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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;

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
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Description
Brief memory tasks for use with pet dogs were developed using radial arm maze performance as a standard comparison measurement of memory capacity. Healthy pet dogs were first tested in a radial arm maze, where more errors made in completing the maze indicated poorer memory. These dogs were later tested

Brief memory tasks for use with pet dogs were developed using radial arm maze performance as a standard comparison measurement of memory capacity. Healthy pet dogs were first tested in a radial arm maze, where more errors made in completing the maze indicated poorer memory. These dogs were later tested with five novel memory tests, three of which utilized a treat placed behind a box with an identical distracter nearby. The treat placement was shown to each dog, and a 35 second delay, a 15 second delay with occluder, or a 15 second delay with room exit was observed before the dog could approach and find the treat. It was found that errors on the delayed match to sample (35 second delay) and occluder/object permanence (15 second delay with occluder) tasks were significantly positively correlated with the average number of errors made in the 8th trial of the radial arm maze (r =.58, p<.01** and r =.49, p<.05*, respectively) indicating that these new brief tests can reliably be used to assess memory in pet dogs.
ContributorsBoileau, Rae Nicole (Author) / Wynne, Clive (Thesis director) / Knight, George (Committee member) / Bimonte-Nelson, Heather (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2015-05
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Description
Menopause is associated with a wide array of negative symptoms. As average lifespan increases due to advances in healthcare and technology, more women are spending a larger portion of their lives in a menopausal state low in estrogen and progesterone. Hormone therapies such as Conjugated Equine Estrogens (CEE) and the

Menopause is associated with a wide array of negative symptoms. As average lifespan increases due to advances in healthcare and technology, more women are spending a larger portion of their lives in a menopausal state low in estrogen and progesterone. Hormone therapies such as Conjugated Equine Estrogens (CEE) and the bioidentical estrogen, 17-estradiol (E2), are commonly prescribed to treat the negative symptoms of menopause. Our laboratory has previously shown that CEE has differential effects on cognitive ability depending on whether menopause is transitional (VCD) or surgical (ovariectomy, OVX). Further, the negative impact of CEE on cognitive function in a transitional ovary-intact model of menopause was associated with high levels of serum androstenedione; the primary hormone circulating in a follicle-deplete menopausal state. Here, we investigate the cognitive effects of these two common hormone therapies separately, and in conjunction with the hormone androstenedione, in a "blank-slate" OVX mouse model. We assessed cognitive ability using two behavioral tasks such at the Water Radial Arm Maze (WRAM, measuring spatial working and reference memory) and the Morris water maze (MM, measuring spatial reference memory). In the WRAM, every treatment group saw impaired performance compared to Vehicle but the combination group of E2 plus Androstenedione. In the MM, the combination group of E2 plus Androstenedione actually enhanced performance in the maze compared to every other comparable group. Translationally, these results suggest that CEE given in the presence of an androstenedione-dominant hormone milieu is impairing to cognition, E2 in this same manner is not. These results yield valuable insight into optimal hormone therapies for menopausal women.
ContributorsGranger, Steven Jay (Author) / Bimonte-Nelson, Heather (Thesis director) / Presson, Clark (Committee member) / Hiroi, Sheri (Committee member) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
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Description
Chronic stress often leads to cognitive deficits, especially within the spatial memory domain mediated by the hippocampus. When chronic stress ends and a no-stress period ensues (i.e., washout, WO), spatial ability improves, which can be better than non-stressed controls (CON). The WO period is often the same duration as the

Chronic stress often leads to cognitive deficits, especially within the spatial memory domain mediated by the hippocampus. When chronic stress ends and a no-stress period ensues (i.e., washout, WO), spatial ability improves, which can be better than non-stressed controls (CON). The WO period is often the same duration as the chronic stress paradigm. Given the potential benefit of a post-stress WO period on cognition, it is important to investigate whether this potential benefit of a post-stress WO period has long-lasting effects. In this project, chronic restraint (6hr/d/21d) in Sprague-Dawley rats was used, as it is the minimum duration necessary to observe spatial memory deficits. Two durations of post-stress WO were used following the end of chronic restraint, 3 weeks (STR-WO3) and 6 weeks (STR-WO6). Immediately after chronic stress (STR-IMM) or the WO periods, rats were tested on various cognitive tests. We corroborated past studies that chronic stress impaired spatial memory (STR-IMM vs CON). Interestingly, STR-WO3 and STR-WO6 failed to demonstrate improved spatial memory on a radial arm water maze task, performing similarly as STR-IMM. Performance outcomes were unlikely from differences in anxiety or motivation because rats from all conditions performed similarly on an open field task and on a simple object recognition paradigm, respectively. However, performance on object placement was unusual in that very few rats explored, suggesting some degree of anxiety or fear in all groups. One possible interpretation of the unusual results of the 3 week washout group may be attributed to the different spatial memory tasks used across studies or external factors from the study. Further exploration of these other factors led to the conclusion that they did not play a role and the STR-WO3 RAWM data were anomalous to other studies. This suggests that a washout period following chronic stress may not be fully understood.
ContributorsFlegenheimer, Aaron Embden (Author) / Conrad, Cheryl (Thesis director) / Bimonte-Nelson, Heather (Committee member) / Ortiz, J. Bryce (Committee member) / School of Life Sciences (Contributor) / School of Human Evolution and Social Change (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
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Description
Drospirenone (DRSP) is a novel, pharmacologically unique synthetic progestin with properties more similar to the endogenous progestogen, progesterone, than any other progestin currently on the market. While a significant amount of research has been conducted on the risks associated with DRSP, the impact of DRSP on cognition, especially in reference

