The circadian oscillator organization underlying the regulation of goal directed behaviour in mammals

我们研究计划的广泛目标是了解哺乳动物的昼夜节律是如何在不同的生物组织(分子、细胞和电路)水平上产生的，如何聚集在一起产生生理和行为的日常时间程序。在小鼠的运动活动中，两个相互作用的时钟的活动是明显的。其中之一是下丘脑的生物钟(SCN)。另一个尚未本地化，但对于在遇到重大环境事件或情况时，对日常活动的时间进行短期调整很重要。特别是，第二个时钟与预测重要条件的能力有关，例如食物的可获得性或捕食者的存在。要做到这一点，时钟必须将一天中的时间传达给动物的其余部分，以预测事件再次发生。这是时间记忆。我们将研究目标导向的行为，如转轮活动，因为这可能是自然界中探索性行为的替代品。目前的发现表明，生物钟是由多巴胺调节的，这表明节律可以由神经回路产生。我们简单地将这种输出称为多巴胺调节的昼夜节律振荡，或DARCO。我们的数据表明，时间记忆反映在Darco回路的设置中。*该项目有两个主要假设和每个假设中的几个目标。*假设1：苯丙胺诱导的Darco出现在一个包括上行多巴胺通路和谷氨酸/GABA反馈的回路中。*为了测试这一点，我们将首先开发SCN通过向下丘脑后部的抑制性投射来调节Darco。*为了检验这一假设，我们将首先使用轨迹追踪技术验证是否确实存在一条通路。然后，我们将通过将抑制或兴奋蛋白工程到这些神经元中，并控制它们的活动来研究这一途径的功能。*结合起来，研究将告知(1)时钟如何在目标导向的行为中产生Darco节奏；以及(2)SCN时钟如何在自然情况下控制Darco。这项研究的主要影响将是扩大我们对昼夜节律等级的组织和意义的理解。我们的项目提出了一个迄今未被探索的观点，从分子到电路的机制，通过这些机制，活的有机体已经适应了24小时环境中的生活。

The broad aim of our research program is to understand how circadian rhythms in mammals that are produced at different levels of biological organization (molecules, cells, and circuits), come together to produce the daily temporal program of physiology and behavior. The activity of two interacting clocks is evident in the locomotor activity of mice. One of these is the biological clock in the hypothalamus (the SCN). The other has not been localized, but it is important for producing short-term adjustments to the daily timing of activity when significant events or conditions n the environment are encountered. In particular, the second clock is connected with the ability to predict important conditions such as the availability of food or the presence of a predator. To do this, the clock must communicate time of day to the rest of the animal in anticipation of the event occurring again. This is time memory. We will examine goal directed behaviors such as running wheel activity, as this likely serves as a surrogate for exploratory behavior in nature. Current findings indicate that the clock is regulated by dopamine, which suggests that rhythms could be produce by neural circuit. We have simply called the output a dopamine regulated circadian oscillation, or DARCO. Our data suggest that time memory is reflected in the setting of the DARCO circuit.***The project has two main hypotheses and several objectives within each.***Hypothesis 1: The amphetamine-induced DARCO arises in a circuit that includes the ascending dopamine pathways and glutamate/GABA feedback.***To test this, we will first develop The SCN regulates the DARCO via an inhibitory projection to posterior hypothalamus.***To test this hypothesis we will first verify that a pathway actually exists using tract tracing techniques. Then we will investigate the functionality of this pathway by engineering the inhibitory or excitatory proteins into those neurons, and controlling their activity.***Together, the research will inform about (1) how the clock generates the DARCO rhythm in the goal directed behavior; and (2) how the SCN clock controls the DARCO under natural situations. the major impact of this research will be to expand our understanding of the organization and significance of the circadian hierarchy. Our project presents a heretofore unexplored perspective on the mechanisms from molecules to circuits, by which living organisms have adapted to life in the 24 hr environment.