Date of Award

Summer 2022

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

James Fadel

Abstract

Age-related cognitive decline (ARCD) is one of the most dreaded aspects of growing old and a public health concern. Unfortunately, there is currently no treatment that effectively ameliorates ARCD. In recent decades, intranasal insulin (INI) has demonstrated promising memory enhancements for rodents and individuals with Alzheimer’s disease, both in basic science research laboratories and multi-center clinical trials. Other studies have shown INI improves memory and cognition in healthy rodents and humans, indicating that INI may hold promise as a successful ARCD therapeutic. However, there is a glaring lack of evidence regarding how INI produces these effects. The goal of these studies is to work toward the elucidation of this underlying mechanism of action, as INI eventually could be used in a broader clinical setting to treat the cognitive dysfunction seen with aging. Further, fully understanding this mechanism could lead to the development of other successful treatments for ARCD that exploit the same mechanism. Before beginning a thorough mechanistic examination, it was critical to ensure that IN delivery successfully targeted insulin to the brain and could elicit a behavioral effect. Indeed, insulin localized in the medial forebrain bundle, islands of Calleja, piriform cortex, medial septum, diagonal band of Broca, and spinal trigeminal nucleus and reduced food intake in young animals. Using in vivo microdialysis, the effects of INI on neurotransmission were also explored. An increase in acetylcholine (ACh) efflux was observed in the PFC of aged animals after INI administration. An increase in glutamate efflux was observed in both the PFC and hippocampus of young, but not aged animals. This increase in glutamate efflux seen in the young animals may be important to overcome glutamatergic hypoactivity. Additionally, we explored the effects of INI in a model of hippocampal-specific insulin resistance, in which the rats had bilateral injections of a lentiviral vector containing an insulin receptor antisense sequence (LV-IRAS) to downregulate insulin receptor (IR) expression and activity selectively in the hippocampus. A dose-dependent decrease in food intake and increase in hippocampal glutamate efflux was observed in these animals following INI administration. Further investigation of the glutamatergic system in this animal model revealed a significant decrease in basal glutamate level in the hippocampus, as well as decreased expression of synaptophysin and a reduced expression of vesicular glutamate transporter 2 (vGluT2) in response to INI administration. These findings indicate that INI may increase glutamate efflux to overcome the glutamatergic hypoactivity that may be seen with brain insulin resistance. Finally, IR signaling and glutamatergic protein expression was examined in response to chronic INI treatment. More studies are needed to fully explore the most efficacious INI dose and dosing regimen; this will be clinically applicable if INI is one day used to treat ARCD. In sum, the studies presented here were designed to uncover the mechanistic basis of the pro-cognitive effects of INI through the exploration of IR signaling pathway activation and changes in neurotransmission that occur post-administration.

Available for download on Thursday, October 05, 2023

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