Matching Items (16)
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- All Subjects: Neurosciences
- Creators: Newbern, Jason
- Member of: Theses and Dissertations
Description
Following a traumatic brain injury (TBI) 5-50% of patients will develop post traumatic epilepsy (PTE). Pediatric patients are most susceptible with the highest incidence of PTE. Currently, we cannot prevent the development of PTE and knowledge of basic mechanisms are unknown. This has led to several shortcomings to the treatment of PTE, one of which is the use of anticonvulsant medication to the population of TBI patients that are not likely to develop PTE. The complication of identifying the two populations has been hindered by the ability to find a marker to the pathogenesis of PTE. The central hypothesis of this dissertation is that following TBI, the cortex undergoes distinct cellular and synaptic reorganization that facilitates cortical excitability and promotes seizure development. Chapter 2 of this dissertation details excitatory and inhibitory changes in the rat cortex after severe TBI. This dissertation aims to identify cortical changes to a single cell level after severe TBI using whole cell patch clamp and electroencephalogram electrophysiology. The work of this dissertation concluded that excitatory and inhibitory synaptic activity in cortical controlled impact (CCI) animals showed the development of distinct burst discharges that were not present in control animals. The results suggest that CCI induces early "silent" seizures that are detectable on EEG and correlate with changes to the synaptic excitability in the cortex. The synaptic changes and development of burst discharges may play an important role in synchronizing the network and promoting the development of PTE.
ContributorsNichols, Joshua (Author) / Anderson, Trent (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Newbern, Jason (Committee member) / Arizona State University (Publisher)
Created2014
Description
Cell morphology and the distribution of voltage gated ion channels play a major role in determining a neuron's firing behavior, resulting in the specific processing of spatiotemporal synaptic input patterns. Although many studies have provided insight into the computational properties arising from neuronal structure as well as from channel kinetics, no comprehensive theory exists which explains how the interaction of these features shapes neuronal excitability. In this study computational models based on the identified Drosophila motoneuron (MN) 5 are developed to investigate the role of voltage gated ion channels, the impact of their densities and the effects of structural features.
First, a spatially collapsed model is used to develop voltage gated ion channels to study the excitability of the model neuron. Changing the channel densities reproduces different in situ observed firing patterns and induces a switch from resonator to integrator properties. Second, morphologically realistic multicompartment models are studied to investigate the passive properties of MN5. The passive electrical parameters fall in a range that is commonly observed in neurons, MN5 is spatially not compact, but for the single subtrees synaptic efficacy is location independent. Further, different subtrees are electrically independent from each other. Third, a continuum approach is used to formulate a new cable theoretic model to study the output in a dendritic cable with many subtrees, both analytically and computationally. The model is validated, by comparing it to a corresponding model with discrete branches. Further, the approach is demonstrated using MN5 and used to investigate spatially distributions of voltage gated ion channels.
First, a spatially collapsed model is used to develop voltage gated ion channels to study the excitability of the model neuron. Changing the channel densities reproduces different in situ observed firing patterns and induces a switch from resonator to integrator properties. Second, morphologically realistic multicompartment models are studied to investigate the passive properties of MN5. The passive electrical parameters fall in a range that is commonly observed in neurons, MN5 is spatially not compact, but for the single subtrees synaptic efficacy is location independent. Further, different subtrees are electrically independent from each other. Third, a continuum approach is used to formulate a new cable theoretic model to study the output in a dendritic cable with many subtrees, both analytically and computationally. The model is validated, by comparing it to a corresponding model with discrete branches. Further, the approach is demonstrated using MN5 and used to investigate spatially distributions of voltage gated ion channels.
