Controlling the Serotonergic System in Mice by Light

描述（由申请人提供）： 理解神经活动和发育之间的关系以及最终理解神经元活动和行为之间的关系的一个主要挑战是能够同时控制许多神经细胞或单个神经细胞区域的活动。理想情况下，控制神经细胞活动的技术应该能够在几毫秒内打开或关闭神经细胞，而不会伤害细胞。因此，我们将开发能够控制细胞膜电位的分子光开关。光激活质子通道将用于触发去极化，而光激活钾通道或Cl-转运蛋白将用于诱导超极化。这些构建体将首先在来自原代海马神经元（通过病毒感染引入）的小神经元网络中进行测试，以更好地理解突触可塑性的细胞机制。第二，将创建转基因小鼠，其中分子光开关将在对多巴胺能神经元特异性的启动子的控制下。5-羟色胺在情绪、性行为、进食、睡眠/觉醒周期、记忆和认知等多种生理功能中发挥重要作用。此外，血清素水平的变化与几种疾病有关，例如抑郁症、焦虑症和精神分裂症。因此，了解多巴胺能活动如何调节脑功能将与理解哺乳动物的行为高度相关，并最终导致治疗多巴胺能传递功能障碍的治疗方法的发展。

DESCRIPTION (provided by applicant): A major challenge to understand the relation between neural activity and development and ultimately between neuronal activity and behavior is to be able to control the activity of many nerve cells or regions of individual nerve cells simultaneously. Ideally, a technique for controlling nerve cell activity should be capable of switching nerve cells on or off within milliseconds without injuring the cells. We therefore will develop molecular light switches capable of controlling the membrane potential of cells. Light activated proton channels will be used to trigger depolarization, while either light activated potassium channels or Cl-transporters will be used to induce hyperpolarization. These constructs will first be tested in small neuronal nets from primary hippocampal neurons (introduced via viral infection) to better understand the cellular mechanisms underlying synaptic plasticity. Second, transgenic mice will be created, in which the molecular light switches will be under the control of a promoter specific for serotonergic neurons. Serotonin has been implicated in playing important roles in various physiological functions such as mood, sexual behavior, feeding, sleep/wake cycle, memory and cognition. Furthermore, changes in serotonin levels have been related to several diseases, e.g. depression, anxiety and schizophrenia. Understanding how serotonergic activity is modulating brain function will therefore be highly relevant for understanding behavior of mammals and will ultimately lead to the development of therapeutic approaches to cure dysfunctions of serotonergic transmission.