Date of Award
Master of Science (MS)
BDNF;estrogen;GSK3;object recognition;western blotting
Medical Sciences | Medicine and Health Sciences | Neurosciences
Brain-derived neurotrophic factor (BDNF) is a widespread neurotrophin implicated in cellular processes underlying memory, socialization, and emotion; however, little is known about how genetic modification of BDNF interacts with BDNF modulators (e.g., hormones) to regulate BDNF-TrkB signaling. BDNF binds to the TrkB receptor and triggers signaling cascades underlying neuroplasticity, learning, and memory. Inhibitory phosphorylation of one downstream target of the BDNF cascade - GSK3β – is also linked to memory improvements. The Val66Met allele – a single nucleotide polymorphism (SNP) in the Bdnf gene - produces impairments in regulated BDNF release from the cell, as well as deficits in spatial memory related to the hippocampus and increases in anxiety-like behavior associated with the striatum in rodent models. The Met allele causes deficits in regulated BDNF release by impairing the trafficking of this neurotrophin to the correct vesicles; however, prior literature has shown increased BDNF and TrkB levels in the hippocampi of Met/Met rodents, indicating a possible compensatory mechanism for said deficits. The goal of this investigation was to explore if the Met allele, when coupled with estrogen, a known promoter of BDNF signaling, suppresses or increases downstream phosphorylation of GSK3β in the striatum. Female middle-aged Val/Val and Met/Met rats were ovariectomized, treated with either vehicle (sesame oil) or 17β-estradiol (EB), and subjected to an object recognition paradigm, which assesses striatum-sensitive response memory. Semiquantitative western blotting was performed on striatal samples from these rats to detect phospho-GSK3β vs. total GSK3β protein signal (i.e., to measure inhibition of GSK3β). GSK3β phosphorylation trended towards being greater in the striata of Met/Met rats than those of the Val/Val rats. However, EB treatments did not alter GSK3β phosphorylation in either Val/Val rats or Met/Met rats. The apparent trend of Met-related increase in GSK3β phosphorylation in the striatum supports the hypothesis that the Met allele may boost BDNF and TrkB levels in compensation for impairments in BDNF secretion. Furthermore, the lack of difference in GSK3β phosphorylation between EB- and vehicle-treated Met/Met rats and between EB- and vehicle-treated Val/Val rats suggests that both genotypes are insensitive to the BDNF-enhancing effects of estrogens, possibly due to increases in regulated BDNF release in response to learning during the dOR task, resulting in saturated BDNF release that could not be enhanced by estradiol.
Harvey, Clementine Faye, "Brain-derived neurotrophic factor (BDNF) signaling mechanisms that regulate learning and memory in rats" (2024). Theses - ALL. 813.