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

Vijayakumar Mavanji, Tammy A. Butterick, Cayla M. Duffy, Joshua P. Nixon, Charles J Billington, Catherine M Kotz

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23 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)21-30
Number of pages10
JournalNeurobiology of Learning and Memory
StatePublished - Dec 2017

Bibliographical note

Funding Information:
This work was supported by the Department of Veterans Affairs (5I01BX003004-01A2 and 1I01BX003687-02 to CMK and CJB; 1IK2 BX001686-01A1 to TAB), the National Institute of Health (5R01DK100281-03 to CMK and CJB), and the Minnesota Obesity Center (5R01DK100281-03), and by Award Number T32DK083250 from the National Institute of Diabetes and Digestive and Kidney Diseases (CMK). We are grateful to all the members of the Obesity Neuroscience group at the Minneapolis VA, especially Martha M. Grace for her support in performing the experiments.


  • Hypocretin
  • Orexin 1 receptor
  • Orexin ataxin-3

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