Format

Send to

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

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

Author information

1
Research Service, Veterans Affairs Health Care System, Minneapolis, MN 55417 USA.
2
Research Service, Veterans Affairs Health Care System, Minneapolis, MN 55417 USA; Department of Food Science and Nutrition, University of Minnesota, St Paul, MN 55108 USA; Minnesota Obesity Center, St Paul, MN 55108 USA.
3
Research Service, Veterans Affairs Health Care System, Minneapolis, MN 55417 USA; Department of Food Science and Nutrition, University of Minnesota, St Paul, MN 55108 USA; Minnesota's Discovery, Research and Innovation Economy, Brain Conditions, University of Minnesota, Minneapolis, MN 55455.
4
Research Service, Veterans Affairs Health Care System, Minneapolis, MN 55417 USA; Department of Food Science and Nutrition, University of Minnesota, St Paul, MN 55108 USA.
5
Research Service, Veterans Affairs Health Care System, Minneapolis, MN 55417 USA; Minnesota Obesity Center, St Paul, MN 55108 USA; Department of Medicine, University of Minnesota, Minneapolis, MN 55455 USA.
6
Research Service, Veterans Affairs Health Care System, Minneapolis, MN 55417 USA; Minnesota Obesity Center, St Paul, MN 55108 USA; Geriatric Research Education Clinical Center, Veterans Affairs Health Care System, Minneapolis, MN 55417 USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455 USA. Electronic address: kotzx004@umn.edu.

Abstract

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

PMID:
29107703
PMCID:
PMC5798856
DOI:
10.1016/j.nlm.2017.10.014
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center