Date of Award

5-2018

Document Type

Honors Thesis

Degree Name

Bachelor of Science

Department

Biological Science

Advisor/Committee Chair

Ewan C. McNay

Committee Member

Ben Szaro

Abstract

Insulin resistance is the defining symptom of type 2 diabetes and a key risk factor for Alzheimer’s disease. Work from our lab and others has shown that insulin is a key component of brain pathways mediating cognition; specifically, mechanisms that transduce hippocampal memory processing. In the hippocampus, insulin regulates glucose metabolism through translocation of the glucose transporter GluT4 and modulates several other molecular cascades. Studies where insulin is studied as a cognitive modulator have generally used a formulation that contains zinc to stabilize insulin. However, zinc itself modulates molecular signaling pathways including AKT and GSK3β, which are both downstream of insulin; as well as having a known effect in modulating neuronal glutamate release, suggesting a role in memory. Hence, delivery of zinc as an artifact of administering treatment to insulin-treated animals may confound the impact of insulin on cognition and metabolism. This is especially true since in vivo, the insulin hexamer, stabilized by zinc and calcium, breaks apart almost immediately after being released from beta cells in the pancreas; thus, insulin delivery would not produce an increase in zinc at the site of action. This project therefore aimed to parse the distinct effects of zinc and insulin on hippocampal metabolism and cognitive processes. Sprague-Dawley rats received a microinjection guide cannulae into their left hippocampus and were then treated with intrahippocampal delivery of Humulin (a zinc-containing insulin), Apidra (a zinc-free form of insulin), artificial extracellular fluid (aECF; a vehicle control condition), or zinc dissolved in aECF. Post injection the animals were placed in a plus maze for 20 mins for a spontaneous alternation test, followed immediately by a novel object recognition test spread over one day, both of which test cognition 3 and short-term memory. Brain samples from the left and right hippocampus along with the prefrontal cortex were removed and were analyzed for the presence of key proteins in the activation cascades via western blots. Evidence from current literature indicates a strong possibility of finding a confound, to some degree, between the known actions of zinc and insulin in the hippocampus.

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