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After natural menopause in women, androstenedione becomes the primary hormone secreted by the residual follicle deplete ovaries. Two independent studies, in rodents that had undergone ovarian follicular depletion, found that higher serum androstenedione levels correlated with increased working memory errors. This led to the hypothesis that androstenedione impairs memory. The

After natural menopause in women, androstenedione becomes the primary hormone secreted by the residual follicle deplete ovaries. Two independent studies, in rodents that had undergone ovarian follicular depletion, found that higher serum androstenedione levels correlated with increased working memory errors. This led to the hypothesis that androstenedione impairs memory. The current study directly tested this hypothesis, examining the cognitive effects of androstenedione administration in a rodent model. Middle-aged ovariectomized rats received vehicle or one of two doses of androstenedione (4 or 8 mg/kg daily). Rats were tested on a spatial working and reference memory maze battery including the water radial arm maze, Morris maze, and delay-match-to-sample task. Results showed that androstenedione at the highest dose impaired reference memory and working memory, including ability to maintain performance as memory demand was elevated. The latter was true for both high temporal demand memory retention of one item of spatial information, as well as the ability to handle multiple items of spatial working memory information. Glutamic acid decarboxylase (GAD) levels were measured in multiple brain regions to determine whether the gamma-aminobutyric acid (GABA) system mediates androstenedione's cognitive impairments. Results showed that higher entorhinal cortex GAD levels were correlated with poorer Morris maze performance, regardless of androstenedione treatment. These findings suggest that androstenedione, the main hormone produced by the follicle deplete ovary, is detrimental to spatial learning, reference memory, and working memory, and that spatial reference memory performance might be related to the GABAergic system.
ContributorsCamp, Bryan Walter (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Olive, Michael F (Committee member) / Conrad, Cheryl D. (Committee member) / Arizona State University (Publisher)
Created2012
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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

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
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Description
Chronic restraint stress impairs hippocampal-mediated spatial learning and memory, which improves following a post-stress recovery period. Here, we investigated whether brain derived neurotrophic factor (BDNF), a protein important for hippocampal function, would alter the recovery from chronic stress-induced spatial memory deficits. Adult male Sprague-Dawley rats were infused into the hippocampus

Chronic restraint stress impairs hippocampal-mediated spatial learning and memory, which improves following a post-stress recovery period. Here, we investigated whether brain derived neurotrophic factor (BDNF), a protein important for hippocampal function, would alter the recovery from chronic stress-induced spatial memory deficits. Adult male Sprague-Dawley rats were infused into the hippocampus with adeno- associated viral vectors containing the coding sequence for short interfering (si)RNA directed against BDNF or a scrambled sequence (Scr), with both containing the coding information for green fluorescent protein to aid in anatomical localization. Rats were then chronically restrained (wire mesh, 6h/d/21d) and assessed for spatial learning and memory using a radial arm water maze (RAWM) either immediately after stressor cessation (Str-Imm) or following a 21-day post-stress recovery period (Str-Rec). All groups learned the RAWM task similarly, but differed on the memory retention trial. Rats in the Str-Imm group, regardless of viral vector contents, committed more errors in the spatial reference memory domain than did non-stressed controls. Importantly, the typical improvement in spatial memory following recovery from chronic stress was blocked with the siRNA against BDNF, as Str-Rec-siRNA performed worse on the RAWM compared to the non-stressed controls or Str-Rec-Scr. These effects were specific for the reference memory domain as repeated entry errors that reflect spatial working memory were unaffected by stress condition or viral vector contents. These results demonstrate that hippocampal BDNF is necessary for the recovery from stress-induced hippocampal dependent spatial memory deficits in the reference memory domain.
ContributorsOrtiz, J. Bryce (Author) / Conrad, Cheryl D. (Thesis advisor) / Olive, M. Foster (Committee member) / Taylor, Sara (Committee member) / Bimonte-Nelson, Heather A. (Committee member) / Arizona State University (Publisher)
Created2013
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Description
The present series of studies examined whether a novel implementation of an

intermittent restraint (IR) chronic stress paradigm could be used to investigate hippocampal-dependent spatial ability in both sexes. In experiments 1 and 2, Sprague- Dawley male rats were used to identify the optimal IR parameters to assess spatial ability. For

