，所述方法包括 (i) 将鱼置于游泳室中，并且将所述鱼暴露于刺激；以及 (ii) 在存在或不存在应激物的情况下分析所述鱼的刺激依赖性行为； 其中与不存在应激物的情况下在（ii)中观察到的行为相比，在存在应激物的情况下 于（ii)中观察到的行为的改变指示应激。11. 权利要求10的方法，其中所述刺激选自温度变化、照明变化或机械感觉刺激。12. 权利要求10或11的方法，其中所述刺激为食物。13. 权利要求10或11的方法，其中所述方法为主动回避测试。14. 权利要求10-13中任一项的方法，其中所述鱼选自斑马鱼和青鏘。15. 权利要求10-13中任一项的方法，其中所述鱼是通过权利要求3或4中任一项的方 法获得的动物模型。
【专利摘要】本发明涉及一种产生诱导型应激动物模型的方法，所述方法包括遗传修饰非人脊椎动物以表达在下丘脑-垂体-肾上腺轴细胞中可以通过光激活的一种或多种蛋白，其中可以通过光激活的蛋白能够诱导(i)从下丘脑前区的室旁核中的神经元释放促皮质素释放激素(CRH)和/或精氨酸-加压素(AVP)；(ii)从垂体前叶中的促肾上腺皮质激素细胞释放促肾上腺皮质激素；和/或(iii)从肾上腺皮质中的细胞释放糖皮质激素。本发明进一步涉及通过本发明的方法获得的应激动物模型以及所述动物模型在筛选用于预防、改善或治疗应激和/或应激相关疾病的化合物中的用途。此外，本发明还涉及一种筛选用于预防、改善和/或治疗应激和/或应激相关疾病的化合物的方法以及在鱼中分析应激行为的方法。
【IPC分类】A61K49/00, A01K67/027, C12N9/88, C12N15/85
【公开号】CN104981150
【申请号】CN201380072299
【发明人】S·柳, R·德马尔科
【申请人】马克思-普朗克科学促进协会
【公开日】2015年10月14日
【申请日】2013年12月5日
【公告号】EP2740353A1, EP2928288A1, US20150282462, WO2014086938A1