Matching Items (28)

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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 of sex hormones, and a dysregulation of gonadotrophin feedback loops.

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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Age related changes in cognition and brain: a focus on progestogens

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

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.

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Date Created
2012

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Hippocampal BDNF mediates recovery from chronic stress-induced spatial reference memory deficits

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

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.

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Date Created
2013

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The temporal organization of operant behavior: a response bout analysis

Description

Many behaviors are organized into bouts – brief periods of responding punctuated by pauses. This dissertation examines the operant bouts of the lever pressing rat. Chapter 1 provides a brief history of operant response bout analyses. Chapters 2, 3, 5,

Many behaviors are organized into bouts – brief periods of responding punctuated by pauses. This dissertation examines the operant bouts of the lever pressing rat. Chapter 1 provides a brief history of operant response bout analyses. Chapters 2, 3, 5, and 6 develop new probabilistic models to identify changes in response bout parameters. The parameters of those models are demonstrated to be uniquely sensitive to different experimental manipulations, such as food deprivation (Chapters 2 and 4), response requirements (Chapters 2, 4, and 5), and reinforcer availability (Chapters 2 and 3). Chapter 6 reveals the response bout parameters that underlie the operant hyperactivity of a common rodent model of attention deficit hyperactivity disorder (ADHD), the spontaneously hypertensive rat (SHR). Chapter 6 then ameliorates the SHR’s operant hyperactivity using training procedures developed from findings in Chapters 2 and 4. Collectively, this dissertation provides new tools for the assessment of response bouts and demonstrates their utility for discerning differences between experimental preparations and animal strains that may be otherwise indistinguishable with more primitive methods.

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Date Created
2015

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Promoting self-regulation and metacognition through the use of online trace data within a game-based environment

Description

Computer-based environments provide a window into the complex and multifaceted learning process. These systems often collect a vast amount of information concerning how users choose to engage and behave within the interface (i.e., click streams, language input, and choices). Researchers

Computer-based environments provide a window into the complex and multifaceted learning process. These systems often collect a vast amount of information concerning how users choose to engage and behave within the interface (i.e., click streams, language input, and choices). Researchers have begun to use this information to gain a deeper understanding of users’ cognition, attitudes, and abilities. This dissertation is comprised of two published articles that describe how post-hoc and real-time analyses of trace data provides fine-grained details about how users regulate, process, and approach various learning tasks within computer-based environments. This work aims to go beyond simply understanding users’ skills and abilities, and instead focuses on understanding how users approach various tasks and subsequently using this information in real-time to enhance and personalize the user’s learning experience.

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Date Created
2015

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The epigenome: possible mechanisms by which early life stress may prime vulnerability towards substance use disorder

Description

Evidence from the 20th century demonstrated that early life stress (ELS) produces long lasting neuroendocrine and behavioral effects related to an increased vulnerability towards psychiatric illnesses such as major depressive disorder, post-traumatic stress disorder, schizophrenia, and substance use disorder. Substance

Evidence from the 20th century demonstrated that early life stress (ELS) produces long lasting neuroendocrine and behavioral effects related to an increased vulnerability towards psychiatric illnesses such as major depressive disorder, post-traumatic stress disorder, schizophrenia, and substance use disorder. Substance use disorders (SUDs) are complex neurological and behavioral psychiatric illnesses. The development, maintenance, and relapse of SUDs involve multiple brain systems and are affected by many variables, including socio-economic and genetic factors. Pre-clinical studies demonstrate that ELS affects many of the same systems, such as the reward circuitry and executive function involved with addiction-like behaviors. Previous research has focused on cocaine, ethanol, opiates, and amphetamine, while few studies have investigated ELS and methamphetamine (METH) vulnerability. METH is a highly addictive psychostimulant that when abused, has deleterious effects on the user and society. However, a critical unanswered question remains; how do early life experiences modulate both neural systems and behavior in adulthood? The emerging field of neuroepigenetics provides a potential answer to this question. Methyl CpG binding protein 2 (MeCP2), an epigenetic tag, has emerged as one possible mediator between initial drug use and the transition to addiction. Additionally, there are various neural systems that undergo long lasting epigenetics changes after ELS, such as the response of the hypothalamo-pituitary-adrenal (HPA) axis to stressors. Despite this, little attention has been given to the interactions between ELS, epigenetics, and addiction vulnerability. The studies described herein investigated the effects of ELS on METH self-administration (SA) in adult male rats. Next, we investigated the effects of ELS and METH SA on MeCP2 expression in the nucleus accumbens and dorsal striatum. Additionally, we investigated the effects of virally-mediated knockdown of MeCP2 expression in the nucleus accumbens core on METH SA, motivation to obtain METH under conditions of increasing behavioral demand, and reinstatement of METH-seeking in rats with and without a history of ELS. The results of these studies provide insights into potential epigenetic mechanisms by which ELS can produce an increased vulnerability to addiction in adulthood. Moreover, these studies shed light on possible novel molecular targets for treating addiction in individuals with a history of ELS.

