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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.

SUBMITTER: Huang J

PROVIDER: S-EPMC4323534 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Circadian modulation of dopamine levels and dopaminergic neuron development contributes to attention deficiency and hyperactive behavior.

Huang Jian J Zhong Zhaomin Z Wang Mingyong M Chen Xifeng X Tan Yicheng Y Zhang Shuqing S He Wei W He Xiong X Huang Guodong G Lu Haiping H Wu Ping P Che Yi Y Yan Yi-Lin YL Postlethwait John H JH Chen Wenbiao W Wang Han H

The Journal of neuroscience : the official journal of the Society for Neuroscience 20150201 6

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 dopamin ...[more]

PMID: 25673850

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Project description:BackgroundAttention-deficit/hyperactive disorder (ADHD) is a neurodevelopmental disorder that commonly occurs in children with a prevalence ranging from 3.4 to 7.2%. It profoundly affects academic achievement, well-being, and social interactions. As a result, this disorder is of high cost to both individuals and society. Despite the availability of knowledge regarding the mechanisms of ADHD, the pathogenesis is not clear, hence, the existence of many challenges especially in making correct early diagnosis and provision of accurate management.ObjectivesWe aimed to review the pathogenic pathways of ADHD in children. The major focus was to provide an update on the reported etiologies in humans, animal models, modulators, therapies, mechanisms, epigenetic changes, and the interaction between genetic and environmental factors.MethodsReferences for this review were identified through a systematic search in PubMed by using special keywords for all years until January 2022.ResultsSeveral genes have been reported to associate with ADHD: DRD1, DRD2, DRD4, DAT1, TPH2, HTR1A, HTR1B, SLC6A4, HTR2A, DBH, NET1, ADRA2A, ADRA2C, CHRNA4, CHRNA7, GAD1, GRM1, GRM5, GRM7, GRM8, TARBP1, ADGRL3, FGF1, MAOA, BDNF, SNAP25, STX1A, ATXN7, and SORCS2. Some of these genes have evidence both from human beings and animal models, while others have evidence in either humans or animal models only. Notably, most of these animal models are knockout and do not generate the genetic alteration of the patients. Besides, some of the gene polymorphisms reported differ according to the ethnic groups. The majority of the available animal models are related to the dopaminergic pathway. Epigenetic changes including SUMOylation, methylation, and acetylation have been reported in genes related to the dopaminergic pathway.ConclusionThe dopaminergic pathway remains to be crucial in the pathogenesis of ADHD. It can be affected by environmental factors and other pathways. Nevertheless, it is still unclear how environmental factors relate to all neurotransmitter pathways; thus, more studies are needed. Although several genes have been related to ADHD, there are few animal model studies on the majority of the genes, and they do not generate the genetic alteration of the patients. More animal models and epigenetic studies are required.

Project description:Mesoventromedial dopamine neurons projecting from the medial ventral tegmental area to the ventromedial shell of the nucleus accumbens play a role in attributing incentive salience to environmental stimuli that predict important events, and appear to be particularly sensitive to the effects of psychostimulant drugs. Despite the observation that these dopamine neurons make up almost the entire complement of neurons in the projection, stimulating their cell bodies evokes a fast glutamatergic response in accumbens neurons. This is apparently due to dopamine neuron glutamate cotransmission, suggested by the extensive coexpression of vesicular glutamate transporter 2 (VGLUT2) in the neurons. To examine the interplay between the dopamine and glutamate signals, we used acute quasi-horizontal brain slices made from DAT-YFP mice in which the intact mesoventromedial projection can be visualized. Under current clamp, when dopamine neurons were stimulated repeatedly, dopamine neuron glutamate transmission showed dopamine-mediated facilitation, solely at higher, burst-firing frequencies. Facilitation was diminished under voltage clamp and flipped to inhibition by intracellular Cs(+) or GDPbetaS, indicating that it was mediated postsynaptically. Postsynaptic facilitation was D1 mediated, required activation of NMDA receptors and closure of voltage gated K(+)-channels. When postsynaptic facilitation was blocked, D2-mediated presynaptic inhibition became apparent. These counterbalanced pre- and postsynaptic actions determine the frequency dependence of dopamine modulation; at lower firing frequencies dopamine modulation is not apparent, while at burst firing frequency postsynaptic facilitation dominates and dopamine becomes facilitatory. Dopamine neuron glutamate cotransmission may play an important role in encoding the incentive salience value of conditioned stimuli that activate goal-directed behaviors, and may be an important subtract for enduring drug-seeking behaviors.

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Circadian modulation of dopamine levels and dopaminergic neuron development contributes to attention deficiency and hyperactive behavior.

Publications

Circadian modulation of dopamine levels and dopaminergic neuron development contributes to attention deficiency and hyperactive behavior.

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