Our circadian clocks have evolved to synchronize behavioral and physiological activities to a specific time of the day in order to optimize survival. Although Darwinian pressures have declined for humans, many of the emergent stresses of modern society burdens our ancient circuitry governing circadian synchrony. As such, new pathologies are emerging including mental, cardiovascular, metabolic disorders and cancer. The synchronization process of biological rhythms, termed entrainment, requires environmental cues (zeitgebers) that are able to reset the molecular clock machinery. For mammals, the most dominant daily zeitgeber is light. During photoentrainment, the ambient light levels that are detected by photoreceptors are conveyed to the central circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus to permit synchrony to day/night cycles. However, other cues such as availability of food, social interactions or physical exercise also influence the phase of the SCN. Why have multiple modes of entrainment evolved? Perhaps the most parsimonious explanation for the evolution of these circuits is that they inform the central circadian clock of salient events such as availability of food or a mate during a temporally distinct niche. These types of behaviors are thought to be regulated by neural circuits associated with dopamine (DA). Existence of SCN independent oscillators that are closely associated with DA further highlights the importance of this neurotransmitter in establishment of an integrated and well informed biological timing process. In this proposal, we hypothesize that increased DA signaling in the SCN allows the central oscillator to enter a more ?entrainment susceptible? state where new cues are able to adjust the circadian clock more readily. To address this idea we provide preliminary evidence and propose two specific aims.
In Aim 1, we examine the existence of a functional connection between a select group of DA producing cells and the recipients of these connections in the SCN, which express the DA receptor Drd1. To this end, we propose to measure DA release and ensuing changes in SCN-neuron activity by using pharmacological methods and actuator systems that elevate or inhibit the activity of a genetically defined group of DA-neurons. The functional mapping strategy outlined in this aim provides the framework to delineate this previously undefined neural circuit in circadian entrainment.
In Aim 2, we seek to define the molecular mechanism(s) of how DA-induced activation of Drd1-expressing neurons in the SCN modulates circadian entrainment. To accomplish this, we will first confirm that elevated or reduced activity of Drd1-expressing SCN neurons modulates entrainment. Subsequently, we determine whether DA release in the SCN hastens circadian clock entrainment and whether Drd1 expression in the SCN is necessary and/or sufficient for this response. The findings and proposed experiments outlined here have implications beyond the circadian entrainment and could provide new principles in delineating information processing in the central nervous system at large.

Public Health Relevance

Necessities of modern society put immense pressure on human physiology by forcing incongruity between endogenous circadian rhythms and environmental cycles, which leads to a range of health issues including psychological abnormalities, cardiovascular diseases, cancer and obesity. This project aims to identify novel neural circuits that govern biological rhythms in the brain and therefore provide unique therapeutic targets to circumvent these pathologies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Sesma, Michael A
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University of Virginia
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United States
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