Ali Deniz Guler, Ph.D. - US grants

Project Summary/Abstract: 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.

Project Summary: Biological processes ranging from gene transcription to behavior oscillate and are synchronized to the 24-hour day/night cycle. Mammalian circadian rhythms, orchestrated by the hypothalamic suprachiasmatic nucleus (SCN) allow appropriately timed physiological and behavioral responses to daily recurring external cues (i.e. sunrise or timed meal availability). The resulting synchrony of physiology to the astronomical day maximizes metabolic efficiency and good health. However, many of the stresses of modern society (i.e. artificial lighting and omnipresence of food) weaken and desynchronize circadian rhythms. This in turn increases the prevalence of many pathologies including metabolic disorders and neurodegenerative diseases. The aim of my laboratory is to determine how circadian rhythms are synchronized to external cues (circadian entrainment) and how desynchronization impacts health. Although the neuronal pathways of light- driven entrainment are well-established, how other external cues, such as food availability, social interactions or exercise, influence the workings of the SCN remains unknown. In a recent breakthrough, we identified a neuronal connection between midbrain dopaminergic neurons that are activated in response to salient events and SCN neurons that express the dopamine receptor Drd1. We showed that this pathway accelerates photoentrainment and drives palatable food consumption outside of mealtimes. In parallel, we identified a novel molecular player that is necessary for anticipation-related activity to time-restricted food access. Here, we propose to leverage our expertise in disentangling circadian entrainment neurocircuitry to delineate the mechanisms by which rewarding cues modulate the SCN circadian clock. Furthermore, we will determine whether strengthening circadian rhythmicity ameliorates symptoms of neurodegenerative diseases. Our first objective is to gain a mechanistic understanding of how salient events impact SCN activity and circadian entrainment. We hypothesize that activation of dopaminergic signaling decreases the amplitude of SCN oscillation and allows faster photoentrainment. This novel insight will be useful to develop strategies to curb the negative impact of circadian desynchrony. Our second goal is to identify the midbrain dopaminergic cell population that targets the SCN and promotes palatable food consumption outside of meal times, leading to weight gain and metabolic disorder. We predict that by mimicking dopaminergic signaling in the SCN, we will control food consumption. Delineating this pathway will provide therapeutic targets against diet induced metabolic dysfunction and obesity. Our final objective is to determine if high amplitude circadian rhythms, by daily consolidation of light and food access, is sufficient to slow the progression of a mouse model of Alzheimer?s disease (AD). If successful, entrainment strategies will become potential treatments for AD patients and people with high-risk of developing AD. We expect our work will provide a better understanding of the relationship between entrainment cues, physiology and behavior while providing tangible strategies against the adverse consequences of circadian misalignment.