Role of orexin in non-photic phase shifting of the circadian clock

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Our 24-hour day presents organisms with regular and predictable challenges to which they have adapted. We organize our biology and behavior in a manner to anticipate these predictable challenges. In animals, the job of anticipating these needs and organizing our behavior and physiology across the 24-hour day falls to our circadian clock located in the hypothalamus of our brains. This circadian clock generates these daily rhythms in physiology and behavior. To effectively anticipate the timing of these rhythmic challenges our clock must be synchronized to the time cues in our environment. While light is the most reliable and dominant cue used by most organisms to achieve this synchrony, the circadian clock is also sensitive to cues other than light. These so-called "non-photic" cues affect the clock in a manner distinct from light. Notably, exercise, loss of sleep and arousal all seem to be related non-photic cues that adjust our circadian clocks in a similar fashion, implying a similar underlying neural mechanism. With this proposal, we will uncover how these non-photic cues input to the circadian clock and its wider network. Recently we have identified key arousal systems in the brain (i.e., acetylcholine from the basal forebrain) that are critical to these non-photic responses. These signals operate in parallel to another well defined system that is also essential to non-photic responses, namely Neuropeptide Y that originates in the thalamic intergeniculate leaflet (IGL). The IGL is embedded in a visual area, so it is surprising that this structure plays such a critical role not in visual responses, but rather in these non-visual responses. How arousal recruits the IGL in non-photic responses is unknown. We hypothesize that the critical arousal signal comes from another critical arousal system in the brain that uses the neurotransmitter Orexin. We will test this hypothesis through a number of complementary experimental approaches including pharmacology (Objective 1), anatomical investigation (Objective 2), chemogenetic approaches (Objective 3), and monitoring cellular activity in vivo during non-photic treatments. Furthermore, as much of the historical data in this field derives from male animals, we will also be developing a novel experimental approach that will allow us to study this phenomenon in female animals (Objective 5). The circadian system has become a model system for understanding both genetic and neural control of behavior. The work carried out in this proposal will uncover the inner workings of not only the circadian system, but also of the sleep/wake system, helping to demonstrate the interplay between them. The young scientists conducting this work will develop a strong skill-set that will facilitate their transition into independent scientists themselves. Living in the north, Canadians feel the impact of seasonal photoperiod changes. Understanding how our circadian system works will help mitigate adverse photoperiod effects.