Energy balance drives diurnal and nocturnal brain transcriptome rhythms.

Plasticity in daily timing of activity has been observed in many species, yet the underlying mechanisms driving nocturnality and diurnality are unknown. By regulating how much wheel-running activity will be rewarded with a food pellet, we can manipulate energy balance and switch mice to be nocturnal or diurnal. Here, we present the rhythmic transcriptome of 21 tissues, including 17 brain regions, sampled every 4 h over a 24-h period from nocturnal and diurnal male CBA/CaJ mice. Rhythmic gene expression across tissues comprised different sets of genes with minimal overlap between nocturnal and diurnal mice. We show that non-clock genes in the suprachiasmatic nucleus (SCN) change, and the habenula was most affected. Our results indicate that adaptive flexibility in daily timing of behavior is supported by gene expression dynamics in many tissues and brain regions, especially in the habenula, which suggests a crucial role for the observed nocturnal-diurnal switch.

Neuronal reprogramming of mouse and human fibroblasts using transcription factors involved in suprachiasmatic nucleus development.

The hypothalamic suprachiasmatic nucleus (SCN) is composed of heterogenous populations of neurons that express signaling peptides such as vasoactive intestinal polypeptide (VIP) and arginine vasopressin (AVP) and regulate circadian rhythms in behavior and physiology. SCN neurons acquire functional and morphological specializations from waves of transcription factors (TFs) that are expressed during neurogenesis. However, the in vitro generation of SCN neurons has never been achieved. Here we supplemented a highly efficient neuronal conversion protocol with TFs that are expressed during SCN neurogenesis, namely Six3, Six6, Dlx2, and Lhx1. Neurons induced from mouse and human fibroblasts predominantly exhibited neuronal properties such as bipolar or multipolar morphologies, GABAergic neurons with expression of VIP. Our study reveals a critical contribution of these TFs to the development of vasoactive intestinal peptide (Vip) expressing neurons in the SCN, suggesting the regenerative potential of neuronal subtypes contained in the SCN for future SCN regeneration and in vitro disease remodeling.