In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which transmits circadian information to other brain regions and regulates the timing of sleep and wakefulness. Neurons in the lateral hypothalamus (LH), particularly those producing melanin-concentrating hormone (MCH)- and orexin are key regulators of sleep and wakefulness. Although the SCN receives non-photic input from other brain regions, the mechanisms of functional input from the LH to the SCN remain poorly understood. Here, we show that orexin and MCH peptides influence the circadian period within the SCN of both sexes. When these neurons are ablated, the circadian behavioral rhythms are lengthened under constant darkness. Using anterograde and retrograde tracing, we found that orexin and MCH neurons project to the SCN. Furthermore, the application of these peptides to cultured SCN slices shortened circadian rhythms and reduced intracellular cAMP levels. Additionally, pharmacological reduction of intracellular cAMP levels similarly shortened the circadian period in SCN slices. These findings suggest that orexin and MCH peptides from the LH contribute to the modulation of the circadian period in the SCN.

Significance statementIn mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, where it regulates circadian rhythms, including sleep and wakefulness. The SCN receives both neuronal and humoral input signals from external brain regions, which can modify circadian rhythms within the SCN. While several brain regions that project to the SCN have been anatomically identified, the specific regions, neuronal cell types, and neurotransmitters that influence SCN circadian rhythms remain largely uncharacterized. This study identifies two neuronal populations within the lateral hypothalamus that project to the SCN and modulate the circadian period.