ContributorsBerger, Sandra (Author) / Crook, Sharon (Thesis advisor) / Baer, Steven (Committee member) / Hamm, Thomas (Committee member) / Smith, Brian (Committee member) / Arizona State University (Publisher)
Created2014
Description
The ability to detect and appropriately respond to chemical stimuli is important for many organisms, ranging from bacteria to multicellular animals. Responses to these stimuli can be plastic over multiple time scales. In the short-term, the synaptic strengths of neurons embedded in neural circuits can be modified and result in various forms of learning. In the long-term, the overall developmental trajectory of the olfactory network can be altered and synaptic strengths can be modified on a broad scale as a direct result of long-term (chronic) stimulus experience. Over evolutionary time the olfactory system can impose selection pressures that affect the odorants used in communication networks. On short time scales, I measured the effects of repeated alarm pheromone exposure on the colony-level defense behaviors in a social bee. I found that the responses to the alarm pheromone were plastic. This suggests that there may be mechanisms that affect individual plasticity to pheromones and regulate how these individuals act in groups to coordinate nest defense. On longer time scales, I measured the behavioral and neural affects of bees given a single chronic odor experience versus bees that had a natural, more diverse olfactory experience. The central brains of bees with a deprived odor experience responded more similarly to odorants in imaging studies, and did not develop a fully mature olfactory network. Additionally, these immature networks showed behavioral deficits when recalling odor mixture components. Over evolutionary time, signals need to engage the attention of and be easily recognized by bees. I measured responses of bees to a floral mixture and its constituent monomolecular components. I found that natural floral mixtures engage the orientation of bees’ antennae more strongly than single-component odorants and also provide more consistent central brain responses between stimulations. Together, these studies highlight the importance of olfactory experience on different scales and how the nervous system might impose pressures to select the stimuli used as signals in communication networks.
ContributorsJernigan, Christopher (Author) / Smith, Brian H. (Thesis advisor) / Newbern, Jason (Committee member) / Harrisoin, Jon (Committee member) / Rutowski, Ronald (Committee member) / Pratt, Stephen (Committee member) / Arizona State University (Publisher)
Created2018
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
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by developmental delays, intellectual disabilities, impaired language and speech, and movement defects. Most AS cases are caused by dysfunction of a maternally-expressed E3 ubiquitin ligase (UBE3A, also known as E6 associated protein, E6-AP) in neurons. Currently, the mechanism on how loss-of-function of the enzyme influences the nervous system development remains unknown. We hypothesize that impaired metabolism of proteins, most likely those related to E6-AP substrates, may alter the developmental trajectory of neuronal structures including dendrites, spines and synaptic proteins, which leads to disrupted activity/experience-dependent synaptic plasticity and maturation. To test this hypothesis, we conducted a detailed investigation on neuronal morphology and electrophysiological properties in the prefrontal cortex (PFC) layer 5 (L5) corticostriatal pyramidal neurons (target neurons). We found smaller soma size in the maternal Ube3a deficient mice (m-/p+; 'AS' mice) at postnatal 17-19 (P17-19), P28-35 and older than 70 days (>P70), and decreased basal dendritic processes at P28-35. Surprisingly, both excitatory and inhibitory miniature postsynaptic currents (mEPSCs and mIPSCs) decreased on these neurons. These neurons also exhibited abnormalities in the local neural circuits, short-term synaptic plasticity and AMPA/NMDA ratio: the excitatory inputs from L2/3 and L5A, and inhibitory inputs from L5 significantly reduced in AS mice from P17-19; Both the release probability (Pr) and readily-releasable vesicle (RRV) pool replenishment of presynaptic neurons of the target neurons were disrupted at P17-19 and P28-35, and the change of RRV pool replenishment maintained through adulthood (>P70). The AMPA/NMDA ratio showed abnormality in the L5 corticostriatal neurons of PFC in AS mice older than P28-35, during which it decreased significantly compared to that of age-matched WT littermates. Western Blot analysis revealed that the expression level of a key regulator of the cytoskeleton system, Rho family small GTPase cell division control protein 42 homolog (cdc42), reduced significantly in the PFC of AS mice at P28-35.These impairments of synaptic transmission and short-term synaptic plasticity may account for the impaired neuronal morphology and synaptic deficits observed in the PFC target neurons, and contribute to the phenotypes in AS model mice. The present work reveals for the first time that the E6-AP deficiency influences brain function in both brain region-specific and age-dependent ways, demonstrates the functional impairment at the neural circuit level, and reveals that the presynaptic mechanisms are disrupted in AS model. These novel findings shed light on our understanding of the AS pathogenesis and inform potential novel therapeutic explorations.