The present series of studies examined whether a novel implementation of an

intermittent restraint (IR) chronic stress paradigm could be used to investigate hippocampal-dependent spatial ability in both sexes. In experiments 1 and 2, Sprague- Dawley male rats were used to identify the optimal IR parameters to assess spatial ability. For IR, rats were restrained for 2 or 6hrs/day (IR2, IR6, respectively) for five days and then given two days off, a process that was repeated for three weeks and compared to rats restrained for 6hrs/d for each day (DR6) and non-stressed controls (CON). Spatial memory was tested on the radial arm water maze (RAWM), object placement (OP), novel object recognition (NOR) and Y-maze. The results for the first two experiments revealed that IR6, but not IR2, was effective in impairing spatial memory in male rats and that task order impacted performance. In experiment 3, an extended IR paradigm for six weeks was implemented before spatial memory testing commenced in male and female rats (IR- M, IR-F). Unexpectedly, an extended IR paradigm failed to impair spatial memory in either males or females, suggesting that when extended, the IR paradigm may have become predictable. In experiment 4, an unpredictable IR (UIR) paradigm was implemented, in which restraint duration (30 or 60-min) combined with orbital shaking, time of day, and the days off from UIR were varied. UIR impaired spatial memory in males, but not females. Together with other reports, these findings support the interpretation that chronic stress negatively impairs hippocampal-dependent function in males, but not females, and that females appear to be resilient to spatial memory deficits in the face of chronic stress.
ContributorsPeay, Dylan (Author) / Conrad, Cheryl D. (Thesis advisor) / Bimonte-Nelson, Heather A. (Committee member) / Wynne, Clive (Committee member) / Arizona State University (Publisher)
Created2019
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Description
The Soviet Union suffered immensely as a result of World War II. When the dust settled and Soviet citizens began to rebuild their lives, the memory of the social, economic, and human costs of the war still remained. The Soviet state sought to frame the conflict in a way that

The Soviet Union suffered immensely as a result of World War II. When the dust settled and Soviet citizens began to rebuild their lives, the memory of the social, economic, and human costs of the war still remained. The Soviet state sought to frame the conflict in a way that provided meaning to the chaos that so drastically shaped the lives of its citizens. Film was one such way. Film, heavily censored until the Gorbachev period, provided the state with an easily malleable and distributable means of sharing official history and official memory. However, as time went on, film began to blur the lines between official memory and real history, providing opportunities for directors to create stories that challenged the regime's official war mythology. This project examines seven Soviet war films (The Fall of Berlin (1949), The Cranes are Flying (1957), Ballad of a Soldier (1959), Ivan's Childhood (1962), Liberation (1970-1971), The Ascent (1977), and Come and See (1985)) in the context of the regimes under which they were released. I examine the themes present within these films, comparing and contrasting them across multiple generations of Soviet post-war memory.
Created2014-05
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Description
The Soviet Union suffered immensely as a result of World War II. When the dust settled and Soviet citizens began to rebuild their lives, the memory of the social, economic, and human costs of the war still remained. The Soviet state sought to frame the conflict in a way that

The Soviet Union suffered immensely as a result of World War II. When the dust settled and Soviet citizens began to rebuild their lives, the memory of the social, economic, and human costs of the war still remained. The Soviet state sought to frame the conflict in a way that provided meaning to the chaos that so drastically shaped the lives of its citizens. Film was one such way. Film, heavily censored until the Gorbachev period, provided the state with an easily malleable and distributable means of sharing official history and official memory. However, as time went on, film began to blur the lines between official memory and real history, providing opportunities for directors to create stories that challenged the regime's official war mythology. This project examines seven Soviet war films (The Fall of Berlin (1949), The Cranes are Flying (1957), Ballad of a Soldier (1959), Ivan's Childhood (1962), Liberation (1970-1971), The Ascent (1977), and Come and See (1985)) in the context of the regimes under which they were released. I examine the themes present within these films, comparing and contrasting them across multiple generations of Soviet post-war memory.
Created2014-05
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Description
Aging and the menopause transition are both intricately linked to cognitive changes

during mid-life and beyond. Clinical literature suggests the age at menopause onset can differentially impact cognitive status later in life. Yet, little is known about the relationship between behavioral and brain changes that occur during the transitional stage into

