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- Creators: Department of Psychology
- Creators: Baxter, Leslie C
Description
Cognitive function declines with normal age and disease states, such as Alzheimer's disease (AD). Loss of ovarian hormones at menopause has been shown to exacerbate age-related memory decline and may be related to the increased risk of AD in women versus men. Some studies show that hormone therapy (HT) can have beneficial effects on cognition in normal aging and AD, but increasing evidence suggests that the most commonly used HT formulation is not ideal. Work in this dissertation used the surgically menopausal rat to evaluate the cognitive effects and mechanisms of progestogens proscribed to women. I also translated these questions to the clinic, evaluating whether history of HT use impacts hippocampal and entorhinal cortex volumes assessed via imaging, and cognition, in menopausal women. Further, this dissertation investigates how sex impacts responsiveness to dietary interventions in a mouse model of AD. Results indicate that the most commonly used progestogen component of HT, medroxyprogesterone acetate (MPA), impairs cognition in the middle-aged and aged surgically menopausal rat. Further, MPA is the sole hormone component of the contraceptive Depo Provera, and my research indicates that MPA administered to young-adult rats leads to long lasting cognitive impairments, evident at middle age. Natural progesterone has been gaining increasing popularity as an alternate option to MPA for HT; however, my findings suggest that progesterone also impairs cognition in the middle-aged and aged surgically menopausal rat, and that the mechanism may be through increased GABAergic activation. This dissertation identified two less commonly used progestogens, norethindrone acetate and levonorgestrel, as potential HTs that could improve cognition in the surgically menopausal rat. Parameters guiding divergent effects on cognition were discovered. In women, prior HT use was associated with larger hippocampal and entorhinal cortex volumes, as well as a modest verbal memory enhancement. Finally, in a model of AD, sex impacts responsiveness to a dietary cognitive intervention, with benefits seen in male, but not female, transgenic mice. These findings have clinical implications, especially since women are at higher risk for AD diagnosis. Together, it is my hope that this information adds to the overarching goal of optimizing cognitive aging in women.
ContributorsBraden, Brittany Blair (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Neisewander, Janet L (Committee member) / Conrad, Cheryl D. (Committee member) / Baxter, Leslie C (Committee member) / Arizona State University (Publisher)
Created2012
Description
Women are now living longer than ever before, yet the age of spontaneous menopause has remained stable. This results in an increasing realization of the need for an effective treatment of cognitive and physiological menopausal and post-menopausal symptoms. The most common estrogen component of hormone therapy, conjugated equine estrogens (CEE; Premarin) contains many estrogens that are not endogenous to the human body, and that may or may not be detrimental to cognition (Campbell and Whitehead, 1977; Engler-Chiurazzi et al., 2011; Acosta et al., 2010). We propose the use of a novel treatment option in the form of a naturally-circulating (bioidentical) estrogen called estriol. Due to estriol’s observed positive effects on synaptic functioning and neuroprotective effects in the hippocampus (Ziehn et al., 2012; Goodman et al., 1996), a brain structure important for spatial learning and memory, estriol is promising as a hormone therapy option that may attenuate menopausal- and age- related memory decline. In the current study, we administered one of the three bioidentical estrogens (17β-Estradiol, 4.0 µg/day; Estrone, 8.0 µg/day; Estriol, 8.0 µg/day) or the vehicle polyethylene glycol by subcutaneous osmotic pump to ovariectomized Fisher-344 rats. We compared these groups to each other using a battery of spatial learning tasks, including the water radial-arm maze (WRAM), Morris water maze (MM), and delayed-match-to-sample maze (DMS). We found that all estrogens impaired performance on the WRAM compared to vehicle, while 17β-estradiol administration improved overnight forgetting performance for the MM. The estriol group showed no cognitive enhancements relative to vehicle; however, there were several factors indicating that both our estriol and estradiol doses were too high, so future studies should investigate whether lower doses of estriol may be beneficial to cognition.
ContributorsStonebarger, Gail Ashley (Author) / Bimonte-Nelson, Heather (Thesis director) / Knight, George (Committee member) / Engler-Chiurrazzi, Elizabeth (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2015-05
Description
Regional and geographical differences may explain variability in menopausal symptom occurrence due to development of climate-specific thermoneutral zones leading to population-specific hot flash frequencies. Limited information available regarding menopausal symptoms in underserved women living in extreme heat.
Understanding the perception of menopausal symptoms in underserved women living in extreme heat regions to identify if heat impacts perception of menopausal symptoms was the objective of this study. Women in free, low-income, and homeless clinics in Phoenix were surveyed during summer and winter months using a self-administered, written questionnaire including demographic, climate and menopause related questions, including the Green Climacteric Scale (GCS).
A total of 139 predominantly Hispanic (56 %), uninsured (53 %), menopausal (56 %), mid-aged (mean 49.9, SD 10.3) women were surveyed— 36% were homeless or in shelters. Most women were not on menopausal hormone therapy (98 %). Twenty-two percent reported hot flashes and 26% night sweats. Twenty-five percent of women reported previously becoming ill from heat. More women thought season influenced menopausal symptoms during summer than winter (41 % vs. 14 %, p = 0.0009). However, majority of women did not think temperature outside influenced their menopausal symptoms and that did not differ by season (73 % in winter vs. 60% in summer, p=0.1094). No statistically significant differences seen for vasomotor symptoms between winter and summer months.
