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

Abstract

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.

An integrated modelling framework for neural circuits with multiple neuromodulators

“…We discuss such modelling approach in the context of developing and simulating a neural circuit model interconnected among the dorsal raphe nucleus (DRN), locus coeruleus (LC) and lateral hypothalamus areas (LHA), which are major sources of the important neuromodulators serotonin (5-HT), NE and orexin, respectively. The motivations for selecting these brain systems to model are that they are important in regulating physiological functions especially in arousal, are known to interact mutually with each other, and are the targets of several drugs [ 13 , 18 – 21 ]. In particular, the neuropeptide Ox is known to play an important role in energy homeostasis, food intake and appetite regulation, neuroendocrine functions and sleep–wake regulation [ 22 – 24 ].…”

Opportunities for multiscale computational modelling of serotonergic drug effects in Alzheimer's disease

“…Newer generation of antidepressant drugs such as SNRIs (e.g., venlafaxine) can provide an alternative route for the treatment of AD, as there is emerging evidence that suggests that norepinephrine system is also involved in Aβ regulation ( Liu et al, 2015 ; Mokhber et al, 2014 ; Ross et al, 2015 ). Hence, further modelling work on the interaction of neuromodulators will potentially be enlightening ( Jalewa et al, 2014 ; Joshi et al, 2011 , Joshi et al, 2015 , Joshi et al, 2017 ; Wang and Wong-Lin, 2013 ).…”