ASU Electronic Theses and Dissertations
This collection includes most of the ASU Theses and Dissertations from 2011 to present. ASU Theses and Dissertations are available in downloadable PDF format; however, a small percentage of items are under embargo. Information about the dissertations/theses includes degree information, committee members, an abstract, supporting data or media.
In addition to the electronic theses found in the ASU Digital Repository, ASU Theses and Dissertations can be found in the ASU Library Catalog.
Dissertations and Theses granted by Arizona State University are archived and made available through a joint effort of the ASU Graduate College and the ASU Libraries. For more information or questions about this collection contact or visit the Digital Repository ETD Library Guide or contact the ASU Graduate College at gradformat@asu.edu.
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- All Subjects: Neurosciences
- Creators: Lewis, Candace
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
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
ABSTRACTAutism spectrum disorder (ASD) is a neurodevelopmental condition associated with social communication challenges and restrictive and repetitive behaviors [2]. Despite known lifelong challenges, understanding of cognitive and brain aging with ASD is lacking. Middle-aged adults with ASD have a higher chance of developing Alzheimer’s disease (Alz) and other dementias compared to neurotypical (NT) adults [12].
Apolipoprotein E (APOE) is a lipid transport protein involved in neuronal repair and cholesterol transport and is the strongest genetic risk factor for Alz [22]. Others demonstrated that individuals with ASD are more likely to carry the APOE ε4-allele [21]. This study aimed to determine if the APOE ε4-allele negatively impacts verbal learning and memory in ASD compared to NT adults.
Participants were intellectually able 76 middle-age and older adults (MA+) between the ages of 40-71, including 35 with ASD [mean age=53.06 (±8.91)] and 41 NT adults [mean age=53.90 (±8.44)]. APOE allelic distribution was determined from salivary samples via polymerase chain reaction amplification and genotyped on a tapestation. The Auditory Verbal Learning Test (AVLT) variables were short-term memory, long-term memory, and total learning.
There was a main effect of APOE ε4 for short-term memory and verbal learning, with ε4 carriers performing worse across diagnosis groups. For verbal learning, sex was a significant predictor. So, exploratory analyses separating diagnosis groups by sex were conducted. Only males with ASD were found to be carrying APOE ε4 associated with reduced verbal learning (p=0.02). Finally, the APOE ε4-allele did not significantly affect the participants’ long-term memory.
These findings suggest that the APOE ε4-allele negatively impacts short-term memory and verbal learning in MA+ adults, and that autistic men may be particularly vulnerable to the effects of APOE ε4 on verbal learning. This study is the first to incorporate ASD in APOE’s association with cognition and investigate how sex differences impact memory function. Future research is needed to replicate these findings using a larger sample size to further understand how the ε4-allele affects memory function trajectories in MA+ ASD as they grow older.
ContributorsAl-Hassan, Lamees (Author) / Braden, Blair (Thesis advisor) / Lewis, Candace (Committee member) / Rogalsky, Corianne (Committee member) / Arizona State University (Publisher)
Created2023