ContributorsLi, Guohui (Author) / Qiu, Shenfeng (Thesis advisor) / Newbern, Jason (Committee member) / Wu, Jie (Committee member) / Vu, Eric (Committee member) / Arizona State University (Publisher)
Created2017
Description
The GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common genetic abnormality associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastatingly progressive neurodegenerative diseases. The discovery of this genetic link confirmed that ALS and FTD reside along a spectrum with clinical and pathological commonalities. Historically understood as diseases resulting in neuronal death, the role of non-neuronal cells like astrocytes is still wholly unresolved. With evidence of cortical neurodegeneration leading to cognitive impairments in C9orf72-ALS/FTD, there is a need to investigate the role of cortical astrocytes in this disease spectrum. Here, a patient-derived induced pluripotent stem cell (iPSC) cortical astrocyte model was developed to investigate consequences of C9orf72-HRE pathogenic features in this cell type. Although there were no significant C9orf72-HRE pathogenic features in cortical astrocytes, transcriptomic, proteomic and phosphoproteomic profiles elucidated global disease-related phenotypes. Specifically, aberrant expression of astrocytic-synapse proteins and secreted factors were identified. SPARCL1, a pro-synaptogenic secreted astrocyte factor was found to be selectively decreased in C9orf72-ALS/FTD iPSC-cortical astrocytes. This finding was further validated in human tissue analyses, indicating that cortical astrocytes in C9orf72-ALS/FTD exhibit a reactive transformation that is characterized by a decrease in SPARCL1 expression. Considering the evidence for substantial astrogliosis and synaptic failure leading to cognitive impairments in C9orf72-ALS/FTD, these findings represent a novel understanding of how cortical astrocytes may contribute to the cortical neurodegeneration in this disease spectrum.
ContributorsBustos, Lynette (Author) / Sattler, Rita (Thesis advisor) / Newbern, Jason (Committee member) / Zarnescu, Daniela (Committee member) / Brafman, David (Committee member) / Mehta, Shwetal (Committee member) / Arizona State University (Publisher)
Created2023
Description
Serotonin 1B receptors (5-HT1BRs) are a novel target for developing pharmacological therapies to reduce psychostimulant craving. 5-HT1BRs are expressed in the mesolimbic pathway projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), which is involved in reward and motivation. 5-HT1BR agonists modulate both cocaine- and methamphetamine-seeking behaviors in rat models of psychostimulant craving. In this dissertation, I tested the central hypothesis that 5-HT1BRs regulate cocaine and methamphetamine stimulant and rewarding effects in mice. I injected mice daily with cocaine for 20 days and then tested them 20 days after their last injection. The results showed that the 5-HT1BR agonist CP94253 attenuated sensitization of cocaine-induced locomotion and cocaine-seeking behavior, measured as a decrease in the ability of a cocaine priming injection to reinstate extinguished cocaine-conditioned place preference (CPP). Subsequent experiments showed that CP94253 given prior to conditioning sessions had no effect on acquisition of methamphetamine-CPP, a measure of drug reward; however, CP94253 given prior to testing attenuated expression of methamphetamine-CPP, a measure of drug seeking. To examine brain regions and cell types involved in CP94253 attenuation of methamphetamine-seeking, I examined changes in the immediate early gene product, Fos, which is a marker of brain activity involving gene transcription changes. Mice expressing methamphetamine-CPP showed elevated Fos expression in the VTA and basolateral amygdala (BlA), and reduced Fos in the central nucleus of the amygdala (CeA). In mice showing CP94253-induced attenuation of methamphetamine-CPP expression, Fos was increased in the VTA, NAc shell and core, and the dorsal medial caudate-putamen. CP94253 also reversed the methamphetamine-conditioned decrease in Fos expression in the CeA and the increase in the BlA. In drug-naïve, non-conditioned control mice, CP94253 only increased Fos in the CeA, suggesting that the increases observed in methamphetamine-conditioned mice were due to conditioning rather than an unconditioned effect of CP94253 on Fos expression. In conclusion, 5-HT1BR stimulation attenuates both cocaine and methamphetamine seeking in mice, and that the latter effect may involve normalizing activity in the amygdala and increasing activity in the mesolimbic pathway. These findings further support the potential efficacy of 5-HT1BR agonists as pharmacological interventions for psychostimulant craving in humans.
ContributorsDer-Ghazarian, Taleen (Author) / Neisewander, Janet (Thesis advisor) / Olive, Foster (Committee member) / Newbern, Jason (Committee member) / Wu, Jie (Committee member) / Arizona State University (Publisher)
Created2018
Description
LKB1/STK11 is a serine/threonine kinase first identified in C.elegans as a gene important for cell polarity and proliferation. Mutations in LKB1 are the primary cause of Peutz-Jegher’s cancer syndrome, an autosomal dominantly inherited disease, in which patients are predisposed to benign and malignant tumors. Past studies have focused on defining LKB1 functions in various tissue types, for example LKB1 regulates axonal polarization and dendritic arborization by activating downstream substrates in excitatory neurons of the developing neocortex. However, the implications of LKB1, specifically in the developing cortical inhibitory GABAergic interneurons is unknown. LKB1 deletion was achieved by using Cre-lox technology to induce LKB1 loss in cells localized in the medial ganglionic eminence (MGE) that express Nkx2.1 and generate cortical GABAergic neurons. In this research study it is suggested that LKB1 plays a role in GABAergic interneuron specification by specifically regulating the expression of parvalbumin during the development of fast-spiking interneurons. Preliminary evidence suggest LKB1 also modulates the number of Nkx2.1-derived oligodendrocytes in the cortex. By utilizing a GABAergic neuron specific LKB1 deletion mutant, we confirmed that the loss of parvalbumin expression was due to a GABAergic neuron autonomous function for LKB1. These data provide new insight into the cell specific functions of LKB1 in the developing brain.
