HIPPOCAMPAL GLUCOSE TRANSPORT AND OXIDATION IN RESPONSE TO DISRUPTED BLOOD FLOW IN AN AGING RAT MODEL OF HEART FAILURE

Abstract

The primary objective of this dissertation was to investigate, in a rodent model of cardiovascular disease promoted by transverse aortic constriction (TAC), whether cerebral hypoperfusion stemming from chronic high pulsatile blood flow, and cerebral hypoperfusion stemming from low cerebral blood flow differentially affected hippocampal glucose transport and hippocampal mitochondrial function. We first, characterized the changes in right and left carotid hemodynamics and diameter in response to TAC and in a SHAM control group at three different time points (20-, 30-, and 40 weeks) post-surgery. Then, right, and left hippocampal mitochondrial content and substrate oxidation were investigated, and protein expression of glucose transporters and mitochondrial quality control markers were quantified. In this study, both the SHAM and TAC conditions included male and female rats to address possible sex differences. We report that all time points within TAC, right carotid blood flow velocities and pulsatility were greater than the left, but did not worsen over time. No differences in mitochondrial content were found within TAC nor between TAC and SHAM, but within TAC animals there were impairments in right hippocampal coupled and uncoupled respiration when compared to the left. When compared to the SHAM controls, right and left hippocampi of TAC animals had higher protein expression of mitochondrial quality control markers, but no differences in glucose transporter expression were found. Thus, while both high blood flow and/or pulsatility as well as low cerebral blood flow may lead to brain hypoperfusion, the metabolic consequences of the two may not be the same. The results from this dissertation contribute to the expanding literature characterizing the intersection between cardiovascular disease and neurodegeneration.