Involvement of dopamine signaling in the circadian modulation of interval timing

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Duration discrimination within the seconds-to-minutes range, known as interval timing, involves the interaction of cortico-striatal circuits via dopaminergic–glutamatergic pathways. Besides interval timing, most (if not all) organisms exhibit circadian rhythms in physiological, metabolic and behavioral functions with periods close to 24 h. We have previously reported that both circadian disruption and desynchronization impaired interval timing in mice. In this work we studied the involvement of dopamine (DA) signaling in the interaction between circadian and interval timing. We report that daily injections of levodopa improved timing performance in the peak-interval procedure in C57BL/6 mice with circadian disruptions, suggesting that a daily increase of DA is necessary for an accurate performance in the timing task. Moreover, striatal DA levels measured by reverse-phase high-pressure liquid chromatography indicated a daily rhythm under light/dark conditions. This daily variation was affected by inducing circadian disruption under constant light (LL). We also demonstrated a daily oscillation in tyrosine hydroxylase levels, DA turnover (3,4-dihydroxyphenylacetic acid/DA levels), and both mRNA and protein levels of the circadian component Period2 (Per2) in the striatum and substantia nigra, two brain areas relevant for interval timing. None of these oscillations persisted under LL conditions. We suggest that the lack of DA rhythmicity in the striatum under LL – probably regulated by Per2 – could be responsible for impaired performance in the timing task. Our findings add further support to the notion that circadian and interval timing share some common processes, interacting at the level of the dopaminergic system.

Striatal dopamine (DA) content and turnover, tyrosine hydroxylase and Per2 levels are rhythmic under light/dark (LD) cycles but not in constant light (LL). In search for the link between interval and circadian timing, we found that daily injections of levodopa improved timing in mice with circadian disruption under LL. DA arhythmicity in the striatum could be responsible for impaired timing performance, while daily levodopa might restore such rhythm and improve interval timing mechanisms.

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