Drospirenone (DRSP) is a novel, pharmacologically unique synthetic progestin with properties more similar to the endogenous progestogen, progesterone, than any other progestin currently on the market. While a significant amount of research has been conducted on the risks associated with DRSP, the impact of DRSP on cognition, especially in reference to learning and memory, is not well understood. However, it is imperative to fully understand the cognitive effects of DRSP, both alone and in combination with EE (as taken in a combined oral contraceptive [COC]), so that women and their physicians can make a fully-informed decision when deciding to take a DRSP-containing COC. Study 1 examined the effects of three doses of DRSP in order to determine the optimal dose for combining with EE, and found that the medium dose of DRSP (30 µg/day) enhanced spatial working memory performance. In Study 2, the medium dose of DRSP from Study 1 was combined with low (0.125 µg/day) and high (0.3 µg/day) doses of EE to examine the effects of DRSP as taken with EE in a COC. The results from Study 2 indicated that when DRSP was combined with a low, but not high, dose of EE, spatial working memory impairments were seen at the highest working memory load. Anxiety-like behavior was evaluated using the OFT, and DRSP was shown to decrease measures of anxiety-like behavior. Additionally, while treatment with a high dose of EE decreased several measures of anxiety-like behavior, a low dose of EE did not, suggestive of a dose response. Taken together, the findings presented from both studies suggest that some of the cognitive effects of the combination of DRSP with EE are different than those of either hormone administered on its own. Further exploration in a preclinical, ovary-intact animal model is a next step to fully understand these effects in the translational context of a contraceptive, given that women taking an EE-DRSP combination are typically ovary-intact.
ContributorsPoisson, Mallori Louise (Author) / Bimonte-Nelson, Heather (Thesis director) / Doane, Leah (Committee member) / School of Nutrition and Health Promotion (Contributor) / School of Molecular Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
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Description
The aim of this study was to determine whether IUD administration, with and without the presence of Levo, and with and without the presence of the ovaries, impacts cognition in a rat model. Rats received either Sham or Ovariectomy (Ovx) surgery (removal of the ovaries), plus either no IUD, a

The aim of this study was to determine whether IUD administration, with and without the presence of Levo, and with and without the presence of the ovaries, impacts cognition in a rat model. Rats received either Sham or Ovariectomy (Ovx) surgery (removal of the ovaries), plus either no IUD, a Blank IUD (without Levo), or a Levo-releasing IUD (Levo IUD), enabling us to evaluate the effects of Ovx and the effects of IUD administration on cognition. Two weeks after surgery, all treatment groups were tested on the water radial arm maze, Morris water maze, and visible platform task to evaluate cognition. At sacrifice, upon investigation of the uteri, it was determined that some of the IUDs were no longer present in animals from these groups: Sham\u2014Blank IUD, Ovx\u2014Blank IUD, and Sham\u2014Levo IUD. Results from the remaining three groups showed that compared to Sham animals with no IUDs, Ovx animals with no IUDs had marginally impaired working memory performance, and that Ovx animals with Levo IUDs as compared to Ovx animals with no IUDs had marginally enhanced memory performance, not specific to a particular memory type. Results also showed that Ovx animals with Levo IUDs had qualitatively more cells in their vaginal smears and increased uterine horn weight compared to Ovx animals with no IUDs, suggesting local stimulation of the Levo IUDs to the uterine horns. Overall, these results provide alternative evidence to the hypothesis that the Levo IUD administers Levo in solely a localized manner, and suggests that the possibility for the Levo IUD to affect reproductive cyclicity in ovary-intact animals is not rejected. The potential for the Levo IUD to exert effects on cognition suggests that either the hormone does in fact systemically circulate, or that the Levo IUD administration affects cognition by altering an as yet undetermined hormonal or other feedback between the uterus and the brain.
ContributorsStrouse, Isabel Martha (Author) / Bimonte-Nelson, Heather (Thesis director) / Glenberg, Arthur (Committee member) / Sirianni, Rachael (Committee member) / Conrad, Cheryl (Committee member) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
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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

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

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