Matching Items (8)
Filtering by
- All Subjects: psychology
- All Subjects: Cellular Biology
Description
Cells live in complex environments and must be able to adapt to environmental changes in order to survive. The ability of a cell to survive and thrive in a changing environment depends largely on its ability to receive and respond to extracellular signals. Initiating with receptors, signal transduction cascades begin translating extracellular signals into intracellular messages. Such signaling cascades are responsible for the regulation of cellular metabolism, cell growth, cell movement, transcription, translation, proliferation and differentiation. This dissertation seeks to dissect and examine critical signaling pathways involved in the regulation of proliferation in neural stem cells (Chapter 2) and the regulation of Glioblastoma Multiforme pathogenesis (GBM; Chapter 3). In Chapter 2 of this dissertation, we hypothesize that the mTOR signaling pathway plays a significant role in the determination of neural stem cell proliferation given its control of cell growth, metabolism and survival. We describe the effect of inhibition of mTOR signaling on neural stem cell proliferation using animal models of aging. Our results show that the molecular method of targeted inhibition may result in differential effects on neural stem cell proliferation as the use of rapamycin significantly reduced proliferation while the use of metformin did not. Abnormal signaling cascades resulting in unrestricted proliferation may lead to the development of brain cancer, such as GBM. In Chapter 3 of this dissertation, we hypothesize that the inhibition of the protein kinase, aPKCλ results in halted GBM progression (invasion and proliferation) due to its central location in multiple signaling cascades. Using in-vitro and in-vivo models, we show that aPKCλ functions as a critical node in GBM signaling as both cell-autonomous and non-cell-autonomous signaling converge on aPKCλ resulting in pathogenic downstream effects. This dissertation aims to uncover the molecular mechanisms involved in cell signaling pathways which are responsible for critical cellular effects such as proliferation, invasion and transcriptional regulation.
ContributorsKusne, Yael (Author) / Sanai, Nader (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Tran, Nhan (Committee member) / Hammer, Ronald (Committee member) / Narayanan, Vinodh (Committee member) / Shapiro, Joan (Committee member) / Arizona State University (Publisher)
Created2014
Description
Globally, addiction to stimulants such as methamphetamine (METH) remains a significant public health problem. Despite decades of research, no approved anti-relapse medications for METH or any illicit stimulant exist, and current treatment approaches suffer from high relapse rates. Recently, synthetic cathinones have also emerged as popular abused stimulants, leading to numerous incidences of toxicity and death. However, contrary to traditional illicit stimulants, very little is known about their addiction potential. Given the high relapse rates and lack of approved medications for METH addiction, chapters 2 and 3 of this dissertation assessed three different glutamate receptor ligands as potential anti-relapse medications following METH intravenous self-administration (IVSA) in rats. In chapters 4 through 7, using both IVSA and intracranial self-stimulation (ICSS) procedures, experiments assessed abuse liability of the popular synthetic cathinones 3,4-Methylenedioxypyrovalerone (MDPV) , methylone, α-pyrrolidinovalerophenone (α-PVP) and 4-methylethylcathinone (4-MEC). Results from these seminal studies suggest that these drugs possess similar abuse potential to traditional illicit stimulants such as METH, cocaine, and 3,4-methylenedioxymethamphetamine (MDMA). Finally, studies outlined in chapter 8 assessed the potential neurotoxic or adverse cognitive effects of METH and MDPV following IVSA procedures for the purpose of identifying potential novel pharmacotherapeutic targets. However, results of these final studies did not reveal neurotoxic or adverse cognitive effects when using similar IVSA procedural parameters that were sufficient for establishing addiction potential, suggesting that these parameters do not allow for sufficient drug intake to produce similar neurotoxicity or cognitive deficits reported in humans. Thus, these models may be inadequate for fully modeling the adverse neural and psychological consequences of stimulant addiction. Together, these studies support the notion for continued research into the abuse liability and toxicity of METH and synthetic cathinones and suggest that refinements to traditional IVSA models are needed for both more effective assessment of potential cognitive and neural deficits induced by these drugs and screening of potentially clinically efficacious pharmacotherapeutics.
