Orexin and Circadian Influences in Sleep and Psychiatric Disorders: A Review of Experimental and Computational Modelling Studies



Psychiatric disorders such as unipolar depression have complex pathologies, which include disruptions in circadian and sleep-wake cycles. At the neurochemical level, psychiatric diseases can also be accompanied by changes in neuromodulator systems such as orexin/hypocretin and the monoamines. Indeed, for decades the monoamine hypothesis of depression has been instrumental in driving discoveries and developments of antidepressant drugs. Recent preclinical and clinical advancement strongly suggests that neuropeptides such as orexin can play an important part in the pathophysiology of depression. Due to the complexity and extensive connectedness of neurobiological systems, understanding the biological causes and mechanisms of psychiatric disorders present major research challenges. In this chapter, we review experimental and computational studies investigating the complex relationship between orexinergic, monoaminergic, circadian oscillators, and sleep-wake neural circuitry. Our main aim is to understand how these physiological systems interact and how alteration in any of these factors can contribute to the behaviours commonly observed in depressive patients. Further, we examine how modelling across different levels of neurobiological organization enables insight into these interactions. We propose that a multiscale systems approach is necessary to understand the complex neurobiological systems whose dysfunctions are the underlying causes of psychiatric disorders. Such an approach could illuminate future treatments.


Psychiatric disorders Sleep Neuromodulators Orexin (hypocretin) Monoamines Circadian rhythms Computational models 



This work was supported by the Human Frontier Science Program (AJ, HDP), BBSRC (MDCB, HDP), and Northern Ireland Functional Brain Mapping Facility (1303/101154803) funded by InvestNI and the University of Ulster, Innovate UK (102161), and The Royal Society—NSFC International Exchanges (KFW-L). The authors would like to thank Daniel B. Forger, Beatriz Baño Otálora, Joseph Timothy, Jaishree Jalewa, Christian Hölscher, T. Martin McGinnity and Girijesh Prasad for previous discussions in helping to generate some of the presented ideas.


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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Faculty of Life SciencesUniversity of ManchesterManchesterUK
  2. 2.Intelligent Systems Research CentreUniversity of Ulster, Magee CampusDerryNorthern Ireland, UK

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