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: 7679338
• 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/7679338
• 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; 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; depression; 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（由申请人提供）： 摘要 血清素（5-羟色胺；5HT）已被证明在各种生理功能中发挥重要作用，例如情绪、性行为、进食、睡眠/觉醒周期、记忆、认知、血压调节和呼吸（Mooney 等，1998）。此外，5HT水平的变化与多种疾病有关，例如高血压。抑郁症、焦虑症、精神分裂症和哮喘（Davidson 等人，2000 年；Lucki，1998 年；Mann 等人，2001 年；Nelson 和 Chiavegatto，2001 年）。因此，了解 5HT 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，通过非侵入性技术控制大脑中5HT系统的活性和调节将最终导致对哺乳动物行为的理解，并可能加速上述疾病治疗方法的发展。血清素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腹侧区域，并聚集在细胞核中。 5HT 神经元投射到几乎每个大脑区域，通过 5HT 受体调节下游神经元回路。血清素能递质系统的活性通过从局部神经元和/或传入细胞到含有细胞核的不同 5HT 神经元的递质释放来调节（异质调节），特别是通过血清素能神经元本身产生的自动调节机制（自动调节）。可以假设，5HT 核中的自动调节所设定的总体活动决定了 5HT 向前脑和外周输出的强度。自我调节是通过 5HT-1 受体特异性介导的，该受体与抑制性 G 蛋白途径 (Gi/o) 偶联。我们的实验室，包括我自己，最近开发了一种非侵入性技术，利用脊椎动物视紫红质通过光控制 Gi/o 通路。我已经创造了小鼠，允许在小鼠的血清素能系统中神经元类型特异性表达脊椎动物视紫红质。我将使用这些小鼠来表征和理解 Gi/o 通路激活在 5HT 递质系统自动调节和大脑中 5HT 水平控制中的作用。 公共健康相关性：项目叙述 血清素 (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。许多疾病都与 5HT 水平改变有关，例如焦虑症和抑郁症。该提议的相关性在于了解 5HT 如何调节大脑中自身递质的释放，这一过程称为自动调节。抗抑郁药通过下调与 Gi/o 通路耦合的 5HT-1 受体来改变自动调节。现在，这条通路将由小鼠大脑中的 5HT 发射系统中的光直接、非侵入性且专门地控制。