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Date Created
2015

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Maternal depression and stress response: the effect on offspring in emerging adulthood

Description

Dysregulated cortisol has been linked to a variety of adverse physical and psychological consequences. Stressors in the childhood family environment can influence cortisol activity throughout development. For example, research has shown that both infants and children of depressed mothers exhibit

Dysregulated cortisol has been linked to a variety of adverse physical and psychological consequences. Stressors in the childhood family environment can influence cortisol activity throughout development. For example, research has shown that both infants and children of depressed mothers exhibit altered levels of cortisol compared to infants and children of non-depressed mothers. It is unclear, however, whether exposure to maternal depression in childhood and adolescence is related to cortisol activity at later stages of development. The current study examined the longitudinal relation between maternal depressive symptoms during late childhood (9-12 years old) and adolescence (15-19 years old) and cortisol activity in offspring in young adulthood (24- 28 years old) in a sample of 40 young adults and their mothers. Maternal depressive symptoms were prospectively assessed at four time points across the 15 year study. Cortisol samples were collected from young adult offspring at the final time point. Findings revealed that higher levels of maternal depressive symptoms during late childhood were associated with lower total cortisol output in young adulthood. Results suggest that attenuated cortisol levels, which put these young adults at risk for a variety of stress-related physical and psychological illnesses, may be a long-term consequence of exposure to maternal depression,. Depressive symptoms in mothers during their child's adolescence, however, did not relate to cortisol output. These findings suggest a sensitive period in late childhood during which the development of HPA activity may be susceptible to the environmental stressor of maternal depression.

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Date Created
2011

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Leo Kanner and the psychobiology of autism

Description

Leo Kanner first described autism in his 1943 article in Nervous Child titled "Autistic Disturbances of Affective Contact". Throughout, he describes the eleven children with autism in exacting detail. In the closing paragraphs, the parents of autistic children are described

Leo Kanner first described autism in his 1943 article in Nervous Child titled "Autistic Disturbances of Affective Contact". Throughout, he describes the eleven children with autism in exacting detail. In the closing paragraphs, the parents of autistic children are described as emotionally cold. Yet, he concludes that the condition as he described it was innate. Since its publication, his observations about parents have been a source of controversy surrounding the original definition of autism.

Thus far, histories about autism have pointed to descriptions of parents of autistic children with the claim that Kanner abstained from assigning them causal significance. Understanding the theoretical context in which Kanner's practice was embedded is essential to sorting out how he could have held such seemingly contrary views simultaneously.

This thesis illustrates that Kanner held an explicitly descriptive frame of reference toward his eleven child patients, their parents, and autism. Adolf Meyer, his mentor at Johns Hopkins, trained him to make detailed life-charts under a clinical framework called psychobiology. By understanding that Kanner was a psychobiologist by training, I revisit the original definition of autism as a category of mental disorder and restate its terms. This history illuminates the theoretical context of autism's discovery and has important implications for the first definition of autism amidst shifting theories of childhood mental disorders and the place of the natural sciences in defining them.

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Date Created
2014

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A prospective study of childhood negative events, temperament, adolescent coping, and stress reactivity in young adulthood

Description

Accumulating evidence implicates exposure to adverse childhood experiences in the development of hypocortisolism in the long-term, and researchers are increasingly examining individual-level mechanisms that may underlie, exacerbate or attenuate this relation among at-risk populations. The current study takes a developmentally

Accumulating evidence implicates exposure to adverse childhood experiences in the development of hypocortisolism in the long-term, and researchers are increasingly examining individual-level mechanisms that may underlie, exacerbate or attenuate this relation among at-risk populations. The current study takes a developmentally and theoretically informed approach to examining episodic childhood stressors, inherent and voluntary self-regulation, and physiological reactivity among a longitudinal sample of youth who experienced parental divorce. Participants were drawn from a larger randomized controlled trial of a preventive intervention for children of divorce between the ages of 9 and 12. The current sample included 159 young adults (mean age = 25.5 years; 53% male; 94% Caucasian) who participated in six waves of data collection, including a 15-year follow-up study. Participants reported on exposure to negative life events (four times over a 9-month period) during childhood, and mothers rated child temperament. Six years later, youth reported on the use of active and avoidant coping strategies, and 15 years later, they participated in a standardized psychosocial stress task and provided salivary cortisol samples prior to and following the task. Path analyses within a structural equation framework revealed that a multiple mediation model best fit the data. It was found that children with better mother-rated self-regulation (i.e. low impulsivity, low negative emotionality, and high attentional focus) exhibited lower total cortisol output 15 years later. In addition, greater self-regulation in childhood predicted greater use of active coping in adolescence, whereas a greater number of negative life events predicted increased use of avoidant coping in adolescence. Finally, a greater number of negative events in childhood predicted marginally lower total cortisol output, and higher levels of active coping in adolescence were associated with greater total cortisol output in young adulthood. Findings suggest that children of divorce who exhibit better self-regulation evidence lower cortisol output during a standardized psychosocial stress task relative to those who have higher impulsivity, lower attentional focus, and/or higher negative emotionality. The conceptual significance of the current findings, including the lack of evidence for hypothesized relations, methodological issues that arose, and issues in need of future research are discussed.

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Date Created
2013

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Visual recognition for dynamic scenes

Description

Recognition memory was investigated for naturalistic dynamic scenes. Although visual recognition for static objects and scenes has been investigated previously and found to be extremely robust in terms of fidelity and retention, visual recognition for dynamic scenes has received much

Recognition memory was investigated for naturalistic dynamic scenes. Although visual recognition for static objects and scenes has been investigated previously and found to be extremely robust in terms of fidelity and retention, visual recognition for dynamic scenes has received much less attention. In four experiments, participants view a number of clips from novel films and are then tasked to complete a recognition test containing frames from the previously viewed films and difficult foil frames. Recognition performance is good when foils are taken from other parts of the same film (Experiment 1), but degrades greatly when foils are taken from unseen gaps from within the viewed footage (Experiments 3 and 4). Removing all non-target frames had a serious effect on recognition performance (Experiment 2). Across all experiments, presenting the films as a random series of clips seemed to have no effect on recognition performance. Patterns of accuracy and response latency in Experiments 3 and 4 appear to be a result of a serial-search process. It is concluded that visual representations of dynamic scenes may be stored as units of events, and participant's old
ew judgments of individual frames were better characterized by a cued-recall paradigm than traditional recognition judgments.

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Date Created
2014