Norepinephrine influences the circadian clock in human dermal fibroblasts from study participants with a diagnosis of attention-deficit hyperactivity disorder

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.

The light response in chickens divergently selected for feather pecking behavior reveals mechanistic insights towards psychiatric disorders

“…Various studies reported disturbed circadian rhythms in schizophrenia patients or model systems in connection to PER2 and PER3 expression or gene polymorphisms [ 22 – 25 ]. PER3 in particular was linked to attention-deficit hyperactivity disorder [ 26 , 27 ], which would comply with a hyperactivity disorder model of FP as proposed by Kjaer [ 28 ]. The brain transcriptome response of LFP to the light stimulus leads to an upregulation of numerous KEGG pathways (Fig.…”

The Circadian Molecular Machinery in CNS Cells: A Fine Tuner of Neuronal and Glial Activity With Space/Time Resolution

“…Moreover, in human dermal fibroblasts, the exposure to NA reduced the expression of Bmal1 at ZT12 and Per1 at ZT20 after incubation with NA compared to controls. Meanwhile, the expression of Per3 at CT4 was increased after the incubation with NA compared to cultures without NA treatments (Palm et al, 2021). In addition, in mice, administration of NA for 6 days highly induced Per1 mRNA transcription in the cerebral cortex during the light phase (Burioka et al, 2008).…”

“…Data concerning the synthesis and the uptake of neurotransmitters and their correlation with the expression/functions of circadian pacemakers support the role of certain transmitters (e.g., dopamine -DA-, serotonin -5-HT-, and γ-aminobutyric acid -GABA-) as fine-tuners of daily rhythmicity (Terazono et al, 2003;Imbesi et al, 2009;Nakamaru-Ogiso et al, 2012;Barca-Mayo et al, 2017;Brancaccio et al, 2017;Maejima et al, 2021;Palm et al, 2021). Deepening the knowledge of these correlations may lay the foundation of drug interventions aimed ] i is high, leading to an increased release of extracellular Glu, which, in turn, through the NR2C/NMDA receptors, is able to induce the release of GABA from presynaptic neurons.…”

“…Noradrenaline (NA) is a neurotransmitter mainly synthesized in the locus coeruleus (LC), and it is implicated in the modulation of alertness, arousal, cognition, executive functions, and mammalian circadian rhythmicity (Palm et al, 2021). The release of NA from the LC is a very dynamic process fundamental for the correct alternation between the rapid eye movement (REM) phase and the non-rapid eye movement (NREM) phase of sleep.…”

Atomoxetine and circadian gene expression in human dermal fibroblasts from study participants with a diagnosis of attention-deficit hyperactivity disorder

“…The four manuscripts of this special issue dealing with circadian rhythmicity describe unique research questions (Faltraco et al 2021a, b;Palm et al 2021). Although some samples have been used for more than one research question, the overall sample composition differs from each other and thus is different for each study.…”