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The maternal separation (MS) paradigm is an animal model of early life stress. Animals subjected to MS during the first two weeks of life display altered behavioral and neuroendocrinological stress responses as adults. MS also produces altered responsiveness to and self-administration (SA) of various drugs of abuse including cocaine, ethanol,

The maternal separation (MS) paradigm is an animal model of early life stress. Animals subjected to MS during the first two weeks of life display altered behavioral and neuroendocrinological stress responses as adults. MS also produces altered responsiveness to and self-administration (SA) of various drugs of abuse including cocaine, ethanol, opioids, and amphetamine. Methamphetamine (METH) causes great harm to both the individual user and to society; yet, no studies have examined the effects of MS on METH SA. This study was performed to examine the effects of MS on the acquisition of METH SA, extinction, and reinstatement of METH-seeking behavior in adulthood. Given the known influence of early life stress and drug exposure on epigenetic processes, group differences in levels of the epigenetic marker methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) core were also investigated. Long-Evans pups and dams were separated on postnatal days (PND) 2-14 for either 180 (MS180) or 15 min (MS15). Male offspring were allowed to acquire METH SA (0.05 mg/kg/infusion) in 15 2-hr daily sessions starting at PND67, followed by extinction training and cue-induced reinstatement of METH-seeking behavior. Rats were then assessed for MeCP2 levels in the NAc core by immunohistochemistry. The MS180 group self-administered significantly more METH and acquired SA earlier than the MS15 group. No group differences in extinction or cue-induced reinstatement were observed. MS15 rats had significantly elevated MeCP2-immunoreactive cells in the NAc core as compared to MS180 rats. Together, these data suggest that MS has lasting influences on METH SA as well as epigenetic processes in the brain reward circuitry.
ContributorsLewis, Candace (Author) / Olive, Micheal F (Thesis advisor) / Conrad, Cheryl (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2013
Description

Chronic pain, or reoccurring pain lasting longer than three months, is frequently co- morbid with other chronic conditions. Physiological health problems such as overall general health, immune function, inflammation, stress, and sleep, as well as psychological problems like depression and anxiety are all associated with chronic pain. Previous studies have

Chronic pain, or reoccurring pain lasting longer than three months, is frequently co- morbid with other chronic conditions. Physiological health problems such as overall general health, immune function, inflammation, stress, and sleep, as well as psychological problems like depression and anxiety are all associated with chronic pain. Previous studies have also shown evidence for the heritability of chronic pain, indicating a genetic factor for chronic pain in children. However, few studies have investigated potential epigenetic processes involved in childhood chronic pain. DNA methylation and other epigenetic processes are highly susceptible to changes during crucial developmental periods in children, and they are heavily influenced by psychosocial factors and environmental factors. During an immune response, various cytokines such as TNFα, IL-6, and CRP are released. Cytokines are involved in the production of pain through their pro-inflammatory properties. Additionally, there is evidence to believe they increase pain sensitivity acutely by acting directly on nociceptors. Previous studies have shown that higher levels of inflammatory cytokines are associated with more pain because the inflammatory response from our immune cells activates pain pathways. A constant or prolonged activation of the immune response may consequently result in chronic pain. In many cases of chronic pain, there is an increase in the circulating pro-inflammatory cytokines in the blood that also leads to hypersensitivity.

ContributorsBaca, Itzahiana (Author) / Lewis, Candace (Thesis director) / Gewirtz, Jonathan (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2023-05
Description

For my thesis, I conducted a study on a healthy pediatric cohort to investigate how DNA methylation of genes related to myelin may predict total white matter volume in a healthy pediatric cohort. The relatively new field of neuroimaging epigenetics investigates how methylation of genes in peripheral tissue samples is

For my thesis, I conducted a study on a healthy pediatric cohort to investigate how DNA methylation of genes related to myelin may predict total white matter volume in a healthy pediatric cohort. The relatively new field of neuroimaging epigenetics investigates how methylation of genes in peripheral tissue samples is related to certain structural or functional features of the brain, as measured by neuroimaging data. Research has already demonstrated that methylation of genes in peripheral tissues is related to a variety of brain disorders. We hypothesized that methylation of myelin-related genes as measured in saliva samples would predict total white matter volume in a healthy pediatric cohort. After processing DNA methylation data from saliva samples from participants, multiple linear regressions were ran to determine if DNA methylation of myelin related genes was related to total white matter volume, as measured by data from structural MRIs. Results showed that these genes, which included MOG, MBP, and MYRF, significantly predicted total white matter volume. Two genes that were significant in our results have been previously shown to produce proteins that are essential to the structure of myelin.

ContributorsSpencer, Sophie (Author) / Lewis, Candace (Thesis director) / Braden, Blair (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor) / College of Integrative Sciences and Arts (Contributor)
Created2023-05
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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.

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