Controlling the Serotonergic System in Mice by Light

通过光控制小鼠的血清素系统

• 批准号: 7173727
• 负责人: STEFAN HERLITZE
• 金额: $ 33.55万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173727
• 关键词: Action Potentials; Activator Appliances; Aggressive behavior; Algae; Animals; Anxiety; Behavior; Behavioral; Brain; Brain region; Cells; Circadian Rhythms; Cognition; Complementary DNA; Coupled; Cyclophosphamide/Fluorouracil/Prednisone; Data; Development; Devices; Disease; Fire - disasters; Functional disorder; Gene Expression; Hippocampus (Brain); Homeostasis; Individual; Invasive; Lead; Light; Mammals; Membrane; Membrane Potentials; Memory; Mental Depression; Methyl Green; Molecular; Moods; Mus; Neurons; Neurotransmitters; Numbers; Pathway interactions; Pattern; Physiological; Play; Potassium Channel; Promoter Regions; Property; Proteins; Proton Pump; Protons; Rattus; Reporter; Rhodopsin; Role; Schizophrenia; Semliki forest virus; Serotonin; Sex Behavior; Sleep Wake Cycle; Slice; Spinal Cord; Synaptic plasticity; System; Techniques; Testing; Therapeutic; Transgenes; Transgenic Mice; Virus; Virus Diseases; Visual system structure; feeding; hindbrain; injured; light effects; millisecond; mind control; promoter; raphe nuclei; relating to nervous system; transcription factor; transmission process

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.

描述（由申请人提供）： 了解神经活动与发育之间以及最终神经元活动与行为之间的关系的主要挑战是能够同时控制许多神经细胞或单个神经细胞的活性。理想情况下，控制神经细胞活性的技术应能够在毫秒内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。光活化的质子通道将用于触发去极化，而光活化的钾通道或Cl-Transporter都将用于诱导超极化。这些构建体将首先在原发性海马神经元（通过病毒感染引入）的小神经元网中进行测试，以更好地了解突触可塑性的细胞机制。其次，将创建转基因小鼠，其中分子光开关将在特异性的血清素能神经元的控制下。 5-羟色胺与在情绪，性行为，进食，睡眠/唤醒周期，记忆和认知等各种生理功能中发挥重要作用有关。此外，5-羟色胺水平的变化与几种疾病有关，例如抑郁，焦虑和精神分裂症。因此，了解5-羟色胺活性如何调节大脑功能将与理解哺乳动物的行为高度相关，并最终导致治疗方法的发展以治愈血清素能传播的功能障碍。