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- All Subjects: Stress (Psychology)
- Creators: Olive, M. Foster
- Creators: Doane, Leah D
Description
The brain is a fundamental target of the stress response that promotes adaptation and survival but the repeated activation of the stress response has the potential alter cognition, emotion, and motivation, key functions of the limbic system. Three structures of the limbic system in particular, the hippocampus, medial prefrontal cortex (mPFC), and amygdala, are of special interest due to documented structural changes and their implication in post-traumatic stress disorder (PTSD). One of many notable chronic stress-induced changes include dendritic arbor restructuring, which reflect plasticity patterns in parallel with the direction of alterations observed in functional imaging studies in PTSD patients. For instance, chronic stress produces dendritic retraction in the hippocampus and mPFC, but dendritic hypertrophy in the amygdala, consistent with functional imaging in patients with PTSD. Some have hypothesized that these limbic region's modifications contribute to one's susceptibility to develop PTSD following a traumatic event. Consequently, we used a familiar chronic stress procedure in a rat model to create a vulnerable brain that might develop traits consistent with PTSD when presented with a challenge. In adult male rats, chronic stress by wire mesh restraint (6h/d/21d) was followed by a variety of behavioral tasks including radial arm water maze (RAWM), fear conditioning and extinction, and fear memory reconsolidation to determine chronic stress effects on behaviors mediated by these limbic structures. In chapter 2, we corroborated past findings that chronic stress caused hippocampal CA3 dendritic retraction. Importantly, we present new findings that CA3 dendritic retraction corresponded with poor spatial memory in the RAWM and that these outcomes reversed after a recovery period. In chapter 3, we also showed that chronic stress impaired mPFC-mediated extinction memory, findings that others have reported. Using carefully assessed behavior, we present new findings that chronic stress impacted nonassociative fear by enhancing contextual fear during extinction that generalized to a new context. Moreover, the generalization behavior corresponded with enhanced functional activation in the hippocampus and amygdala during fear extinction memory retrieval. In chapter 5, we showed for the first time that chronic stress enhanced amygdala functional activation during fear memory retrieval, i.e., reactivation. Moreover, these enhanced fear memories were resistant to protein synthesis interference to disrupt a previously formed memory, called reconsolidation in a novel attempt to weaken chronic stress enhanced traumatic memory. Collectively, these studies demonstrated the plastic and dynamic effects of chronic stress on limbic neurocircuitry implicated in PTSD. We showed that chronic stress created a structural and functional imbalance across the hippocampus, mPFC, and amygdala, which lead to a PTSD-like phenotype with persistent and exaggerated fear following fear conditioning. These behavioral disruptions in conjunction with morphological and functional imaging data reflect a chronic stress-induced imbalance between hippocampal and mPFC regulation in favor of amygdala function overdrive, and supports a novel approach for traumatic memory processing in PTSD.
ContributorsHoffman, Ann (Author) / Conrad, Cheryl D. (Thesis advisor) / Olive, M. Foster (Committee member) / Hammer, Jr., Ronald P. (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2013
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
Daily life stressors and negative emotional experiences predict poor physical and psychological health. The stress response of the hypothalamic-pituitary-adrenal axis is a primary biological system through which stressful experiences impact health and well-being across development. Individuals differ in their capacity for self-regulation and utilize various coping strategies in response to stress. Everyday experiences and emotions are highly variable during adolescence, a time during which self-regulatory abilities may become particularly important for adapting to shifting social contexts. Many adolescents in the U.S. enter college after high school, a context characterized by new opportunities and challenges for self-regulation. Guided by biopsychosocial and daily process approaches, the current study explored everyday stress and negative affect (NA), cortisol reactivity, and self-regulation assessed at the momentary, daily, and trait level among a racially/ethnically and socioeconomically diverse sample of first-year college students (N = 71; Mage = 18.85; 23% male; 52% non-Hispanic White) who completed a modified ecological momentary assessment. It was expected that within-person increases in momentary stress level or NA would be associated with cortisol reactivity assessed in college students' naturalistic settings. It was predicted that these within-person associations would differ based on engagement coping responses assessed via momentary diary reports, by the range of engagement coping responses assessed via diary reports at the end of the day, and by higher trait levels of self-regulation assessed via standard self-report questionnaire. Within-person increases in momentary stress level were significantly associated with momentary elevations in cortisol only during moments characterized by greater than usual engagement coping efforts (i.e., within-person
increases). At a different level of analysis, within-person increases in momentary stress level were significantly associated with increases in cortisol only for those with low trait levels of coping efficacy and engagement coping. On average, within-person increases in momentary NA were significantly associated with cortisol reactivity. Tests of moderation revealed this momentary association was only significant for those with low trait levels of support-seeking coping.
