Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice

Neurobiol Learn Mem. 2017 Dec:146:21-30. doi: 10.1016/j.nlm.2017.10.014. Epub 2017 Oct 28.


Orexin A is produced in neurons of the lateral, perifornical and dorsomedial regions of the lateral hypothalamic area, which then project widely throughout the central nervous system to regulate arousal state, sleep-wake architecture, energy homeostasis and cognitive processes. Disruption of orexin signaling leads to sleep disturbances and increased body mass index, but recent studies also indicate that orexin neuron activation improves learning and memory. We hypothesized that hippocampal orexin receptor activation improves memory. To test this idea, we obtained orexin/ataxin-3 (O/A3) mice, which become deficient in orexin neurons by about 12 weeks of age. We first measured hippocampal orexin receptor 1 (OX1R) gene expression and protein levels, then tested acquisition and consolidation of two-way active avoidance (TWAA) memory, a hippocampal-dependent learning and memory task. Finally, we determined if exogenous intra-hippocampal OXA treatment could reverse cognitive impairment (as determined by TWAA) in OA/3 mice. We showed that OX1R mRNA expression and protein levels were significantly elevated in O/A3 mice, indicating the potential for preserved orexin responsiveness. The O/A3 mice were significantly impaired in TWAA memory vs. control mice, but OXA treatment (both acute and chronic) reversed these memory deficits. These results demonstrate that orexin plays an important role in hippocampal-dependent consolidation of two-way active avoidance memory, and orexin replacement can rescue the cognitive impairment.

Keywords: Hypocretin; Orexin 1 receptor; Orexin ataxin-3.

MeSH terms

  • Animals
  • Ataxin-3
  • Avoidance Learning* / drug effects
  • Behavior, Animal / drug effects
  • Cognitive Dysfunction* / drug therapy
  • Cognitive Dysfunction* / metabolism
  • Cognitive Dysfunction* / physiopathology
  • Disease Models, Animal
  • Female
  • Hippocampus* / drug effects
  • Hippocampus* / metabolism
  • Hippocampus* / physiopathology
  • Memory Consolidation* / drug effects
  • Memory Disorders* / drug therapy
  • Memory Disorders* / metabolism
  • Memory Disorders* / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Orexin Receptors / genetics
  • Orexin Receptors / metabolism*
  • Orexins / administration & dosage
  • Orexins / deficiency*
  • Orexins / pharmacology*
  • RNA, Messenger / metabolism


  • Hcrtr1 protein, mouse
  • Orexin Receptors
  • Orexins
  • RNA, Messenger
  • Ataxin-3
  • Atxn3 protein, mouse