Aging and the menopause transition are both intricately linked to cognitive changes

during mid-life and beyond. Clinical literature suggests the age at menopause onset can differentially impact cognitive status later in life. Yet, little is known about the relationship between behavioral and brain changes that occur during the transitional stage into the post-menopausal state. Much of the pre-clinical work evaluating an animal model of menopause involves ovariectomy in rodents; however, ovariectomy results in an abrupt loss of circulating hormones and ovarian tissue, limiting the ability to evaluate gradual follicular depletion. The 4-vinylcyclohexene diepoxide (VCD) model simulates transitional menopause in rodents by selectively depleting the immature ovarian follicle reserve and allowing animals to retain their follicle-deplete ovarian tissue, resulting in a profile similar to the majority of menopausal women. Here, Vehicle or VCD treatment was administered to ovary-intact adult and middle-aged Fischer-344 rats to assess the cognitive effects of transitional menopause via VCD-induced follicular depletion over time, as well as to understand potential interactions with age, with VCD treatment beginning at either six or twelve months of age. Results indicated that subjects that experience menopause onset at a younger age had impaired spatial working memory early in the transition to a follicle-deplete state. Moreover, in the mid- and post- menopause time points, VCD-induced follicular depletion amplified an age effect, whereby Middle-Aged VCD-treated animals had poorer spatial working and reference memory performance than Young VCD-treated animals. Correlations suggested that in middle age, animals with higher circulating estrogen levels tended to perform better on spatial memory tasks. Overall, these findings suggest that the age at menopause onset is a critical parameter to consider when evaluating learning and memory across the transition to reproductive senescence. From a translational perspective, this study informs the field with respect to how the age at menopause onset might impact cognition in menopausal women, as well as provides insight into time points to explore for the window of opportunity for hormone therapy during the menopause transition to attenuate age- and menopause- related cognitive decline, and produce healthy brain aging profiles in women who retain their ovaries throughout the lifespan.
ContributorsKoebele, Stephanie Victoria (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Aiken, Leona S. (Committee member) / Conrad, Cheryl D. (Committee member) / Wynne, Clive DL (Committee member) / Arizona State University (Publisher)
Created2015
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Description
In the sixty-seven years following the end of World War II, West Germany and Japan underwent a remarkable series of economic and social changes that irrevocably altered their respective ways of life. Formerly xenophobic, militaristic and highly socially stratified societies, both emerged from the 20th Century as liberal, prosperous and

In the sixty-seven years following the end of World War II, West Germany and Japan underwent a remarkable series of economic and social changes that irrevocably altered their respective ways of life. Formerly xenophobic, militaristic and highly socially stratified societies, both emerged from the 20th Century as liberal, prosperous and free. Both made great strides well beyond the expectations of their occupiers, and rebounded from the overwhelming destruction of their national economies within a few short decades. While these changes have yielded dramatic results, the wartime period still looms large in their respective collective memories. Therefore, an ongoing and diverse dialectical process would engage the considerable popular, official, and intellectual energy of their post-war generations. In West Germany, the term Vergangenheitsbewältigung (VGB) emerged to describe a process of coming to terms with the past, while the Japanese chose kako no kokufuku to describe their similar historical sojourns. Although intellectuals of widely varying backgrounds in both nations made great strides toward making Japanese and German citizens cognizant of the roles that their militaries played in gruesome atrocities, popular cinematic productions served to reiterate older, discredited assertions of the fundamental honor and innocence of the average soldier, thereby nurturing a historically revisionist line of reasoning that continues to compete for public attention. All forms of media would play an important role in sustaining this “apologetic narrative,” and cinema, among the most popular and visible of these mediums, was not excluded from this. Indeed, films would play a unique recurring role, like rhetorical time capsules, in offering a sanitized historical image of Japanese and German soldiers that continues to endure in modern times. Nevertheless, even as West Germany and Japan regained their sovereignty and re-examined their pasts with ever greater resolution and insight, their respective film industries continued to “reset” the clock, and accentuated the visibility and relevancy of apologetic forces still in existence within both societies. However, it is important to note that, when speaking of “Germans” and “Japanese,” that they are not meant to be thought of as being uniformly of one mind or another. Rather, the use of these words is meant as convenient shorthand to refer to the dominant forces in Japanese and German civil society at any given time over the course of their respective post- war histories. Furthermore, references to “Germany” during the Cold War period are to be understood to mean the Federal Republic of Germany, rather than their socialist counterpart, the German Democratic Republic, a nation that undertook its own coming to terms with the past in an entirely distinct fashion.
ContributorsPiscopo, Michael (Author) / Benkert, Volker (Thesis director) / Moore, Aaron (Committee member) / Machander, Sina (Committee member) / Barrett, The Honors College (Contributor) / College of Liberal Arts and Sciences (Contributor)
Created2012-12
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Description
When the Warsaw Ghetto was demolished by German forces towards the end of World War II, there were few physical traces of the Ghetto left standing. As such, both historians and the public must look to other types of sources to understand what life and death were like for the

