RNA Regulation and Cocaine: Novel Links to the Circadian Clock
Circadian rhythms regulate our physiological, metabolic, and behavioral activity in a 24-hour cycle to maintain organismal homeostasis. In virtually all tissues, the intrinsic circadian clock is governed by a canonical molecular transcriptional-translational feedback mechanism that is self-sustained. Whether additional functions for the molecular circadian clock exist remains largely unexplored. Here we investigate an unprecedented role for the circadian clock protein, BMAL1, in the nucleolus. We identified novel BMAL1 interactions with resident nucleolar proteins using biochemical fractionation and pull-down assays. Moreover, through use of molecular assays we reveal a critical role in pre-ribosomal RNA processing and maturation. Instead, environmental-mediated synchronization of peripheral tissues is regulated in part by external cues including light-dark, sleep-wake, and feed-fasting cycles. The degree to which non-photic environmental factors perturb the circadian clock in the brain continues to be a major point of interest. We studied an in vivo model to elucidate the effects of drugs of abuse as stressors on the striatal circadian clock. Mice treated with an acute dose of cocaine were sampled throughout a full circadian cycle. Using high-throughput RNA sequencing, our findings show cocaine drastically reprograms the circadian transcriptional clock in the nucleus accumbens. Furthermore, we reveal dopamine signaling is required for the cocaine-mediated PPARgamma activation that leads to de novo circadian transcriptional rhythmicity. Taken together, in the studies presented, we implement two discrete approaches to further our knowledge on the versatility and reprogrammability of the molecular clock. Our novel findings provide previously unexplored connections between RNA regulation or drugs of abuse and the circadian clock, and uncover new possible therapeutic targets for treatment development for disorders such as addiction.