Interplay between circadian and reward pathways in homeostatic response and pathology

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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.