Molecular basis of circadian and sensory integration in neuronal clocks - Molecular basis of circadian and sensory integration in neuronal clocks In living organisms, cellular and physiological processes are coordinated in time and space to ensure the proper functioning of body systems. In mammals, a central pacemaker housed in the hypothalamic suprachiasmatic nucleus (SCN) orchestrates the regulation of these time-keeping mechanisms. The molecular basis of time- keeping systems involve the expression of circadian clock genes, which generate feedback loops with daily expression patterns. Clock gene rhythms are intrinsic, i.e. they emerge even in the absence of external cues. However, failure to synchronize these endogenous rhythms with environmental cues can lead to diseases such as sleep disruption, metabolic syndrome, and mood disorders. Among environmental signals, changes in light represent the strongest time cue affecting rhythmic SCN gene expression. Recent work from our group and others has revealed that light signals reach multiple brain areas that rhythmically express clock genes. The discovery of such regions, known as brain oscillators, has transformed our understanding of how light regulates brain and organismal physiology, prompting research into the relationships between clock gene expression, brain oscillators, lighting conditions, and disease. Over the next five years, my group aims to address this knowledge gap. Specifically, we propose to investigate the mechanisms that harmonize clock gene expression in brain oscillators with rhythmic SCN signals. To this end, we will investigate how gene expression in brain oscillators is affected when clock gene rhythms are disrupted in SCN neurons, using genetically modified animals and viral strategies. Additionally, we will explore the direct impact of light signals on resetting brain oscillator rhythms in the absence of a functional central pacemaker. We anticipate that these experiments will identify prospective photo-entrainable brain oscillators, challenging the conventional view of the SCN as the exclusive light-sensing circadian clock. Furthermore, we propose to investigate the molecular mechanisms of circadian and sensory integration in clock brain cells. We hypothesize that the expression of the clock gene Period2 mechanistically integrates internal and external time cues, and such integration is crucial for organismal health. To test our hypotheses, we will generate datasets analyzing the transcriptomic landscape of the SCN and brain oscillators, including clock gene expression, and conduct functional in vivo and ex vivo analyses. Lastly, we aim to investigate how cellular mechanisms of circadian and sensory integration are disrupted when external and internal signals are desynchronized, as experienced under unnatural lighting conditions. We will investigate the sustained behavioral consequences associated with light-mediated stress and clock gene dysregulation in longitudinal studies. In summary, our proposal seeks to elucidate how internal and external signals are integrated to coordinate clock gene expression within brain centers that exert circadian control of physiology and behavior and investigate the long-lasting deficits on SCN function resulting from light-mediated stress.
