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- Creators: Arizona State University
- Creators: Goldinger, Stephen
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
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.
ContributorsHagan, Melissa (Author) / Luecken, Linda (Thesis advisor) / MacKinnon, David (Committee member) / Wolchik, Sharlene (Committee member) / Doane, Leah (Committee member) / Arizona State University (Publisher)
Created2013
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
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
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.
ContributorsMahrer, Nicole Eva (Author) / Wolchik, Sharlene (Thesis advisor) / Luecken, Linda (Thesis advisor) / Tein, Jenn-Yun (Committee member) / Arizona State University (Publisher)
Created2011
Description
The transition to college is a time of increased opportunity and stress that spans across multiple domains (e.g., social life, academic workload, finances). Adolescents who encounter significant stress during the transition to college may be vulnerable to adverse outcomes, due to a “wear and tear” of physiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis. Latino students may be particularly at-risk for heightened stress exposure, as minority youth often experience both minority-specific stressors and general life stress. Despite this, the majority of research on Latino students is limited to the examination of singular forms of stress, and little is known regarding the cumulative impact of multiple forms of stress on Latino students’ HPA axis functioning. The present study employed a “multi-risk model approach” to examine the additive, common, and cumulative effects of multiple types of stress (general, academic, social, financial, bicultural, discrimination) on HPA axis functioning in Latino college students (N = 209; 64.4% female; Mage = 18.95). Results from three-level growth curve models indicated that, in the additive model, no stressors were associated with the CAR, but general stress was associated with a flatter diurnal cortisol slope (DCS) and bicultural stress was linked with a steeper DCS. In the common model, the college stress latent factor was related to a reduced cortisol awakening response (CAR), but not the DCS. In the cumulative model, cumulative risk was linked with a lower CAR, but not the DCS. These findings highlight the physiological correlates of various stressors experienced by Latino college students.
ContributorsSasser, Jeri (Author) / Doane, Leah D (Thesis advisor) / Su, Jinni (Committee member) / Grimm, Kevin J (Committee member) / Arizona State University (Publisher)
Created2022
Description
How early life is experienced and perceived can greatly affect mental and physical health outcomes. An individual is greatly influenced by their first models of what social relationships look and feel like, and with time also learn how to survive when less favorable social experiences occur. The lessons learned may lead to healthy problem solving and resilience, or it may lead to unhealthy problem-solving habits that hinder well-being. Anxious thoughts and other mental health symptoms may accompany an individual long-term and hinder an essential need for a healthy life. The first main purpose of this thesis is to examine the impact of Adverse Childhood Experiences (ACEs) on mental health (anxiety symptoms), and on sleep quality (an essential need). The second purpose of my thesis is to investigate the impact of genetics on resilience, specifically, the mu-opioid receptor gene. The first hypothesis proposed ACEs that were perceived as more traumatic and occurred more frequently would be associated with more poor sleep quality symptoms. The second hypothesis predicted that anxiety symptoms would mediate the association. The third hypothesis (exploratory) suggested that an individual’s alleles for the mu-opioid receptor gene would moderate the mediation pathway. The study was conducted with 318 participants between the ages of 18 and 35 years old. The study demonstrated a direct effect for ACEs and sleep. Anxiety mediated the association between ACEs (exposure and severity) and sleep (insomnia, quality, sleepiness), suggesting that ACEs possibly increase feelings of anxiety which, in turn, lead to worse sleep outcomes. Finally, the moderated-mediation model with OPRM1 as the moderator, was not significant for the mediation pathway A; however, there was a significant interaction with anxiety and sleep symptoms.
ContributorsBailey, Elise (Author) / Mickelson, Kristin (Thesis advisor) / Burleson, Mary (Committee member) / Petrov, Megan (Committee member) / Arizona State University (Publisher)
Created2022
Description
The hypothalamic pituitary adrenal (HPA) axis is a primary neuroendocrine system posited to mediate the associations between early life stress and long-term deleterious psychological and physical health outcomes. The effects of early life adversity on HPA axis functioning have been well-documented in primarily White samples, with statistical advances allowing researchers to isolate latent trait cortisol as a stable indicator of HPA axis functioning to account for day-to-day influences on diurnal cortisol patterns. However, directional associations have been mixed depending on developmental stage, demographic composition, and methodological differences across studies. The few studies of early adversity and HPA axis functioning in Hispanic/Latino/a/x samples demonstrate complex interactions between cultural processes and adversity in predicting HPA axis output. Further, nascent literature has isolated the cognitive, meaning-making, and prosocial skills involved in ethnic racial identity (ERI) and its subconstructs of exploration, resolution, and affirmation as promotive during the adolescent stage of development in Latinx youth. Such skills might better prepare youth for neurobiological stress regulation after adversity. To my knowledge, no study has examined whether ERI plays a protective role against the effects of early adversity on trait-level indicators of the HPA axis during adolescence, despite the particularly high rates of cumulative exposure to early life adversity in Latinx youth as compared to White counterparts. Guided by adaptive cultural resilience theories, this study of 197 socioeconomically diverse Latinx older-adolescents aimed to leverage recent findings of stable trait indicators of cortisol output to 1) identify consistent directional markers of the effects of early life adversity on latent trait cortisol in a Latinx sample and 2) elucidate the degree to which ERI might act as a promotive feature for HPA axis levels and protective factor against cumulative early life adversity. Confirmatory factor analyses identified a theory-driven model as an adequate measure of latent trait cortisol. Greater exposure to early adversity predicted lower latent trait cortisol, but ERI demonstrated neither protective nor promotive effects. The present study reifies that early adversity exposure has deleterious effects on trait-level HPA axis functioning, but identifying sources of cultural resilience among Latinx youth remains critical for the future of health equity.
ContributorsGusman, Michaela S. (Author) / Doane, Leah D (Thesis advisor) / Causadias, José M (Committee member) / Grimm, Kevin J (Committee member) / Wolchik, Sharlene A (Committee member) / Arizona State University (Publisher)
Created2022
Description
More than a century of research has investigated the etiology of dyslexia, coalescing around ‘phonological awareness’ – the ability to recognize and manipulate phonemes – as a trait typically deficient in reading disorders. Meanwhile, the last few decades of research in neuroscience have highlighted the brain as a predictive organ, which subliminally calibrates sensory expectations according to experience. Do the brains of adults with dyslexia respond differently than those of matched controls to expected tones and unexpected omissions? While auditory oddball paradigms have previously been used to study dyslexia, these studies often interpret group differences to indicate deficit auditory discrimination rather than deficit auditory prediction. The current study takes a step toward fusing theories of predictive coding and dyslexia, finding that event-related potentials related to auditory prediction are attenuated in adults with dyslexia compared with typical controls. It further suggests that understanding dyslexia, and perhaps other psychiatric disorders, in terms of contributory neural systems will elucidate shared and distinct etiologies.
ContributorsBennett, Augustin (Author) / Peter, Beate (Thesis advisor) / Daliri, Ayoub (Committee member) / Goldinger, Stephen (Committee member) / Arizona State University (Publisher)
Created2023
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