increases). At a different level of analysis, within-person increases in momentary stress level were significantly associated with increases in cortisol only for those with low trait levels of coping efficacy and engagement coping. On average, within-person increases in momentary NA were significantly associated with cortisol reactivity. Tests of moderation revealed this momentary association was only significant for those with low trait levels of support-seeking coping.
ContributorsSladek, Michael Ronald (Author) / Doane, Leah D (Thesis advisor) / Eisenberg, Nancy (Committee member) / Luecken, Linda J. (Committee member) / Arizona State University (Publisher)
Created2015
Description
Rasopathies are a family of developmental syndromes that exhibit craniofacial abnormalities, cognitive disabilities, developmental delay and increased risk of cancer. However, little is known about the pathogenesis of developmental defects in the nervous system. Frequently, gain-of-function mutations in the Ras/Raf/MEK/ERK cascade (aka ERK/MAPK) are associated with the observed pathogenesis. My research focuses on defining the relationship between increased ERK/MAPK signaling and its effects on the nervous system, specifically in the context of motor learning. Motor function depends on several neuroanatomically distinct regions, especially the spinal cord, cerebellum, striatum, and cerebral cortex. We tested whether hyperactivation of ERK/MAPK specifically in the cortex was sufficient to drive changes in motor function. We used a series of genetically modified mouse models and cre-lox technology to hyperactivate ERK/MAPK in the cerebral cortex. Nex:Cre/NeuroD6:Cre was employed to express a constitutively active MEK mutation throughout all layers of the cerebral cortex from an early stage of development. RBP4:Cre, caMEK only exhibited hyper activation in cortical glutamatergic neurons responsible for cortical output (neurons in layer V of the cerebral cortex). First, the two mouse strains were tested in an open field paradigm to assess global locomotor abilities and overall fitness for fine motor tasks. Next, a skilled motor reaching task was used to evaluate motor learning capabilities. The results show that Nex:Cre/NeuroD6:Cre, caMEK mutants do not learn the motor reaching task, although they performed normally on the open field task. Preliminary results suggest RBP4:Cre, caMEK mutants exhibit normal locomotor capabilities and a partial lack of learning. The difference in motor learning capabilities might be explained by the extent of altered connectivity in different regions of the corticospinal tract. Once we have identified the neuropathological effects of various layers in the cortex we will be able to determine whether therapeutic interventions are sufficient to reverse these learning defects.
ContributorsRoose, Cassandra Ann (Author) / Newbern, Jason M. (Thesis director) / Olive, Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
The RAS/MAPK (RAS/Mitogen Activated Protein Kinase) pathway is a highly conserved, canonical signaling cascade that is highly involved in cellular growth and proliferation as well as cell migration. As such, it plays an important role in development, specifically in development of the nervous system. Activation of ERK is indispensable for the differentiation of Embryonic Stem Cells (ESC) into neuronal precursors (Li z et al, 2006). ERK signaling has also shown to mediate Schwann cell myelination of the peripheral nervous system (PNS) as well as oligodendrocyte proliferation (Newbern et al, 2011). The class of developmental disorders that result in the dysregulation of RAS signaling are known as RASopathies. The molecular and cell-specific consequences of these various pathway mutations remain to be elucidated. While there is evidence for altered DNA transcription in RASopathies, there is little work examining the effects of the RASopathy-linked mutations on protein translation and post-translational modifications in vivo. RASopathies have phenotypic and molecular similarities to other disorders such as Fragile X Syndrome (FXS) and Tuberous Sclerosis (TSC) that show evidence of aberrant protein synthesis and affect related pathways. There are also well-defined downstream RAS pathway elements involved in translation. Additionally, aberrant corticospinal axon outgrowth has been observed in disease models of RASopathies (Xing et al, 2016). For these reasons, this present study examines a subset of proteins involved in translation and translational regulation in the context of RASopathy disease states. Results indicate that in both of the tested RASopathy model systems, there is altered mTOR expression. Additionally the loss of function model showed a decrease in rps6 activation. This data supports a role for the selective dysregulation of translational control elements in RASopathy models. This data also indicates that the primary candidate mechanism for control of altered translation in these modes is through the altered expression of mTOR.
