Investigation of Gi/o Signaling in the 5HT System

5HT 系统中 Gi/o 信号传导的研究

• 批准号: 7826667
• 负责人: Davina Gutierrez
• 金额: $ 3.78万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-05 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826667
• 关键词: Actins; Address; Affect; Anxiety; Anxiety Disorders; Area; Asthma; Behavior; Brain; Breathing; Cell Nucleus; Cells; Cognition; Couples; Data; Development; Disease; Down-Regulation; Emotions; Enhancers; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Homeostasis; Investigation; Lead; Light; Mammals; Mediating; Memory; Mental Depression; Midbrain structure; Moods; Mus; Neurons; Neurotransmitters; Organ; Output; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiology; Play; Potassium Channel; Presynaptic Terminals; Process; Prosencephalon; Receptor Signaling; Regulation; Rhodopsin; Role; Schizophrenia; Serotonin; Sex Behavior; Signal Pathway; Signal Transduction; Site; Sleep; Sleep Wake Cycle; Slice; Specificity; System; Techniques; Time; Transgenic Mice; Work; abstracting; blood pressure regulation; cell type; dorsal raphe nucleus; feeding; hindbrain; mouse Cre recombinase; mouse model; postsynaptic; pre-doctoral; presynaptic; public health relevance; receptor; receptor coupling; recombinase; response; therapeutic development; transcription factor

DESCRIPTION (provided by applicant): Abstract Serotonin (5-hydroxytryptamine; 5HT) has been demonstrated to play important roles in various physiological functions such as mood, sexual behavior, feeding, sleep/wake cycle, memory, cognition, blood pressure regulation and breathing (Mooney et al., 1998). In addition, changes in 5HT levels have been related to several diseases, e.g. depression, anxiety, schizophrenia and asthma (Davidson et al., 2000; Lucki, 1998; Mann et al., 2001; Nelson and Chiavegatto, 2001). Thus, understanding how 5HT signaling modulates the brain and the periphery is very relevant for understanding the physiology and behavior of mammals. Furthermore, controlling the activity and modulation of the 5HT system in the brain with non-invasive techniques will ultimately lead to the understanding of mammalian behavior and may accelerate the development of therapeutic treatments for diseases mentioned above. The serotonergic neurotransmitter system consists of a small number of neurons that are mainly restricted to the ventral regions of the hindbrain and are clustered in nuclei. 5HT neurons project into almost every brain area to modulate downstream neuronal circuits via 5HT receptors. The activity of the serotonergic transmitter system is regulated via transmitter release from local neurons and/or afferents to the different 5HT neuron containing nuclei (hetero-regulation) and in particular via autoregulatory mechanisms arising from the serotonergic neurons themselves (autoregulation). It can be assumed that the overall activities set by the autorgulation in the 5HT nuclei determine the strength of the output of 5HT to the forebrain and periphery. The autoregulation is specifically mediated via 5HT-1 receptors, which couple to the inhibitory G protein pathway (Gi/o). Our lab, including myself, has recently developed a non-invasive technique to control the Gi/o pathway by light using vertebrate rhodopsin. I have created mice that will allow for the neuron-type specific expression of vertebrate rhodopsin in the serotonergic system of mice. I will use these mice to characterize and understand the role of the Gi/o pathway activation within the autoregulation of the 5HT transmitter system and for the control of 5HT levels in the brain. PUBLIC HEALTH RELEVANCE: Project narrative Serotonin (5HT) is an important transmitter for modulating important physiological functions such as emotions, sleep, cognition and breathing. Various diseases have been associated with altered 5HT levels such as anxiety disorders and depression. The relevance of this proposal lies in the understanding of how 5HT regulates its own transmitter release in the brain, a process called autoregulation. The autoregulation has been suggested to be altered by anti-depressants via downregulation of 5HT-1 receptors coupling to the Gi/o pathway. This pathway will now be controlled by light directly, non-invasively and exclusively in the 5HT transmitter system in the mouse brain.

描述(申请人提供)：摘要5-羟色胺(5-羟色胺；5-羟色胺)已被证明在情绪、性行为、进食、睡眠/觉醒周期、记忆、认知、血压调节和呼吸等各种生理功能中发挥重要作用(Mooney等，1998)。此外，5-羟色胺水平的变化与几种疾病有关，例如抑郁症、焦虑症、精神分裂症和哮喘(Davidson等人，2000；Lucki，1998；Mann等人，2001；Nelson和Chiavegatto，2001)。因此，了解5-羟色胺信号如何调节大脑和外周，对于了解哺乳动物的生理和行为非常相关。此外，利用非侵入性技术控制脑内5-羟色胺系统的活动和调节，最终将有助于理解哺乳动物的行为，并可能加速上述疾病的治疗方法的发展。5-羟色胺能神经递质系统由少量神经元组成，这些神经元主要局限于后脑的腹侧区域，并聚集在核团中。5-羟色胺神经元投射到几乎每个大脑区域，通过5-羟色胺受体调节下游神经元回路。5-羟色胺能递质系统的活动是通过从局部神经元和/或传入含有核团的不同5-羟色胺神经元的递质释放来调节的(异位调节)，特别是通过5-羟色胺能神经元本身产生的自我调节机制(自动调节)。可以假定，5HT核团中自调节所设置的整体活动决定了5HT向前脑和外周输出的强度。这种自我调节是通过与抑制性G蛋白通路(Gi/o)偶联的5HT-1受体特异性地介导的。我们的实验室，包括我自己，最近开发了一种非侵入性的技术，利用脊椎动物视紫红质通过光来控制GI/O通路。我创造的小鼠将允许脊椎动物视紫红质在小鼠的5-羟色胺能系统中进行神经元类型的特异性表达。我将利用这些小鼠来描述和理解Gi/o通路激活在5-羟色胺递质系统的自动调节中的作用，以及对大脑中5-羟色胺水平的控制。 与公共健康相关：项目叙述性5-羟色胺(5HT)是调节情绪、睡眠、认知和呼吸等重要生理功能的重要递质。各种疾病都与5-羟色胺水平改变有关，如焦虑症和抑郁症。这一建议的相关性在于对5-羟色胺如何调节自己在大脑中的递质释放的理解，这一过程被称为自动调节。这种自我调节被认为是通过下调连接到Gi/o通路的5HT-1受体而被抗抑郁药物改变的。这一途径现在将由光直接、非侵入性地、唯一地在小鼠大脑中的5HT递质系统中控制。