Schematic depicting the currently accepted hierarchal model for circadian rhythm generation. Light information is conveyed by the optic nerve to the SCN, a region of the ventral hypothalamus. There, light entrains clocks within SCN neurons, and this is ultimately converted by the CNS into pulsatile chemical and neurological cues, which entrain cell-autonomous circadian clocks residing in peripheral cells. These peripheral clocks impart circadian patterns on gene expression and overall cellular physiology. For simplicity, only the core molecular clock circuitry is depicted, with positive regulatory proteins labeled green and negative regulators labeled red. However, there are many accessory proteins and metabolic pathways that can adjust the periodicity and phase of the clock but are not central to rhythm generation (for example, casein kinase 1δ/ε [ref. 23], AMPK [ref. 149], mTOR [ref. 150], p53 [ref. 151], and SIRT1 [ref. 152]). There are additional molecular clock constituents (not depicted) that in the basal state appear to have more prominent roles in CNS clocks than clocks in peripheral cells. For example, NPAS2 (a functional homolog of CLOCK) and DEC1/2 provide additional negative feedback to BMAL1/CLOCK (16, 153). Yellow boxes represent E-boxes or ROR-responsive elements (RREs), which are the promoter motifs recognized by BMAL1/CLOCK or REV-ERB/ROR proteins, respectively. Clock genes and clock-controlled genes (CGs) are represented by green and purple arrows, respectively. Illustrated by Rachel Davidowitz.