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- All Subjects: Aging
- All Subjects: psychology
- Genre: Academic theses
Description
Progestogens, such as progesterone (P4), medroxyprogesterone acetate (MPA), and micronized progesterone (mP4), are given to ovary-intact women during the transition to menopause to attenuate heavy uterine bleeding and other symptoms. Both progesterone and MPA administration have been shown to impair cognition in ovariectomized (Ovx) rats compared to vehicle-treated controls. mP4, however, has yet to be investigated for cognitive effects in a preclinical setting. Further, progestogens affect the GABA (-aminobutyric acid) ergic system, specifically glutamic acid decarboxylase (GAD) the rate limiting enzyme necessary for synthesizing GABA. The goal of this experiment was to investigate the cognitive impact of P4, MPA, and mP4, in an ovary-intact transitional menopause model using 4-vinylcyclohexene diepoxide (VCD) and assess whether these potential changes were related to the GABAergic system. One group of rats received vehicle injections, and the remainder of the groups received VCD to induce follicular depletion, modeling transitional menopause in women. Vehicle or hormone administration began during perimenopause to model the time period when women often take progestogens alone. Rats then underwent testing to assess spatial working and reference memory in the water radial-arm maze (WRAM) and spatial reference memory in the Morris water maze (MWM). Results indicate that P4 and MPA improved learning for working memory measure, but only MPA impaired memory retention in the WRAM. For the WRAM reference memory measure, VCD only treated rats showed impaired learning and memory retention compared to vehicle controls; progestogens did not impact this impairment. Although GAD expression did not differ between treatment groups, in general, there was a relationship between GAD expression and WRAM performance such that rats that tended to have higher GAD levels also tended to make more WRAM working memory errors. Thus, while P4 and MPA have been previously shown to impair cognition in an Ovx model, giving these hormones early in an ovary-intact perimenopause model elicits divergent effects, such that these progestogens can improve cognition. Additionally, these findings suggest that the cognitive changes seen herein are related to the interaction between progestogens and the GABAergic system. Further investigation into progestogens is warranted to fully understand their impact on cognition given the importance of utilizing progestogens in the clinic.
ContributorsPena, Veronica Leigh (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Conrad, Cheryl (Committee member) / Gipson-Reichardt, Cassandra (Committee member) / Arizona State University (Publisher)
Created2019
Description
Hysterectomy is the second most common gynecological surgery performed in women. Half of these surgeries involve removal of the uterus alone, and half involve concomitant removal of the ovaries. While the field has retained the notion that the nonpregnant uterus is dormant, more recent findings suggest that hysterectomy is associated with cognitive detriment. Of note, the clinical literature suggests that an earlier age at hysterectomy, with or without concomitant ovarian removal, increases dementia risk, implicating age at surgery as a variable of interest. While preclinical work in a rodent model of hysterectomy has demonstrated spatial working memory impairments, the role of age at surgery has yet to be addressed. The current experiment utilized a rodent model of hysterectomy to investigate the importance of age at surgery in post- surgical cognitive outcomes and to evaluate relative protein expression related to brain activity, FosB and ∆FosB, in regions critical to spatial learning processes. Young adult and middle-aged female rats underwent sham surgery, hysterectomy, or hysterectomy with ovariectomy, and were tested on a behavioral battery that evaluated spatial working and reference memory. Following the behavioral battery, animals were sacrificed and brain tissues from the Dorsal Hippocampus and Entorhinal Cortex were processed via Western Blot for relative FosB and ∆FosB expression. Behavioral analyses demonstrated that animals receiving hysterectomy, regardless of age or ovarian status, were generally impaired in learning a complex spatial working memory task. However, rats that received hysterectomy in middle-age uniquely demonstrated persistent working memory impairment, particularly with a high working memory demand. Subsequent neurobiological analyses revealed young rats that underwent hysterectomy had reduced relative FosB expression in the Entorhinal Cortex compared to sham controls, where no significant effects were observed for rats that received surgery in middle-age. Finally, unique relationships between neurobiological and behavioral outcomes were observed largely for sham rats, suggesting that such surgical manipulations might modulate these relationships. Taken together, these findings suggest that age at surgery plays an important role in learning and memory outcomes following hysterectomy, and demonstrate the need for further research into the role of the uterus in communications between the reproductive tract and brain.
ContributorsWoner, Victoria (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Trumble, Benjamin C (Committee member) / Conrad, Cheryl D. (Committee member) / Arizona State University (Publisher)
Created2020