Comparative rhythmic transcriptome profiling of human and mouse striatal subregions.

The human striatum can be subdivided into the caudate, putamen, and nucleus accumbens (NAc). In mice, this roughly corresponds to the dorsal medial striatum (DMS), dorsal lateral striatum (DLS), and ventral striatum (NAc). Each of these structures have some overlapping and distinct functions related to motor control, cognitive processing, motivation, and reward. Previously, we used a "time-of-death" approach to identify diurnal rhythms in RNA transcripts in these three human striatal subregions. Here, we identify molecular rhythms across similar striatal subregions collected from C57BL/6J mice across 6 times of day and compare results to the human striatum. Pathway analysis indicates a large degree of overlap between species in rhythmic transcripts involved in processes like cellular stress, energy metabolism, and translation. Notably, a striking finding in humans is that small nucleolar RNAs (snoRNAs) and long non-coding RNAs (lncRNAs) are among the most highly rhythmic transcripts in the NAc and this is not conserved in mice, suggesting the rhythmicity of RNA processing in this region could be uniquely human. Furthermore, the peak timing of overlapping rhythmic genes is altered between species, but not consistently in one direction. Taken together, these studies reveal conserved as well as distinct transcriptome rhythms across the human and mouse striatum and are an important step in understanding the normal function of diurnal rhythms in humans and model organisms in these regions and how disruption could lead to pathology.

The Suprachiasmatic Nucleus Regulates Anxiety-Like Behavior in Mice.

Individuals suffering from mood and anxiety disorders often show significant disturbances in sleep and circadian rhythms. Animal studies indicate that circadian rhythm disruption can cause increased depressive- and anxiety-like behavior, but the underlying mechanisms are unclear. One potential mechanism to explain how circadian rhythms are contributing to mood and anxiety disorders is through dysregulation of the suprachiasmatic nucleus (SCN) of the hypothalamus, known as the "central pacemaker." To investigate the role of the SCN in regulating depressive- and anxiety-like behavior in mice, we chronically manipulated the neural activity of the SCN using two optogenetic stimulation paradigms. As expected, chronic stimulation of the SCN late in the active phase (circadian time 21, CT21) resulted in a shortened period and dampened amplitude of homecage activity rhythms. We also repeatedly stimulated the SCN at unpredictable times during the active phase of mice when SCN firing rates are normally low. This resulted in dampened, fragmented, and unstable homecage activity rhythms. In both chronic SCN optogenetic stimulation paradigms, dampened homecage activity rhythms (decreased amplitude) were directly correlated with increased measures of anxiety-like behavior. In contrast, we only observed a correlation between behavioral despair and homecage activity amplitude in mice stimulated at CT21. Surprisingly, the change in period of homecage activity rhythms was not directly associated with anxiety- or depressive-like behavior. Finally, to determine if anxiety-like behavior is affected during a single SCN stimulation session, we acutely stimulated the SCN in the active phase (zeitgeber time 14-16, ZT14-16) during behavioral testing. Unexpectedly this also resulted in increased anxiety-like behavior. Taken together, these results indicate that SCN-mediated dampening of rhythms is directly correlated with increased anxiety-like behavior. This work is an important step in understanding how specific SCN neural activity disruptions affect depressive- and anxiety-related behavior.

Photoresponsivity and motility in the planarian Schmidtea mediterranea vary diurnally.

The planarian flatworm has become one of the leading animal model systems for studying stem cell behavior and tissue regeneration. Recent studies have shown that components of the circadian clockwork have important roles in tissue homeostasis and repair. However, it remains unknown whether planarians exhibit circadian or diurnal rhythms in physiology or behavior. Here, we developed a behavioral assay to evaluate diurnal activity in planarians based upon their well-established propensity to swim away from light (negative phototaxis). We show evidence that the planarian Schmidtea mediterranea has diurnal variability in negative phototaxis as a function of daily variation in motility. We also demonstrate that variation in planarian motility over 48 h occurs with 24-h periodicity. Our data suggest that S. mediterranea may be a useful model for studying the interplay between the circadian system and tissue regeneration.