ContributorsHilbert, Alexander Robert (Author) / Newbern, Jason (Thesis director) / Olive, M. Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Objective: The present study sought to 1) examine the measurement of emotional complexity (EC) by examining the associations among different indicators of EC (i.e., covariation between positive affect and negative affect; overall, negative, and positive granularity; overall, negative, and positive differentiation) derived from the same data set and identifying a latent factor structure; and 2) evaluate the predictive ability of EC on psychological distress, emotional well-being, and physical functioning while accounting for stressful contexts. The utility of assessing emotion diversity (ED) as another aspect of EC was also explored.
Methods: 191 middle-aged adults from a community-based study on resilience were asked to complete 30 daily diaries assessing positive and negative affect. At least 6 months later, participants completed a phone interview that assessed distress (i.e., depressive and anxiety symptoms), well-being (i.e., WHO-5 well-being, vitality, social functioning), physical functioning, and perceived stress.
Results: A three-factor solution with latent factors representing overall, negative, and positive EC was identified. Overall EC significantly predicted enhanced physical functioning, but was not associated with distress or well-being. Contrary to study hypotheses, positive and negative EC were not associated with future distress, well-being, or physical functioning, though a trend toward improved physical functioning was noted for positive EC. In contrast, positive and negative ED were both associated with less distress, and better well-being and physical functioning. Overall ED was unexpectedly related to worse outcomes (i.e., more distress, less well-being, decreased physical functioning). Stress did not moderate the relationship between emotional complexity and the outcome variables.
Conclusions: Different indicators of EC represent distinct aspects of emotional experience. Partial support of the hypotheses found. Physical functioning was the only outcome influenced by EC. The inclusion of stress did not change the results. The discrepancy between the findings and those in the literature may be related to reliability of EC indicators and absence of contextual factors. Further exploration of ED revealed a potentially important construct of emotional experience that is deserving of further inquiry.
Methods: 191 middle-aged adults from a community-based study on resilience were asked to complete 30 daily diaries assessing positive and negative affect. At least 6 months later, participants completed a phone interview that assessed distress (i.e., depressive and anxiety symptoms), well-being (i.e., WHO-5 well-being, vitality, social functioning), physical functioning, and perceived stress.
Results: A three-factor solution with latent factors representing overall, negative, and positive EC was identified. Overall EC significantly predicted enhanced physical functioning, but was not associated with distress or well-being. Contrary to study hypotheses, positive and negative EC were not associated with future distress, well-being, or physical functioning, though a trend toward improved physical functioning was noted for positive EC. In contrast, positive and negative ED were both associated with less distress, and better well-being and physical functioning. Overall ED was unexpectedly related to worse outcomes (i.e., more distress, less well-being, decreased physical functioning). Stress did not moderate the relationship between emotional complexity and the outcome variables.
Conclusions: Different indicators of EC represent distinct aspects of emotional experience. Partial support of the hypotheses found. Physical functioning was the only outcome influenced by EC. The inclusion of stress did not change the results. The discrepancy between the findings and those in the literature may be related to reliability of EC indicators and absence of contextual factors. Further exploration of ED revealed a potentially important construct of emotional experience that is deserving of further inquiry.
ContributorsArewasikporn, Anne (Author) / Zautra, Alex J (Thesis advisor) / Davis, Mary C. (Committee member) / Doane, Leah D (Committee member) / Infurna, Frank J. (Committee member) / Arizona State University (Publisher)
Created2016