Optogenetic modulation of stress signaling - towards a new animal model for depression

光控/激活的通道和酶为非侵入性和精确地控制细胞反应提供了独特的机会。利用“光开关”蛋白质研究复杂的动物生理和行为是一个令人兴奋的领域，这才刚刚开始。斑马鱼因其可遗传的透明胚胎，为脊椎动物行为和生理的光遗传分析提供了一个有吸引力的系统。然而，到目前为止，斑马鱼的系统还没有得到充分的探索，只有两份出版物报道了光遗传工具的使用。因此，这项提议的一个主要目标是扩大用于斑马鱼的光开关工具箱。我们将实现并测试由For成员生成的几个新型光开关的功能。该提案的第二个目的是使用这些光遗传工具来控制斑马鱼的神经内分泌反应。重点将是动物对威胁动态平衡的环境刺激的复杂适应性荷尔蒙反应，称为应激反应。应激反应对动物的生存至关重要，而应激反应系统的故障与包括焦虑和抑郁在内的许多人类疾病有关。通过实施新的光开关，包括具有不同颜色调节的通道视紫红质变体、光激活的腺苷环化酶(PAC)和光驱动的谷氨酸受体(GluRs)，我们将创造出应激反应可以被光精确控制的动物。这些动物模型将为研究慢性应激的影响提供前所未有的机会。

Light-gated/actuated channels and enzymes provide a unique opportunity to noninvasively and precisely control cellular responses. The usage of “Light-switch” proteins to investigate complex animal physiology and behavior is an exciting field, which is just beginning. The zebrafish offers an attractive system for optogenetic analysis of vertebrate behavior and physiology due to its genetically amenable and transparent embryos. However, the zebrafish system has been under-explored so far with only two publications reporting the usage of optogenetic tools. Therefore a major goal of this proposal is to expand the toolbox of light-switches for the usage in zebrafish. We will implement and test the functionality of several novel light-switches generated by members of FOR. The second aim of the proposal is to use these optogenetic tools to control neuroendocrine responses in zebrafish. A focus will be the complex adaptive hormonal response of an animal to environmental stimuli that threaten homeostasis, called the stress response. The stress response is critical for the survival of an animal and malfunctioning of the stress response system is implicated in a number of human diseases including anxiety and depression. By implementing new light switches including Channelrhodopsin variants with different color tuning, photo-activated adenylate cyclase (PAC) and light-actuated glutamate receptors (GluRs), we will generate animals where the stress response can be precisely controlled by light. These animal models will provide hitherto unprecedented opportunities to investigate the effects of chronic stress.