Circadian Modulation of Dopamine Levels and Dopaminergic Neuron Development Contributes to Attention Deficiency and Hyperactive Behavior

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children and adults. While ADHD patients often display circadian abnormalities, the underlying mechanisms are unclear. 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. We found that the circadian clock directly regulates dopamine-related genes monoamine oxidase and dopamine ␤ 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. 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. Our studies demonstrate that disruption of a circadian clock gene elicits ADHD-like syndrome. 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.

The Zebrafish Period2 Protein Positively Regulates the Circadian Clock through Mediation of Retinoic Acid Receptor (RAR)-related Orphan Receptor α (Rorα)

“…2, A and B) and a 2-h phase delay and a 1.1-h prolonged period under DD (Fig. 2, C and D), which are completely different from the phenotypes of the zebrafish per1b insertional null mutant that displays hyperactivities under LD and a 2-h phase advance under DD (73). Hence, like mammalian Per2, zebrafish per2 also is critical for maintaining fish locomotor rhythmicity.…”

“…2, E and F), which diametrically differs from the repressive role of Per1b in regulating other per genes; i.e. all three other per genes are significantly up-regulated in the per1b-null mutant fish (73). Although Per1 knock-out mice have no effects on rhythmic expression of Per1 or Per2, both Per1 and Per2 are significantly down-regulated in Per2 knockout mice (21,40).…”

Contribution of animal models to contemporary understanding of Attention Deficit Hyperactivity Disorder

“…Furthermore, even though functional investigation methods of the brain are the leading technology in contemporary brain disorder research (Marcucci and Vandresen, 2006;Labate et al, 2013), the emergence and development of transgenic animal models has also led to an exponential growth of animal use in neuroscience research, including in ADHD (Porter et al, 2015). Within ADHD, animals are used to model ADHD-related behaviors and traits (Yen et al, 2013), to seek understanding of ADHD's biochemical pathways (Yen et al, 2013;Huang et al, 2015) as well as responses to putative drugs (Dudley et al, 2013) and other therapies (Ouchi et al, 2013).…”

Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior

“…This study is the first, to our knowledge, to demonstrate that a deficiency of NDRG2, a known tumor suppressor (16,17), leads to a canonical ADHD-like phenotype, including hyperactivity, impulsivity, attention deficits, and impaired memory, which meet the face validity criteria for ADHD animal models (28,29,44,45). Increased interstitial glutamate levels and excitatory transmission underlie the behavioral abnormalities in Ndrg2 -/-mice.…”

“…Several animal models of ADHD exhibit cognitive deficits, such as impaired memory (27)(28)(29), which are consistent with the clinical symptoms of the multiple behavioral abnormalities in children with ADHD (30,31). Thus, we investigated both short-and long-term memory in the Ndrg2 -/-mice.…”