Abstract
Attention-deficit hyperactivity disorder (ADHD) is characterized by changes to the circadian process. Many medications used to treat the condition, influence norepinephrine levels. Several studies have, in addition, reported that norepinephrine itself has an effect on circadian function. The aim of this study was to investigate the circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after norepinephrine exposure. We analyzed circadian preference, behavioral circadian and sleep parameters as well as the circadian gene expression in a cohort of healthy controls and participants with an ADHD diagnosis. Circadian preference was evaluated with German Morningness–Eveningness Questionnaire (D-MEQ) and rhythms of sleep/wake behavior were assessed via actigraphy. After ex vivo exposure to different norepinephrine concentrations in HDF cultures, the rhythmicity of circadian gene expression was analyzed via qRT-PCR. The exposure of 1 µM norepinephrine to confluent cultures of human dermal fibroblasts from participants with a diagnosis of ADHD, was shown to dampen Per1 rhythmicity. The expression of Bmal1, Per1 and Per3 in control subjects was also influenced by incubation with 1 µM norepinephrine. Cultures from the ADHD group revealed no statistically significant overall differences in circadian gene expression, between cultures with and without norepinephrine incubation. Per3 expression showed a significant ZT × group interaction via mixed ANOVA. Per3 expression at ZT4 was significant higher in the group of control samples incubated with 1 µM norepinephrine, compared to the control group without norepinephrine. This effect was also shown in the control samples incubated with 1 µM norepinephrine and cultures from subjects with ADHD without norepinephrine incubation. Per3 expression differed between the healthy control group and the ADHD group without norepinephrine incubation at ZT28. The results of the present study illustrate that norepinephrine impacts on circadian function. In both groups, control group and cultures taken from subjects with ADHD, the expression of the periodic genes (Per1–3) was significantly influenced by incubation with norepinephrine.
Highlights
The regulation of the norepinephrine (NE) homeostasis as well as the NE re-uptake into presynaptic nerve terminals among other substances is mediated by the NE transporter (NET) (Xu et al 2000)
Goal of this study is to investigate the effects of NE on circadian rhythmicity using the fibroblast model
The viability of the cultivated human dermal fibroblasts (HDF) after norepinephrine (NE) incubation was compared with Human dermal fibroblasts (HDF) without NE
Summary
The regulation of the norepinephrine (NE) homeostasis as well as the NE re-uptake into presynaptic nerve terminals among other substances is mediated by the NE transporter (NET) (Xu et al 2000). NE has been demonstrated to influence mammalian circadian rhythmicity. Studies have demonstrated that NE can reactivate the circadian rhythm of adult rat cardiomyocytes, as well as regulate the physiological expression of mPer, mPer and mBmal in mice livers, and the rhythmic oscillation of gBmal, gClock, gCry and gCry in chicken pineal glands (Durgan et al 2005; Li and Cassone 2015; Terazono et al 2003). Andrade-Silva et al, a group that studied the circadian gene expression in rat pineal gland cultures in respect to NE synchronization, concluded that NE synchronization mimics its natural release in pineal glands (Andrade-Silva et al 2014)
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