We also determined that Per1 knock-out mice display ADHD-like symptoms, reduced levels of DA, and disregulation of DA-related genes, thereby suggesting that the regulatory roles of Per1 in ADHD behaviors are conserved across vertebrates. Per1b acts via enzymes critical for DA metabolism to directly regulate the endogenous DA levels, and also through genes critical for development of dopaminergic neurons to possibly regulate their number and spatial organization. This zebrafish model with altered circadian rhythms demonstrates that ADHD behaviors in humans, rodents, and zebrafish are all associated with a dysfunctional DA system. We showed that zebrafish mutants for the circadian gene period1b ( per1b, an ortholog of human PER1) display hyperactivity, impulsivity-like and inattention-like behaviors, and low levels of dopamine (DA), reminiscent of human ADHD patients. Here, we set out to establish a zebrafish circadian model for attention deficiency and hyperactive behavior and to investigate the regulatory roles of the circadian clock in ADHD. The zebrafish ( Danio rerio) has been validated as a model for studying the genetic and developmental bases of behaviors ( Lieschke and Currie, 2007), and has demonstrated its superiority for high-throughput drug screens for behavioral disorders in whole organisms ( Rihel et al., 2010). The mechanisms by which the circadian clock impacts the pathogenesis of ADHD, however, are far from certain. In addition, dysrhythmias of melatonin production and altered expression of the circadian clock genes BMAL1 and PER2 appear to be associated with adult ADHD patients ( Baird et al., 2012). Mice carrying the dominant negative Clock mutation show mania-like behavior, including hyperactivity, decreased sleep, lowered depression-like behavior, reduced anxiety, and an increased reward value in association with elevated dopaminergic activities in the central tegmental area ( McClung et al., 2005 Roybal et al., 2007), while the circadian nuclear receptor Rev-erbα ( Nr1d1) knock-out mice also display mania-like behavior, particularly hyperactivity and a central hyperdopaminergic state ( Chung et al., 2014). Genome-wide association studies (GWAS) of ADHD patients have implicated genes involved in the endogenous circadian clock as risk factors for ADHD ( Lasky-Su et al., 2008). One of the key clinical manifestations of ADHD patients is obvious hyperactivity that in turn results in sleep deprivation ( Philipsen et al., 2006). ADHD is characterized clinically by hyperactivity, inattention, and impulsivity ( Kendall et al., 2008), which significantly impair normal development of academic and social functions in children, and lead to secondary problems, such as delinquency and drug addiction, in adults ( Rösler et al., 2004). Attention-deficit/hyperactivity disorder (ADHD Online Mendelian Inheritance in Man #143465) is one of the most prevalent psychiatric disorders in children and adults, affecting ∼3–5% of the population ( Geissler and Lesch, 2011). Circadian dysfunctions are thought to underlie the pathogenesis of many psychiatric disorders, including mania-like behavior and bipolar disorder ( McClung, 2013). The circadian clock generates physiological and behavioral rhythms with a period of ∼24 h and plays a critical role in the sleep/wake cycle ( Dijk and von Schantz, 2005). The circadian model for attention deficiency and hyperactive behavior sheds light on ADHD pathogenesis and opens avenues for exploring novel targets for diagnosis and therapy for this common psychiatric disorder. Our studies demonstrate that disruption of a circadian clock gene elicits ADHD-like syndrome. We then found that Per1 knock-out mice also display ADHD-like symptoms and reduced levels of dopamine, thereby showing highly conserved roles of the circadian clock in ADHD. We found that the circadian clock directly regulates dopamine-related genes monoamine oxidase and dopamine β hydroxylase, and acts via genes important for the development or maintenance of dopaminergic neurons to regulate their number and organization in the ventral diencephalic posterior tuberculum. Here we found that the zebrafish mutant for the circadian gene period1b ( per1b) displays hyperactive, impulsive-like, and attention deficit-like behaviors and low levels of dopamine, reminiscent of human ADHD patients. While ADHD patients often display circadian abnormalities, the underlying mechanisms are unclear. Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children and adults.
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