Regional and geographical differences may be key in understanding the variability in menopausal symptoms. Regardless of season, the menopausal, underserved and homeless women living in Arizona reported few vasomotor symptoms. In the summer, they were more likely to report that the season influenced their menopausal symptoms rather than temperature suggesting an influence of the season on symptom perception.
ContributorsMukarram, Mahnoor (Author) / Hondula, David M. (Thesis director) / Kling, Juliana (Committee member) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Estradiol (E2) and Levonorgestrel (Levo) are two hormones commonly used in hormone therapy (HT) to decrease symptoms associated with menopause. Both of these hormones have been shown to have beneficial effects on cognition when given alone in a rodent model of menopause. However, it is unknown whether these hormones, when taken in combination, are beneficial or harmful to cognition. This is a critically important question given that these hormones are most often given in combination versus separately. This thesis is composed of two studies examining the cognitive effects of E2 and Levo using a rat model of surgical menopause. Study 1 assessed how the dose of E2 treatment in rats impacted cognitive performance, and found that low dose E2 enhanced working memory performance. Next, based on the results from Study 1, Study 2 used low dose E2 in combination with different doses of Levo to examine the cognitive effects of several E2 to Levo ratio combinations. The results from Study 2 demonstrated that the combination of low dose E2 with a high dose of Levo at a 1:2 ratio impaired cognition, and that the ratio currently used in HT, 3:1, may also negatively impact cognition. Indeed, there was a dose response effect indicating that working and reference memory performance was incrementally impaired as Levo dose increased. The findings in this thesis suggest that the E2 plus Levo combination is likely not neutral for cognitive function, and prompts further evaluation in menopausal women, as well as drug discovery research to optimize HT using highly controlled preclinical models.
ContributorsBerns-Leone, Claire Elizabeth (Co-author) / Prakapenka, Alesia (Co-author) / Pena, Veronica (Co-author) / Northup-Smith, Steven (Co-author) / Melikian, Ryan (Co-author) / Ladwig, Ducileia (Co-author) / Patel, Shruti (Co-author) / Croft, Corissa (Co-author) / Bimonte-Nelson, Heather (Thesis director) / Glenberg, Arthur (Committee member) / Conrad, Cheryl (Committee member) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
It is well documented that menopause and the related decline in circulatory steroid hormones estrogen and progesterone are associated with memory alterations. Rodent models of surgical menopause can be used to study these effects, including ovariectomy (Ovx), or the surgical removal of the ovaries. This thesis aimed to characterize the effects of surgical menopause on spatial working and reference memory in rats and examine profiles of uterine gene expression alterations that may serve as indications of mechanisms underlying this association. Eighteen female rats were randomly assigned to one of two surgical treatment groups, either Ovx (the surgical menopause group) or sham (the control group). All subjects underwent testing on the water version of the radial arm maze (WRAM) which allows for the assessment of reference memory errors and two types of working memory errors. After behavioral testing, rat uterine tissues were dissected and RNA sequenced. The results showed that Ovx impaired spatial reference memory performance during a maze learning phase, with Ovx rats making reference memory failures earlier in the day, even before working memory load increased, as compared to control rats. There were no surgical menopause effects on spatial working memory, which may be due to the low working memory load and the young age of the rats. Post-hoc analyses showed that reference memory performance was correlated with nerve growth factor (NGF) and acetylcholinesterase (AChE) gene expression in uterine tissues. These findings add to the literature on the impact of estrogen and female cyclicity on memory and cognition. The results suggest that Ovx impairment of the ability to learn long-term spatial memory information relates to uterine gene expression underlying cellular functioning and that NGF and AChE genes are involved in pathways that give way to underlying cellular functioning that impacts cognition. Future studies should continue to evaluate the effects of menopause on memory function and the effectiveness of hormone therapy.
ContributorsOyen, Emma (Author) / Bimonte-Nelson, Heather (Thesis director) / Corbin, William (Committee member) / Wilson, Melissa (Committee member) / Lizik, Camryn (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2024-05
Description
Memory as whole is impacted by changes associated with aging and menopause. Different memory types are often tested preclinically utilizing rats in different task paradigms. Most studies have focused on understanding social recognition or working memory, however these memory types have yet to be studied together. This thesis focuses on the process of creating and testing a new social recognition task that incorporates a working memory load. We tested different types of previously used social recognition paradigms with an increasing load and through qualitative and quantitative observations the task was modified until a final task was developed for a social working memory study. Young female rats were tested in this task in progressive, meaning a chronologically increasing load and nonprogressive, meaning non-chronological increase in load cognitions. It was found that young female rats had the ability to distinguish between the familiar and novel conspecifics before memory load exceeded four familiar and one novel conspecifics. Once validated through future studies, this task may be utilized to understand the impact of different types of menopause on social working memory.
ContributorsAsadifar, Sadaf (Author) / Bimonte-Nelson, Heather (Thesis director) / Corbin, William (Committee member) / Verpeut, Jessica (Committee member) / Barrett, The Honors College (Contributor) / School of Human Evolution & Social Change (Contributor) / Department of Psychology (Contributor)
Created2024-05