Input organization and plasticity of hypocretin neurons: possible clues to obesity's association with insomnia

Cell Metab. 2005 Apr;1(4):279-86. doi: 10.1016/j.cmet.2005.03.003.


The lateral hypothalamic hypocretin (also called orexin) neurons have emerged as instrumental in triggering arousal and regulating energy metabolism. The lack of hypocretin signaling is the cause of narcolepsy while elevated hypocretin levels induce arousal, elevated food intake, and adiposity. Here, we report an unorthodox synaptic organization on the hypocretin neurons in which excitatory synaptic currents and asymmetric synapses exert control on the cell bodies of these long-projective neurons with minimal inhibitory input. Overnight food deprivation promotes the formation of more excitatory synapses and synaptic currents onto hypocretin cells; this is reversed by re-feeding and blocked by leptin administration. This unique wiring and acute stress-induced plasticity of the hypocretin neurons correlates well with their being involved in the control of arousal and alertness that are so vital to survival, but this circuitry may also be an underlying cause of insomnia and associated metabolic disturbances, including obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Dendrites / metabolism
  • Hypothalamus / metabolism
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Male
  • Membrane Potentials / physiology
  • Mice
  • Mice, Transgenic
  • Neuronal Plasticity / physiology*
  • Neurons / metabolism*
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Neuropeptides / physiology*
  • Obesity / metabolism*
  • Orexins
  • Patch-Clamp Techniques
  • Sleep Initiation and Maintenance Disorders / metabolism*
  • Sleep Initiation and Maintenance Disorders / physiopathology*
  • Synapses / metabolism


  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexins