Fig. 1.

Overview of the core clock machinery in the brain. The transcriptional activators circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-Like 1 (BMAL1) form heterodimers that bind to enhancer box (E-box) elements, thereby driving the transcription of cryptochrome (CRY1/2), period (PER1/2/3) and tyrosine-protein kinase transmembrane receptor RORα/β/γ and REV-ERBα/β.^5,6 PER/CRY heterodimers accumulate to inhibit BMAL1/CLOCK activity. Concurrently, RORα/β/γ and REV-ERBα/β compete for binding to ROR response element (RORE) on the BMAL1 promoter, respectively activating or inhibiting its transcription. This intricate feedback loop generates rhythmic fluctuations in clock-controlled gene expression within 24-h cycles.^5,7 The molecular clock is present in virtually all cell types in the human body, including neurons, astrocytes, microglia, and oligodendrocytes and drives daily fluctuations in their morphology and functionality.⁸