Specifically, the locus coeruleus provides norepinephrine-mediated

inhibition of the VLPO during wakefulness. During sleep, activity in the ventral and median preoptic nuclei inhibits the ascending arousal system via the inhibitory neurotransmitters γ-aminobutyric acid and galanin. The sleep-regulatory cells in the VLPO are directly and indirectly regulated by SCN input (Novak & Nunez, 2000; Chou et al., 2002; Kriegsfeld et al., 2004). This circuit enables master clock interactions with homeostatic sleep regulatory systems. Among the most important known homeostatic sleep factors is adenosine (reviewed in Porkka-Heiskanen, 2013). The accumulation of adenosine (a powerful somnogen) during wakefulness is associated with increased VLPO activity upon Small molecule library increased adenosine binding. VLPO activation then inhibits the ascending arousal circuits and promotes non-rapid eye movement sleep. It is beyond question that the most salient aspect of the circadian system is its role in controlling the timing of sleep. Moreover, environmental I BET 762 disruptions to circadian rhythms, including shift work, travel across time zones, and irregular social schedules,

tend to precipitate or exacerbate mood-related episodes. Using shift work or jet lag as a model experimental paradigm, numerous studies, in both humans and animals, have demonstrated the adverse effects of disrupted sleep–wake schedules on health (Wang et al., 2011). Nearly all people suffering from mood disorders have significant disruptions in circadian rhythms, and altered sleep patterns are one of the major diagnostic criteria for these disorders. Importantly, sleep disorders seem to precede clinical diagnoses of mental Clomifene illness, and reduction of sleep disturbances improves mental illness (Ritter et al., 2011; Pritchett et al., 2012). It appears that many pathologies are comorbid in both mental illness and neurodegenerative disease; these include poor vigilance and memory, reduced mental and physical reaction times, reduced motivation, depression, insomnia, and obesity, among other states

(Wulff et al., 2010). Furthermore, manipulation of the timing of sleep can ameliorate symptoms of major depressive disorder and bipolar disorder (Bunney & Bunney, 2013; Kaplan & Harvey, 2013). Although chronic sleep deprivation or disruption exacerbates behavioral problems, and may directly affect cognitive function and mood disorders, there is also evidence of mechanistic links between circadian clocks, sleep and mental illness (reviewed in Lamont et al., 2010; Menet & Rosbash, 2011). For example, in humans, casein kinase 1 epsilon and PER2 mutations are associated with familial advanced sleep phase disorder, which causes patients to fall asleep several hours earlier than normal (Toh et al., 2001). In addition, associations for polymorphisms in other circadian genes, including polymorphisms in the Cry2 locus with bipolar disorder (Shi et al., 2008; Sjoholm et al., 2010) and depression (Lavebratt et al.