ContributorsWatterson, Lucas (Author) / Olive, Michael F (Thesis advisor) / Czyzyk, Traci (Committee member) / Neisewander, Janet (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2014
ContributorsChandler, N. Kayla (Author) / Neisewander, Janet (Thesis director) / Sanabria, Federico (Committee member) / Olive, M. Foster (Committee member) / Barrett, The Honors College (Contributor) / College of Liberal Arts and Sciences (Contributor)
Created2013-05
Description
Abstract White matter thickness correlates with various mental illness. Commissure white matter tracts are responsible for interconnecting the same cortical area in both hemispheres. Injury to the brain can result in thinning and shrinkage even collapsing and detachment of the white matter tracts' myelin sheaths. Injury can affect cognitive function and time points are essential for therapeutic intervention. Research is beginning to identify gradual long-term neurodegenerative effects. With the advancement of brain imaging technology, we know that Wallerian degeneration has a significant negative impact on the white matter tracts throughout the brain (Johnson, Stewart, & Smith, 2013). If major tracts become injured like, the corpus callosum, then it can affect interhemispheric communication. Once myelin is damaged the axon becomes vulnerable, and the mechanisms of nerve recovery are not well known. Myelin sheath recovery has been studied in hopes to proliferate the oligodendrocytes that make up for the atrophied myelin. Neurotoxic chemicals released at activation of macrophages which hinders the brains ability to proliferate myelin protein needed for myelin differentiation adequately. In the central nervous system myelin has mechanisms to recover. Neurogenesis is a naturally occurring recovery mechanism seen after brain injury. Understanding the time points in which brain recovery occurs is important for treatment of diffuse injuries that cannot be identified through some imaging techniques. To better understand critical timepoints of natural recovery after brain injury can allow further investigation for early intervention to promote adequate recovery.
ContributorsLiptow, Kristen Ashley (Author) / Neisewander, Janet (Thesis director) / Law, L. Matthew (Committee member) / School of Social and Behavioral Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
Description
ADHD is a childhood neurobehavioral disorder characterized by inordinate levels of hyperactivity, inattention and impulsivity. The inability to withhold a reinforced response, or response inhibition capacity (RIC), is one aspect of impulsivity associated with ADHD. The first goal of this dissertation was to evaluate the fixed minimum interval (FMI) schedule as a method for assessing RIC. Chapter 2 showed that latencies were substantially more sensitive than FMI-derived estimates of RIC to the effects of pre-feeding and changes in rate and magnitude of reinforcement. Chapter 3 examined the ability of the FMI to discriminate between spontaneously hypertensive rats (SHR), an animal model of ADHD, and Wistar Kyoto (WKY) controls. Results from Chapter 3 showed that RIC was not substantially different between SHR and WKY rats. However, latencies were significantly shorter for SHRs than for WKYs suggesting incentive motivation differed between strains. The second goal of this dissertation was to examine the sensitivity of the SHR to nicotine. ADHD is a risk factor for tobacco dependence. The goal of Chapters 4 and 5 was to determine whether the SHR provided a model of ADHD-related tobacco sensitivity. Chapter 4 examined nicotine's locomotor and rewarding effects in adolescent SHRs using the conditioned place preference (CPP) procedure. SHRs developed CPP to the highest nicotine dose tested and were sensitive to nicotine's locomotor-enhancing properties. WKY controls did not develop CPP to any nicotine dose tested and were not sensitive to nicotine's locomotor properties. However, it is likely that nicotine effects were obscured by a pseudo-conditioning to saline in WKYs. Chapter 5 demonstrated that SHRs were more active than WKYs in the open-field but not in the Rotorat apparatus. Results also showed that SHRs and WKYs were both sensitive to nicotine's locomotor sensitizing effects. However, WKYs were more sensitive than SHRs to nicotine's locomotor suppressing effects. Collectively, results from Chapters 4 and 5 show that SHRs are sensitive to the rewarding and locomotor-enhancing properties of nicotine. However, more research is necessary to confirm that SHRs are a suitable model for studying ADHD-related tobacco use.
