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

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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 & test a mathematical model that describes the interactions of two clocks. Second, the circuit has known components that we will test in two ways. Specific drugs will be used to examine how cells in the circuit communicate. In addition selected pathways will be engineered to produce proteins that can be used to turn activity on or off in those cells. The second hypothesis is that the SCN inhibits activity in the dopamine cells by a neural connection that is active during the daytime. ***Hypothesis 2: 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.