Bmal1 modulates striatal cAMP signaling and motor learning

The circadian rhythm shapes behavioral processes by providing temporal cues for molecular regulation and adaptation in the hypothalamus of the brain. Deeper yet in the striatum of the brain, circadian rhythm also exerts an impact, conditioning diurnal patterns in neurodegenerative-related motor dysfunction. While motor properties are clearly linked to striatal dopamine, the interplay between the circadian rhythm with the key circadian transcription factor Bmal1 and dopamine signal decoding remains unknown. Here, we utilized both sexes of global and local striatal Bmal1 knockout mice to investigate changes in dopamine-mediated cAMP signaling and motor behavior. By conducting a 24-hour time-course study, we first established Bmal1-dependent molecular signatures in striatal dopamine signaling machinery that correlated with cAMP levels. Next, recording real-time signal transduction with a 2-photon FRET biosensor in brain slices revealed diminished efficacy of dopamine signaling in the absence of Bmal1. As a final functional outcome, we then found that striatal Bmal1 was necessary for motor learning in mice. Altogether, our data support a strong connection between striatal Bmal1 and dopamine signaling with potential impact in brain-related motor function. Significance Statement Human physiology is intertwined with the circadian rhythm to orchestrates neuronal activity over a 24-hour period. Interruptions to the circadian rhythm are often met with anomalies in motor behavior, which are processes shaped by dopaminergic signaling. Understanding how dopamine transfers information between neurons remains one of the most important areas of neuroscience research. Yet it remains unclear how regulatory proteins that shape circadian rhythm coordinate decoding of dopamine neurotransmission. By examining the dopamine signaling cascade throughout the day in mice, we found that oscillations in the second messenger cAMP depend on the circadian transcription factor Bmal1. Additionally, disruptions to Bmal1 modulate motor learning. This work provides a strong case that Bmal1 greatly influences encoding of dopamine signals in the striatum.