Matching Items (6)
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- All Subjects: Psychobiology
- Creators: Olive, M. Foster
- Creators: Luecken, Linda
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
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
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
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.
ContributorsLewis, Candace (Author) / Olive, M. Foster (Thesis advisor) / Hammer, Ronald (Committee member) / Neisewander, Janet (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2015
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