ContributorsWatterson, Elizabeth (Author) / Sanabria, Federico (Thesis advisor) / Olive, Foster (Thesis advisor) / Chassin, Laurie (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2015
Description
Free coenzyme A (CoASH) carries acyl groups for the tricarboxylic acid (TCA) cycle and fatty acid metabolism, and donates acyl groups for protein posttranslational modifications. Cellular de novo CoASH synthesis starts with a pantothenate kinase (PANK1-3) phosphorylating pantothenate (vitamin B5). Mutations in PANK2 cause a subtype of neurodegeneration with brain iron accumulation (NBIA). The PANKs have differential subcellular distribution and regulatory properties. However, the purpose of each PANK has remained obscure, with knockout mouse models presenting with mild phenotypes unless challenged with a high-fat diet. Based on PANK2’s known activation by palmitoylcarnitine, the PANK2-deficient cells were challenged with palmitic acid (PAL) added to glucose-containing media. The high nutrient mixture generated a surprising “starvation” profile of reduced proliferation, low ATP, AMPK activation, and autophagy upregulation in PANK2-deficient PAL-challenged cells. Further experiments showed that fatty acids accumulated and that PANK2-deficient cells had reduced respiration when provided with palmitoylcarnitine as a substrate, seemingly due to an impaired ability to oxidize fatty acids during PAL-induced Randle Cycle activation. Intriguingly, whole-cell CoASH levels remained stable despite the PAL-induced starvation phenotype, and increasing CoASH via PANK1β overexpression did not rescue the phenotype, demonstrating a unique role for PANK2 in fatty acid metabolism. Even though a direct CoASH deficiency was not detected, there were changes in short chain CoA-derivatives, including acetyl-CoA, succinyl-CoA, and butyryl-CoA, as well as evidence of impaired TCA cycle function. These impairments in both the TCA cycle and fatty acid oxidation implicate a role for PANK2 in regulating mitochondria CoA dynamics.
ContributorsNordlie, Sandra Maria (Author) / Kruer, Michael C (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Padilla Lopez, Sergio (Committee member) / Katsanos, Christos (Committee member) / Arizona State University (Publisher)
Created2022
Description
MicroRNAs are small, non-coding transcripts that post-transcriptionally regulate expression of multiple genes. Recently microRNAs have been linked to the etiology of neuropsychiatric disorders, including drug addiction. Following genome-wide sequence analyses, microRNA-495 (miR-495) was found to target several genes within the Knowledgebase of Addiction-Related Genes (KARG) database and to be highly expressed in the nucleus accumbens (NAc), a pivotal brain region involved in reward and motivation. The central hypothesis of this dissertation is that NAc miR-495 regulates drug abuse-related behavior by targeting several addiction-related genes (ARGs). I tested this hypothesis in two ways: 1) by examining the effects of viral-mediated miR-495 overexpression or inhibition in the NAc of rats on cocaine abuse-related behaviors and gene expression, and 2) by examining changes in NAc miR-495 and ARG expression as a result of brief (i.e., 1 day) or prolonged (i.e., 22 days) cocaine self-administration. I found that behavioral measures known to be sensitive to motivation for cocaine were attenuated by NAc miR-495 overexpression, including resistance to extinction of cocaine conditioned place preference (CPP), cocaine self-administration on a high effort progressive ratio schedule of reinforcement, and cocaine-seeking behavior during both extinction and cocaine-primed reinstatement. These effects appeared specific to cocaine, as there was no effect of NAc miR-495 overexpression on a progressive ratio schedule of food reinforcement. In contrast, behavioral measures known to be sensitive to cocaine reward were not altered, including expression of cocaine CPP and cocaine self-administration under a low effort FR5 schedule of reinforcement. Importantly, the effects were accompanied by decreases in NAc ARG expression, consistent with my hypothesis. In further support, I found that NAc miR-495 levels were reduced and ARG levels were increased in rats following prolonged, but not brief, cocaine self-administration experience. Surprisingly, inhibition of NAc miR-495 expression also decreased both cocaine-seeking behavior during extinction and NAc ARG expression, which may reflect compensatory changes or unexplained complexities in miR-495 regulatory effects. Collectively, the findings suggest that NAc miR-495 regulates ARG expression involved in motivation for cocaine. Therefore, using microRNAs as tools to target several ARGs simultaneously may be useful for future development of addiction therapeutics.
