Molecular elevation of insulin receptor signaling improves memory recall in aged Fischer 344 rats

Hilaree N. Frazier, Katie L. Anderson, Adam O. Ghoweri, Ruei Lung Lin, Tara R. Hawkinson, Gabriel J. Popa, Pradoldej Sompol, Michael D. Mendenhall, Christopher M. Norris, Olivier Thibault

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

As demonstrated by increased hippocampal insulin receptor density following learning in animal models and decreased insulin signaling, receptor density, and memory decline in aging and Alzheimer's diseases, numerous studies have emphasized the importance of insulin in learning and memory processes. This has been further supported by work showing that intranasal delivery of insulin can enhance insulin receptor signaling, alter cerebral blood flow, and improve memory recall. Additionally, inhibition of insulin receptor function or expression using molecular techniques has been associated with reduced learning. Here, we sought a different approach to increase insulin receptor activity without the need for administering the ligand. A constitutively active, modified human insulin receptor (IRβ) was delivered to the hippocampus of young (2 months) and aged (18 months) male Fischer 344 rats in vivo. The impact of increasing hippocampal insulin receptor expression was investigated using several outcome measures, including Morris water maze and ambulatory gait performance, immunofluorescence, immunohistochemistry, and Western immunoblotting. In aged animals, the IRβ construct was associated with enhanced performance on the Morris water maze task, suggesting that this receptor was able to improve memory recall. Additionally, in both age-groups, a reduced stride length was noted in IRβ-treated animals along with elevated hippocampal insulin receptor levels. These results provide new insights into the potential impact of increasing neuronal insulin signaling in the hippocampus of aged animals and support the efficacy of molecularly elevating insulin receptor activity in vivo in the absence of the ligand to directly study this process.

Original languageEnglish
Article numbere13220
JournalAging Cell
Volume19
Issue number10
DOIs
StatePublished - Oct 1 2020

Bibliographical note

Funding Information:
This work is supported by the National Institutes of Health [R01AG033649 to OT, T32DK007778 to HNF, and T32AG057461 to AOG]. The authors acknowledge the use of facilities in the University of Kentucky Center for Molecular Medicine Genetic Technologies Core. This core is supported in part by the National Institutes of Health [P30GM110787].

Publisher Copyright:
© 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd

Keywords

  • brain
  • gait
  • genetic engineering
  • hippocampus
  • insulin resistance
  • spatial memory

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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