Probing of Hypothalamic circuits in arousal using optogenetics

使用光遗传学探测下丘脑回路在唤醒中的作用

• 批准号: 7638748
• 负责人: Antoine Adamantidis
• 金额: $ 9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7638748
• 关键词: Animals; Anterior Hypothalamus; Architecture; Area; Arousal; Behavior; Behavioral; Biological; Boxing; Brain; Brain Stem; Cell Nucleus; Cells; Chimeric Proteins; Circadian Rhythms; Code; Complex; Disease; Equilibrium; Event; Experimental Models; FOS Protein; Fasting; Genes; Genetic; Homeostasis; Hypothalamic structure; Immunohistochemistry; In Vitro; Lasers; Lateral; Light; Link; Maintenance; Mediating; Melanins; Memory; Methods; Mus; Neuronal Plasticity; Neurons; Optics; Organism; Pattern; Physiologic pulse; Physiological; Population; Posterior Hypothalamus; Preoptic Areas; Principal Investigator; Process; Property; Proto-Oncogene Proteins c-fos; Pump; Resolution; Role; Sleep; Sleep Deprivation; Sleep Wake Cycle; System; Techniques; Technology; Testing; Time; Training; Transgenic Organisms; Wakefulness; cell type; energy balance; gain of function; gamma-Aminobutyric Acid; goal oriented behavior; hypocretin; in vivo; innovation; light gated; loss of function; melanin-concentrating hormone; millisecond; neuronal cell body; neuropsychiatry; neurotransmitter release; patch clamp; pressure; promoter; relating to nervous system; tool; vigilance

Probing of hypothalamic circuits in arousal using optogenetics. While the functions of sleep are still a matter of debate and may include memory consolidation and plasticity, the neural substrates of sleep and wakefulness are the subject of intense study. Successive sleep and wakefulness cycles rely on an appropriate balance between sleep-promoting nuclei of the brain, including inhibitory cells of the ventro-lateral preotpic area and anterior hypothalamus and, arousal-promoting nuclei from the brainstem and the posterior hypothalamus. Hence, the hypothalamus contains cells types able to regulate the occurrence and maintenance of sleep and wake events. Indeed, two distinct neuron populations restricted to the hypothalamus have been recently identified as critical modulator of the sleep-wake cycle: the Melanin-ConcentratingHormone (MCH)- and Hypocretins/Orexins (Hcrt^Ox)- expressing neurons. Although the Hcrt system is involved in boundaries state control, the precise physiological function of the MCH system on the sleep-wake cycle and the mechanisms of action involved remains unclear. Here we propose :o use in vitro and in vivo optogenetics to establish causal link between activation of the MCH system and sleep-wake cycle architecture. My hypothesis is that the sleep-promoting role of the MCH system balances the wake-promoting properties of the Hcrt system, providing a hypothalamic switch that modulates vigilance states according to physiological demands/hemostats including sleep pressure and negative energy balance. To test this hypothesis, our short-term objectives are divided into three specific aims: Specific Aim1: Define a window of efficacy for optical stimulation of ChR2-expressing MCH neurons in vitro and in vivo. Specific Aim2: Manipulate the activity of MCH neurons in vitro to study the dynamic of the MCH-Hcrt hypothalamic circuit. Specific Aim3 : Determine the role of the MCHsystem on the sleep-wake cycle upon specific physiological demands including sleep deprivation and fasting. x>ng-term perspectives of this project envision the study of plasticity of these hypothalamic circuits and its implication n complex behaviors including sleep and goal-oriented behaviors that leads to neuropsychiatric diseases.

使用光遗传学在唤醒中探测下丘脑电路。 虽然睡眠的功能仍然是争论的问题，并且可能包括记忆巩固和可塑性，但睡眠和清醒的神经基板是强烈研究的主题。连续的睡眠和清醒周期依赖于大脑促进睡眠核的适当平衡，包括腹侧前胸腔前区域和下丘脑前的抑制细胞，以及来自脑干和后丘脑的唤醒促进的核。因此，下丘脑包含能够调节睡眠和唤醒事件的发生和维持的细胞类型。实际上，最近仅限制下丘脑的两个不同的神经元种群被确定为睡眠效果周期的关键调节剂：黑色素蛋白 - 浓度激素（MCH）和降钙蛋白/甲状腺素（HCRT^ox） - 表达神经元。尽管HCRT系统涉及边界状态控制，但MCH系统在睡眠效益周期中的精确生理功能且涉及的作用机理尚不清楚。在这里，我们提出：o在体外和体内光遗传学上，在MCH系统的激活与睡眠效果周期结构之间建立因果关系。我的假设是，MCH系统的睡眠促进作用平衡了HCRT系统的唤醒特性，从而提供了下丘脑开关，该开关根据生理需求/止血器（包括睡眠压力和负能量平衡）调节警惕性状态。为了检验这一假设，我们的短期目标分为三个特定的目的：特定目标：定义一个在体外和体内表达ChR2表达MCH神经元的功效窗口。特定AIM2：操纵MCH神经元在体外的活性，以研究MCH-HCRT下丘脑回路的动态。特定AIM3：确定MCHSYSTEM在睡眠效果周期中的作用在特定的生理需求中，包括睡眠剥夺和禁食。该项目的X> ng期望的观点设想了这些下丘脑电路的可塑性及其含义n复杂行为，包括睡眠和面向目标的行为，导致神经精神疾病。