Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Saksida, Lisa M

2nd Supervisor

Bussey, Timothy J

Abstract

Obesity and Type 2 Diabetes (T2D), driven by sedentary lifestyles and poor diets, are associated with a 30% increased risk of dementia and are major public health challenges. These conditions impair hippocampal function, disrupt neurogenesis, and compromise cognitive processes essential for learning and memory. While aerobic exercise is a well-established intervention for mitigating cognitive decline, resistance exercise and metformin may offer added or unique benefits through mechanisms of neuroplasticity in those with obesity and T2D. In this thesis, I employed a bench-to-bedside strategy—integrating preclinical mouse models of diet-induced obesity with a clinical trial in older adults at risk for diabetes (overweight/obese or prediabetes) —to explore the efficacy of resistance exercise and metformin in preventing obesity- and T2D- related cognitive decline. First, we examined whether resistance exercise and metformin treatment can prevent diet-induced deficits in pattern separation, an aspect of memory that is often reduced in older adults. Both interventions were similarly effective to aerobic exercise in mitigating such impairments. These benefits occurred independently of changes in neurogenesis, suggesting alternative mechanisms are likely to be at play. Second, we conducted a six-month randomized controlled trial of resistance exercise in older adults at risk for diabetes. Resistance exercise, compared to balance-and-tone training, improved working memory and cognitive flexibility. Additionally, three touchscreen tests, mirroring their rodent version, were implemented to assess cognition in this clinical trial. While no differences were observed between training groups, this work has provided a strong foundation for the development of future translational cognitive tests. Third, to advance the translational assessment of cognition in diet-induced obesity, we determined if water manipulation using 2% citric acid as an alternative to food restriction can motivate touchscreen task performance in obese mice. Water manipulation successfully elicited task engagement on touchscreen tests in mice with diet-induced obesity. Moreover, although we found reductions in motivation, this did not impact learning in obese mice. Collectively, these findings highlight resistance exercise and metformin as effective strategies for mitigating obesity-related cognitive decline. Moreover, this research advances cross-species cognitive assessments, enabling rigorous investigations into diet and interventions.

Summary for Lay Audience

Obesity and Type 2 Diabetes (T2D) are growing health concerns worldwide driven by increased access to fatty and sugary foods and daily inactivity. Obesity and T2D not only affect physical health but also impair learning and memory and increase dementia risk. Notably, weight gain and dysfunction in glucose control are linked to reductions in the size of the hippocampus–a memory center in the brain– and impairments in neurogenesis– the process of forming new neurons in adulthood. Preventing cognitive decline by enhancing neurogenesis may be a promising intervention in obesity and before the onset of T2D. While aerobic exercise is well-documented to improve memory and brain health, resistance exercise and metformin remain underexplored. This thesis addressed three key questions using a mouse-to-human approach. 1) Can resistance exercise and metformin protect the brain and prevent deficits in memory from a high-fat, high-sugar (HFHS) diet; 2) Can a six-month resistance exercise program improve brain health in older adults at risk for diabetes (overweight/obese or prediabetes)?; and 3) Can mice on HFHS diet be motivated to perform on touchscreen tests by adding 2% citric acid to their drinking water?

We found that 35 days of resistance exercise or metformin treatment in mice prevented impairments in memory following a HFHS diet. In humans, resistance exercise improved working memory, essential for processing and manipulating to-be-remembered information. Additionally, three touchscreen cognitive tests for learning, memory, and motivation were used to test humans in the same way as mice. Finally, limiting daily food amounts and rewarding touchscreen responses with food reward is typically used to motivate touchscreen performance in mice. However, mice on a HFHS diet require constant food access and are less motivated by food rewards. By using citric acid, drinking water becomes slightly sour and reduces water intake. While this method successfully motivated touchscreen performance in HFHS-fed mice, their motivation remained lower than normal-fed mice, but learning remained intact. Overall, this research highlights resistance exercise and metformin as promising tools for preventing cognitive decline. It also advances methods for studying brain health in mice and humans, bridging the gap between mouse-to-human research to improve public health in the face of rising obesity and diabetes rates.

Download

Available for download on Sunday, August 31, 2025

Share

COinS