ContributorsBastle, Ryan (Author) / Neisewander, Janet (Thesis advisor) / Newbern, Jason (Committee member) / Nikulina, Ella (Committee member) / Perrone-Bizzozero, Nora (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2016
Description
Development of the cerebral cortex requires the complex integration of extracellular stimuli to affect changes in gene expression. Trophic stimulation activates specialized intracellular signaling cascades to instruct processes necessary for the elaborate cellular diversity, architecture, and function of the cortex. The canonical RAS/RAF/MEK/ERK (ERK/MAPK) cascade is a ubiquitously expressed kinase pathway that regulates crucial aspects of neurodevelopment. Mutations in the ERK/MAPK pathway or its regulators give rise to neurodevelopmental syndromes termed the “RASopathies.” RASopathy individuals present with neurological symptoms that include intellectual disability, ADHD, and seizures. The precise cellular mechanisms that drive neurological impairments in RASopathy individuals remain unclear. In this thesis, I aimed to 1) address how RASopathy mutations affect neurodevelopment, 2) elucidate fundamental requirements of ERK/MAPK in GABAergic circuits, and 3) determine how aberrant ERK/MAPK signaling disrupts GABAergic development.
Here, I show that a Noonan Syndrome-linked gain-of-function mutation Raf1L613V, drives modest changes in astrocyte and oligodendrocyte progenitor cell (OPC) density in the mouse cortex and hippocampus. Raf1L613V mutant mice exhibited enhanced performance in hippocampal-dependent spatial reference and working memory and amygdala-dependent fear learning tasks. However, we observed normal perineuronal net (PNN) accumulation around mutant parvalbumin-expressing (PV) interneurons. Though PV-interneurons were minimally affected by the Raf1L613V mutation, other RASopathy mutations converge on aberrant GABAergic development as a mediator of neurological dysfunction.
I therefore hypothesized interneuron expression of the constitutively active Mek1S217/221E (caMek1) mutation would be sufficient to perturb GABAergic circuit development. Interestingly, the caMek1 mutation selectively disrupted crucial PV-interneuron developmental processes. During embryogenesis, I detected expression of cleaved-caspase 3 (CC3) in the medial ganglionic eminence (MGE). Interestingly, adult mutant cortices displayed a selective 50% reduction in PV-expressing interneurons, but not other interneuron subtypes. PV-interneuron loss was associated with seizure-like activity in mutants and coincided with reduced perisomatic synapses. Mature mutant PV-interneurons exhibited somal hypertrophy and a substantial increase in PNN accumulation. Aberrant GABAergic development culminated in reduced behavioral response inhibition, a process linked to ADHD-like behaviors. Collectively, these data provide insight into the mechanistic underpinnings of RASopathy neuropathology and suggest that modulation of GABAergic circuits may be an effective therapeutic option for RASopathy individuals.
Here, I show that a Noonan Syndrome-linked gain-of-function mutation Raf1L613V, drives modest changes in astrocyte and oligodendrocyte progenitor cell (OPC) density in the mouse cortex and hippocampus. Raf1L613V mutant mice exhibited enhanced performance in hippocampal-dependent spatial reference and working memory and amygdala-dependent fear learning tasks. However, we observed normal perineuronal net (PNN) accumulation around mutant parvalbumin-expressing (PV) interneurons. Though PV-interneurons were minimally affected by the Raf1L613V mutation, other RASopathy mutations converge on aberrant GABAergic development as a mediator of neurological dysfunction.
I therefore hypothesized interneuron expression of the constitutively active Mek1S217/221E (caMek1) mutation would be sufficient to perturb GABAergic circuit development. Interestingly, the caMek1 mutation selectively disrupted crucial PV-interneuron developmental processes. During embryogenesis, I detected expression of cleaved-caspase 3 (CC3) in the medial ganglionic eminence (MGE). Interestingly, adult mutant cortices displayed a selective 50% reduction in PV-expressing interneurons, but not other interneuron subtypes. PV-interneuron loss was associated with seizure-like activity in mutants and coincided with reduced perisomatic synapses. Mature mutant PV-interneurons exhibited somal hypertrophy and a substantial increase in PNN accumulation. Aberrant GABAergic development culminated in reduced behavioral response inhibition, a process linked to ADHD-like behaviors. Collectively, these data provide insight into the mechanistic underpinnings of RASopathy neuropathology and suggest that modulation of GABAergic circuits may be an effective therapeutic option for RASopathy individuals.
ContributorsHolter, Michael (Author) / Newbern, Jason (Thesis advisor) / Anderson, Trent (Committee member) / Mehta, Shwetal (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2019