Matching Items (11)
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- All Subjects: Aging
- All Subjects: Psychobiology
- Creators: Bimonte-Nelson, Heather A.
Description
Each year, millions of aging women will experience menopause, a transition from reproductive capability to reproductive senescence. In women, this transition is characterized by depleted ovarian follicles, declines in levels of sex hormones, and a dysregulation of gonadotrophin feedback loops. Consequently, menopause is accompanied by hot flashes, urogenital atrophy, cognitive decline, and other symptoms that reduce quality of life. To ameliorate these negative consequences, estrogen-containing hormone therapy is prescribed. Findings from clinical and pre-clinical research studies suggest that menopausal hormone therapies can benefit memory and associated neural substrates. However, findings are variable, with some studies reporting null or even detrimental cognitive and neurobiological effects of these therapies. Thus, at present, treatment options for optimal cognitive and brain health outcomes in menopausal women are limited. As such, elucidating factors that influence the cognitive and neurobiological effects of menopausal hormone therapy represents an important need relevant to every aging woman. To this end, work in this dissertation has supported the hypothesis that multiple factors, including post-treatment circulating estrogen levels, experimental handling, type of estrogen treatment, and estrogen receptor activity, can impact the realization of cognitive benefits with Premarin hormone therapy. We found that the dose-dependent working memory benefits of subcutaneous Premarin administration were potentially regulated by the ratios of circulating estrogens present following treatment (Chapter 2). When we administered Premarin orally, it impaired memory (Chapter 3). Follow-up studies revealed that this impairment was likely due to the handling associated with treatment administration and the task difficulty of the memory measurement used (Chapters 3 and 4). Further, we demonstrated that the unique cognitive impacts of estrogens that become increased in circulation following Premarin treatments, such as estrone (Chapter 5), and their interactions with the estrogen receptors (Chapter 6), may influence the realization of hormone therapy-induced cognitive benefits. Future directions include assessing the mnemonic effects of: 1) individual biologically relevant estrogens and 2) clinically-used bioidentical hormone therapy combinations of estrogens. Taken together, information gathered from these studies can inform the development of novel hormone therapies in which these parameters are optimized.
ContributorsEngler-Chiurazzi, Elizabeth (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Sanabria, Federico (Committee member) / Olive, Michael F (Committee member) / Hoffman, Steven (Committee member) / Arizona State University (Publisher)
Created2013
Description
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
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
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
Description
Cognitive function is multidimensional and complex, and research indicates that it is impacted by age, lifetime experience, and ovarian hormone milieu. One particular domain of cognitive function that is susceptible to age-related decrements is spatial memory. Cognitive practice can affect spatial memory when aged in both males and females, and in females alone ovarian hormones have been found to alter spatial memory via modulating brain microstructure and function in many of the same brain areas affected by aging. The research in this dissertation has implications that promote an understanding of the effects of cognitive practice on aging memory, why males and females respond differently to cognitive practice, and the parameters and mechanisms underlying estrogen's effects on memory. This body of work suggests that cognitive practice can enhance memory when aged and that estrogen is a probable candidate facilitating the observed differences in the effects of cognitive practice depending on sex. This enhancement in cognitive practice effects via estrogen is supported by data demonstrating that estrogen enhances spatial memory and hippocampal synaptic plasticity. The estrogen-facilitated memory enhancements and alterations in hippocampal synaptic plasticity are at least partially facilitated via enhancements in cholinergic signaling from the basal forebrain. Finally, age, dose, and type of estrogen utilized are important factors to consider when evaluating estrogen's effects on memory and its underlying mechanisms, since age alters the responsiveness to estrogen treatment and the dose of estrogen needed, and small alterations in the molecular structure of estrogen can have a profound impact on estrogen's efficacy on memory. Collectively, this dissertation elucidates many parameters that dictate the outcome, and even the direction, of the effects that cognitive practice and estrogens have on cognition during aging. Indeed, many parameters including the ones described here are important considerations when designing future putative behavioral interventions, behavioral therapies, and hormone therapies. Ideally, the parameters described here will be used to help design the next generation of interventions, therapies, and nootropic agents that will allow individuals to maintain their cognitive capacity when aged, above and beyond what is currently possible, thus enacting lasting improvement in women's health and public health in general.
ContributorsTalboom, Joshua S (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Conrad, Cheryl D. (Committee member) / Neisewander, Janet L (Committee member) / West, Stephen G. (Committee member) / Arizona State University (Publisher)
Created2011
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 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.
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
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 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.
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
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
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
Description
Post-Traumatic Stress Disorder (PTSD) is characterized by intrusive memories from a traumatic event. Current therapies rarely lead to complete remission. PTSD can be modeled in rodents using chronic stress (creating vulnerable phenotype) combined with fear conditioning (modeling a traumatic experience), resulting in attenuated extinction learning and impaired recall of extinction. Studies typically investigate cognition soon after chronic stress ends; however, as days and weeks pass (“rest” period) some cognitive functions may improve compared to soon after stress. Whether a rest period between chronic stress and fear conditioning/extinction would lead to improvements is unclear. In Chapter 2, male rats were chronically stressed by restraint (6hr/d/21d), a reliable method to produce cognitive changes, or assigned to a non-stressed control group (CON). After chronic stress ended, fear conditioning occurred within a day (STR-IMM), or after three (STR-R3) or six weeks (STR-R6). During the first three extinction trials, differences emerged in fear to the non-shock context: STR-R3/R6 showed significantly less fear to the context than did STR-IMM or CON. Differences were unlikely attributable to generalization or to second-order conditioning. Therefore, a rest period following chronic stress may lead to improved fear extinction and discrimination between the conditioned stimulus and environment. In Chapter 3, the infralimbic cortex (IL) was investigated due to the IL’s importance in fear extinction. Rats were infused with chemogenetics to target IL glutamatergic neurons and then assigned to CON, STR-IMM or STR-R3. During the rest period of STR-R3 and the restraint for STR-IMM, the IL was inhibited using CNO (1mg/kg BW, i.p., daily), which ended before behavioral testing. STR-R3 with IL inhibition failed to demonstrate a tone-shock association as spontaneous recovery was not observed. CON with IL inhibition behaved somewhat like STR-IMM; freezing to the extinction context was enhanced. Consequently, inhibiting IL function during the rest period following chronic stress was particularly disruptive for learning in STR-R3, impaired freezing to a safe context for CON, and had no effect in STR-IMM. These studies show that time since the end of chronic stress (recently ended or with a delay) can interact with IL functioning to modify fear learning and response.
ContributorsJudd, Jessica Michelle (Author) / Conrad, Cheryl D. (Thesis advisor) / Sanabria, Federico (Committee member) / Olive, Michael F (Committee member) / Bimonte-Nelson, Heather A. (Committee member) / Arizona State University (Publisher)
Created2020