Date of Award


Document Type

Honors Thesis

Degree Name

Bachelor of Science




Insulin is now established as a key regulator of brain mechanisms that include both glucose metabolism and synaptic plasticity, especially within the hippocampus. However, the complex set of signaling cascades mediating these effects is not yet understood. Recent studies, many from our lab, have established that insulin plays multiple roles in the brain: in addition to regulation of energy supply, metabolism, and feeding, our work has shown that hippocampal insulin is a key modulator of learning and memory. Exogneous insulin enhances, while pharmacological blockade of intrahippocampal insulin impairs, both metabolism and cognition. Moreover, when systemic insulin signalling is impaired, such as in Type 2 diabetes, hippocampal function and metabolism are again impaired. Memory processes both in the hippocampus and elsewhere (e.g. amygdala) are well established to be sensitive to glucose supply: performance on memory tasks is limited by glucose availability, and provision of additional glucose supports enhanced task performance. Systemically, insulin regulates glucose transport from the blood into cells; conversely, glucose regulates insulin synthesis and release from the pancreas, so that the two molecules mutually regulate. Although this relationship between insulin and glucose has been well studied, there has been little work on their interaction in the brain. For instance, although we have shown that insulin regulates hippocampal glucose metabolism, it is unknown whether glucose acts to enhance memory via stimulation of insulin release within the hippocampus, or whether insulin's procognitive effects are via stimulation of glucose metabolism or a direct modulation of plasticity. In this study, Glut4, an insulin-dependent glucose transporter found on some hippocampal neurons, was directly blocked. Indinavir, a Glut4 inhibitor, was injected directly into the dorsal hippocampus of rats in the presence or absence of a peritoneal glucose injection in order to assess changes in cognition. It was found that indinavir treatment significantly impaired cognition in spontaneous alternation tasks, reduced anxiety, and, surprisingly, and had no effect on cognitive performance in a novel object recognition task. These data support a novel role for GluT4 as a mediator of hippocampal memory processing and suggest that insulin acts to regulate cognitive function at least in part via GluT4-mediated glucose transport into neurons. In the presence of indinavir, glucose was unable to enhance memory, consistent with this interpretation and suggesting that enhancement of hippocampal memory by glucose may require hippocampal insulin signaling. Post-mortem molecular studies of hippocampal protein expression provided further insight into the molecular impact of both glucose treatment and GluT4 blockade.

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