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

• Published in: Aging cell 2020-10, Vol.19 (10), p.e13220-n/a
• Main Authors: Frazier, Hilaree N., Anderson, Katie L., Ghoweri, Adam O., Lin, Ruei-Lung, Hawkinson, Tara R., Popa, Gabriel J., Sompol, Pradoldej, Mendenhall, Michael D., Norris, Christopher M., Thibault, Olivier
• Format: Article
• Language: English
• Subjects: Age; Aging; Aging - metabolism; Alzheimer's disease; Animal models; Animals; Blood flow; brain; Cerebral blood flow; Gait; Genetic Engineering; Glucose; Hippocampus; Humans; Immunoblotting; Immunofluorescence; Immunohistochemistry; Insulin; insulin resistance; Investigations; Learning; Ligands; Male; Maze Learning; Medical research; Medicine, Experimental; Memory; Memory Disorders - genetics; Memory Disorders - metabolism; Metabolism; Neurodegenerative diseases; Original; Rats; Rats, Inbred F344; Recall; Receptor density; Receptor, Insulin - biosynthesis; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Rodents; Signal Transduction; spatial memory
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13220

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. To assess the impact of increasing insulin signaling on ambulatory performance, spatial memory, and receptor dynamics without the need for intranasal insulin delivery, we expressed a constitutively active insulin receptor (IRβ) in the hippocampus of Fischer 344 rats. In aged animals, IRβ was associated with improved memory performance, higher receptor levels, and increased downstream signaling. This work demonstrates the efficacy of molecularly enhancing receptor activity in vivo.