Project Summary/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 this proposal is to begin to elucidate 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. The overarching hypothesis of this proposal is that INI improves attentional behaviors, stimulates insulin receptor (IR) signaling, and augments cholinergic neurotransmission in the medial prefrontal cortex (mPFC). Examination of these functional relationships will ultimately lead to the elucidation of the mechanism underlying INI. I will test my central hypothesis and fulfill the goal of this proposal through the investigation of the effect of acute and chronic INI on: 1) performance on the PFC-mediated attentional set-shifting task, 2) IR signaling in the mPFC, and 3) acetylcholine efflux in the mPFC in both young and aged rats. To fulfill these aims, I will be trained on several new laboratory techniques, including behavioral assays, assessment of central insulin signaling, microdialysis, and HPLC under the guidance of Drs. Jim Fadel and Lawrence Reagan at the University of South Carolina School of Medicine. My co-sponsors are long-time collaborators with numerous co-author publications and a history of federal funding. This research project is an intersection of the research interests of the two laboratories. Other aspects of my graduate training, including developing my critical thinking, presentation, networking, and scientific writing skills, will be provided through my matriculation through the Biomedical Sciences doctoral program. Finally, access to the clinical setting will be provided through several avenues, including guidance from consultant Dr. Souvik Sen, regular communication with Mrs. Beckler, and proximity to the VA and Prisma Health Hospital Systems.