Gene expression plasticity of the mammalian brain circadian clock in response to photoperiod

Abstract

Seasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus and synchronizes, or entrains, physiology and behavior to the prevailing light cycle from retinal input. The process of entrainment induces considerable plasticity in the SCN, but the molecular mechanisms underlying SCN plasticity are incompletely understood. Entrainment to different photoperiods persistently alters the phase, waveform, period, and resetting properties of the SCN and its driven rhythms. To elucidate novel molecular mechanisms of photoperiod plasticity, we performed RNAseq on whole SCN dissected from mice raised in Long (LD 16:8) and Short (LD 8:16) photoperiods. Using differential rhythms analysis, we showed that fewer rhythmic genes were detected in Long photoperiod and that there was an overall phase advance of gene expression rhythms of 4-6 hours. However, a few genes showed significant phase delays, including GTP binding protein overexpressed in skeletal muscle (Gem), an SCN light responsive gene and light response modulator. Using differential expression analysis, we found significant expression changes in the clock-associated gene timeless circadian clock 1 (Timeless) and abundant changes in expression levels of SCN neural signaling genes related to light responses, neuropeptides, GABA, ion channels, and serotonin. Particularly striking were differences across photoperiods in the expression of the SCN neuropeptide signaling genes, prokineticin receptor 2 (Prokr2) and cholecystokinin (Cck), as well as convergent regulation of the expression of three SCN light response genes, dual specificity phosphatase 4 (Dusp4) and RAS, dexamethasone-induced 1 (Rasd1), andGem. Transcriptional modulation ofDusp4andRasd1,and phase regulation ofGem,are compelling candidate molecular mechanisms for photoperiod-induced plasticity in the SCN light response. Similarly, transcriptional modulation ofProkr2andCckmay critically support SCN neural network reconfiguration during photoperiodic entrainment. Our findings identify the SCN light response and neuropeptide signaling gene sets as rich substrates for elucidating novel mechanisms of photoperiod plasticity.