Investigation of Gi/o Signaling in the 5HT System

描述（由申请人提供）：摘要血清素（5-羟色胺; 5 HT）已被证明在各种生理功能中起重要作用，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等人，1998年）。此外，5 HT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;纳尔逊和Chiavegatto，2001）。因此，了解5 HT信号如何调节大脑和外周是非常相关的了解哺乳动物的生理和行为。此外，用非侵入性技术控制大脑中5 HT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的治疗方法的发展。多巴胺能神经递质系统由少数神经元组成，这些神经元主要局限于后脑的腹侧区域，并聚集在核中。5 HT神经元投射到几乎每个脑区，通过5 HT受体调节下游神经元回路。多巴胺能递质系统的活性通过从局部神经元和/或传入神经释放递质到不同的含5 HT神经元的核（异源调节），特别是通过由多巴胺能神经元本身产生的自动调节机制（自动调节）来调节。可以假定，由5 HT核团中的自调节设置的总体活动决定了5 HT输出到前脑和外周的强度。这种自身调节是通过5 HT-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来控制Gi/o通路。我已经创造了小鼠，将允许神经元类型的特定表达脊椎动物视紫红质在小鼠的神经系统。我将使用这些小鼠来表征和理解Gi/o通路激活在5 HT递质系统的自动调节中的作用，以及对大脑中5 HT水平的控制。 公共卫生相关性：5-羟色胺（Serotonin，5-HT）是调节重要生理功能的重要递质，如情绪、睡眠、认知和呼吸。各种疾病都与5 HT水平的改变有关，如焦虑症和抑郁症。这个建议的相关性在于理解5 HT如何调节大脑中自己的递质释放，这一过程称为自动调节。抗抑郁药通过下调与Gi/o通路偶联的5 HT-1受体来改变自身调节。这一途径现在将由光直接控制，非侵入性地和专门地在小鼠大脑中的5 HT传递系统中。

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.