Neuropeptide Y-induced phase shifts of PER2::LUC rhythms are mediated by long-term suppression of neuronal excitability in a phase-specific manner

Chronobiol Int. 2012 Mar;29(2):91-102. doi: 10.3109/07420528.2011.649382.


Endogenous circadian rhythms are entrained to the 24-h light/dark cycle by both light and nonphotic stimuli. During the day, nonphotic stimuli, such as novel wheel-induced exercise, produce large phase advances. Neuropeptide Y (NPY) release from the thalamus onto suprachiasmatic nucleus (SCN) neurons at least partially mediates this nonphotic signal. The authors examined the hypothesis that NPY-induced phase advances are accompanied by suppression of PER2 and are mediated by long-term depression of neuronal excitability in a phase-specific manner. First, it was found that NPY-induced phase advances in PER2::LUC SCN cultures are largest when NPY (2.35 µM) is given in the early part of the day (circadian time [CT] 0-6). In addition, PER2::LUC levels in NPY-treated (compared to vehicle-treated) samples were suppressed beginning 6-7 h after treatment. Similar NPY application to organotypic Per1::GFP SCN cultures resulted in long-term suppression of spike rate of green fluorescent protein-positive (GFP+) cells when slices were treated with NPY during the early or middle of the day (zeitgeber time [ZT] 2 or 6), but not during the late day (ZT 10). Furthermore, 1-h bath application of NPY to acute SCN brain slices decreased general neuronal activity measured through extracellular recordings. Finally, NPY-induced phase advances of PER2::LUC rhythms were blocked by latent depolarization with 34.5 mM K(+) 3 h after NPY application. These results suggest that NPY-induced phase advances may be mediated by long-term depression of neuronal excitability. This model is consistent with findings in other brain regions that NPY-induced persistent hyperpolarization underlies mechanisms of energy homeostasis, anxiety-related behavior, and thalamocortical synchronous firing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Circadian Rhythm / drug effects*
  • Circadian Rhythm / physiology
  • Electrophysiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / physiology*
  • Neuropeptide Y / pharmacology*
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism*
  • Potassium / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Suprachiasmatic Nucleus / cytology
  • Suprachiasmatic Nucleus / drug effects*
  • Suprachiasmatic Nucleus / physiology


  • Neuropeptide Y
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Recombinant Fusion Proteins
  • Potassium