Matching Items (21)

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Relationships Between the Inflammatory Responses of the Immune System and Periods of Critical Hormonal Shifts in Females Across the Lifespan: A Pregnancy Review

Description

In females, critical hormonal shifts occur during puberty, menstruation, pregnancy, and <br/>menopause. The fluctuating ovarian hormone levels across a woman’s lifespan likely contribute <br/>to inflammatory responses driven by the immune

In females, critical hormonal shifts occur during puberty, menstruation, pregnancy, and <br/>menopause. The fluctuating ovarian hormone levels across a woman’s lifespan likely contribute <br/>to inflammatory responses driven by the immune system, which is regulated by a variety of <br/>physiological pathways and microbiological cues. Pregnancy in particular results in drastic <br/>changes in circulating hormone profiles, and involves a variety of physiological changes, <br/>including inflammatory responses of the immune system. There is evidence that these effects are <br/>mediated, in part, by the significant hormone fluctuations that characterize pregnancy and <br/>postpartum periods. This thesis highlights and synthesizes important physiological changes <br/>associated with pregnancy, and their potential implications on cognitive and brain aging in <br/>women. A tertiary model of cognition is presented depicting interactions between hormonal <br/>history, reproductive history, and immune functions. This research is important to create a better <br/>understanding of women’s health and enhance medical care for women throughout pregnancy <br/>and across reproductive hormone shifts across the lifespan.

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Date Created
  • 2021-05

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Young Adult and Middle-Age Rats Display Unique Working Memory Impairment and Differential Neurobiological Profiles following Hysterectomy

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

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.

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Date Created
  • 2020

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Optimization of menopausal hormone therapies for cognitive and brain aging using a rat model

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

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.

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Date Created
  • 2013

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Chronic unpredictable intermittent restraint stress disrupts hippocampal-dependent spatial memory in male, but not female rats

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

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.

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Date Created
  • 2019

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High serum androstenedione levels correlate with impaired memory in the surgically menopausal rat: a replication and new findings

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

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.

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Date Created
  • 2012

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Progestogens impact cognition during the transition to menopause in the rat: dissociation of progestogen- and memory- type

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.

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.

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Date Created
  • 2019

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Variations in Menopause Etiology Affect Cognitive Outcomes: How Age, Menopause Type, and Exogenous Ovarian Hormone Exposures Across the Lifespan Impact the Trajectory of Brain Aging

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

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.

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Date Created
  • 2019

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Cognitive changes across the menopause transition: a longitudinal evaluation of the impact of age and ovarian status on spatial memory

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

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.

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Date Created
  • 2015

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What's in a name: effect of breed perceptions & labeling on attractiveness, adoptions & length of stay for pit-bull-type dogs

Description

Previous research has indicated that certain breeds of dogs stay longer in shelters than others; however exactly how breed perception and identification influences potential adopters' decisions remains unclear. Current dog

Previous research has indicated that certain breeds of dogs stay longer in shelters than others; however exactly how breed perception and identification influences potential adopters' decisions remains unclear. Current dog breed identification practices in animal shelters are often based upon information supplied by the relinquishing owner, or staff determination based on the dog's phenotype. However discrepancies have been found between breed identification as typically assessed by welfare agencies and the outcome of DNA analysis. In Study 1, the perceived behavioral and adoptability characteristics of a pit-bull-type dog were compared with those of a Labrador Retriever and Border Collie. How the addition of a human handler influenced those perceptions was also assessed. In Study 2, lengths of stay and perceived attractiveness of dogs that were labeled as pit bull breeds to dogs that were phenotypically similar but were labeled as another breed at an animal shelter were compared. The latter dogs were called "lookalikes." In Study 3, perceived attractiveness in video recordings of pit-bull-type dogs and lookalikes with and without breed labels were compared. Lastly, data from an animal shelter that ceased applying breed labeling on kennels was analyzed, and lengths of stay and outcomes for all dog breeds, including pit bulls, before and after the change in labeling practice were compared. In total, these findings suggest that breed labeling influences potential adopters' perceptions and decision-making. Given the inherent complexity of breed assignment based on morphology coupled with negative breed perceptions, removing breed labels is a relatively low-cost strategy that will likely improve outcomes for dogs in animal shelters.

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Date Created
  • 2015

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Dose and delivery method impact cognitive outcome of Ethinyl Estradiol administration in the surgically menopausal rat

Description

Ethinyl estradiol, (EE) a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives (Shively, C., 1998), and is found in at least 30 different

Ethinyl estradiol, (EE) a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives (Shively, C., 1998), and is found in at least 30 different contraceptive formulations currently prescribed to women (Curtis et al., 2005). EE is also used in hormone therapies prescribed to menopausal women, such as FemhrtTM (Simon et al., 2003). Thus, EE is prescribed clinically to women at ages ranging from puberty through reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young, female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection. For these studies, the low and medium doses correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to the range of doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. For each study, cognition was evaluated with a battery of maze tasks tapping several domains of spatial learning and memory. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; this was seen for both cyclic and tonic regimens. Cyclic and tonic delivery of low EE, a dose that corresponds to doses used in the clinic today, resulted in transient and null impairments, respectively, on cognition.

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Date Created
  • 2012