When the Warsaw Ghetto was demolished by German forces towards the end of World War II, there were few physical traces of the Ghetto left standing. As such, both historians and the public must look to other types of sources to understand what life and death were like for the inhabitants of the Ghetto, and how they have remembered their experiences within the Ghetto. These memories and representations of the Warsaw Ghetto can be found in memoir-style written works, and later, in films based on these works. This thesis will examine the ways in which the Warsaw Ghetto was represented by two authors who survived it, Władisław Szpilman and Marcel Reich-Ranicki, and how their memory of the Warsaw Ghetto is represented in the films based on their lives and survival, The Pianist, and Mein Leben: Marcel Reich-Ranicki.
ContributorsSmith, Erin Lianne (Author) / Benkert, Volker (Thesis advisor) / Cichopek-Gajraj, Anna (Committee member) / Gilfillan, Daniel (Committee member) / Arizona State University (Publisher)
Created2020
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Description
Reproductive hormones are recognized for their diverse functions beyond reproduction itself, including a vital role in brain organization, structure, and function throughout the lifespan. From puberty to reproductive senescence, the female is characterized by inherent responsiveness to hormonal cyclicity. For most women, a natural transition to menopause occurs in midlife,

Reproductive hormones are recognized for their diverse functions beyond reproduction itself, including a vital role in brain organization, structure, and function throughout the lifespan. From puberty to reproductive senescence, the female is characterized by inherent responsiveness to hormonal cyclicity. For most women, a natural transition to menopause occurs in midlife, wherein the endogenous hormonal milieu undergoes significant changes and marks the end of the reproductive life stage. Although most women experience natural menopause, many women will undergo gynecological surgery during their lifetime, which can lead to an abrupt surgical menopause. It is of critical importance to better understand how endogenous and exogenous reproductive hormone exposures across the lifespan influence cognitive and brain aging, as women are at a greater risk for developing a variety of diseases after menopause, including dementia. Using rodent models, this dissertation explores how the etiology of reproductive senescence, that is, whether it is transitional or surgical, influences the female phenotype to result in divergent cognitive outcomes dependent upon a variety of factors, with an emphasis on age at the time of intervention playing a key role in brain outcomes. Furthermore, the impact of exogenous hormone therapy on cognition is evaluated in the context of surgical menopause. A novel rat model of hysterectomy is also presented, with results demonstrating for the first time that the nonpregnant uterus, which is typically considered to be a quiescent organ, may play a unique, direct role in modulating cognitive outcomes. Neurobiological mechanisms associated with reproductive hormones and aging are assessed to better recognize neural correlates underlying the observed behavior changes. The overarching goal of this dissertation was to elucidate novel factors contributing to cognitive aging outcomes in females. Collectively, the data presented herein indicate that the age at the onset of reproductive senescence has significant implications for learning and memory outcomes, and that variations in gynecological surgery can have unique, long-lasting effects on the brain and cognition. Translationally, this series of experiments moves the field forward toward the goal of improving the health and quality of life for women throughout the lifespan.
ContributorsKoebele, Stephanie Victoria (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Conrad, Cheryl D. (Committee member) / DeNardo, Dale F (Committee member) / Newbern, Jason M (Committee member) / Reiman, Eric M (Committee member) / Arizona State University (Publisher)
Created2019