ContributorsSebastian, Rebecca (Author) / Newbern, Jason (Thesis advisor) / Neisewander, Janet (Committee member) / Gipson-Reichardt, Cassandra (Committee member) / Arizona State University (Publisher)
Created2019
Description
The process of brain development is magnificently complex, requiring the coordination of millions of cells and thousands of genes across space and time. It is therefore unsurprising that brain development is frequently disrupted. Numerous genetic mutations underlying altered neurodevelopment have been identified and aligned with behavioral changes. However, the cellular mechanisms linking genetics with behavior are incompletely understood. The goal of my research is to understand how intracellular kinase signaling contributes to the development of ventrally derived glia and neurons. Of particular interest are GABAergic interneurons in the cerebral cortex, as GABAergic disruption is observed in multiple neurodevelopmental disorders including epilepsy, schizophrenia, and autism spectrum disorders. In addition, I investigated how kinase signaling influences the number and distribution of ventral born oligodendrocyte lineage cells to gain insight into white matter abnormalities observed in developmental disorders. This work primarily investigates the mitogen associated protein kinase (MAPK) signaling cascade, which is ubiquitously expressed but is particularly important for brain development. Hyperactive MAPK signaling causes RASopathies, a group of neurodevelopmental disorders where affected individuals often exhibit learning disability. MAPK haploinsufficiency, such as in 16p11.2 deletion syndrome, also results in intellectual disability. In both cases, the cells driving cognitive dysfunction are unknown. Using genetically modified mouse models, I found that hyperactivation of MAPK signaling disrupts a subtype of GABAergic neurons that express parvalbumin, though the same cells are resilient to MAPK deletion. In contrast, somatostatin expressing neurons require MAPK for normal development but are less responsive to hyperactivation. Oligodendrocyte lineage cells have a bidirectional response to MAPK signaling, where hyperactivating MAPK increases cell number and deletion reduces glial number.
MAPK signaling activates several hundred downstream cues, but one of particular interest to this work is called Liver Kinase B1 (LKB1). LKB1 is a protein kinase which can regulate cell proliferation, survival, and metabolism. Here, I discovered that LKB1 is necessary for the development of parvalbumin expressing neurons. Collectively, these data identify disruption to certain ventral derivatives as a candidate pathogenic mechanism in neurodevelopmental conditions.
ContributorsKnowles, Sara Jane (Author) / Newbern, Jason (Thesis advisor) / Sattler, Rita (Committee member) / Balmer, Timothy (Committee member) / Velazquez, Ramon (Committee member) / Arizona State University (Publisher)
Created2023
Description
Adults with autism spectrum disorder (ASD) face heightened risk of co-occurring psychiatric conditions, especially depression and anxiety disorders, which contribute to seven-fold higher suicide rates than the general population. Mindfulness-based stress reduction (MBSR) is an 8-week meditation intervention centered around training continuous redirection of attention toward present moment experience, and has been shown to improve mental health in autistic adults. However, the underlying therapeutic neural mechanisms and whether behavioral and brain changes are mindfulness-specific have yet to be elucidated. In this randomized clinical trial, I utilized functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to characterize fMRI functional activity (Study 1) and connectivity (Study 2) and EEG neurophysiological (Study 3) changes between MBSR and a social support/relaxation education (SE) active control group. Study 1 revealed an MBSR-specific increase in the midcingulate cortex fMRI blood oxygen level dependent signal which was associated with reduced depression. Study 2 identified nonspecific intervention improvements in depression, anxiety, and autistic, and MBSR-specific improvements in the mindfulness trait ‘nonjudgment toward experience’ and in the executive functioning domain of working memory. MBSR-specific decreases in insula-thalamus and frontal pole-posterior cingulate functional connectivity was associated with improvements in anxiety, mindfulness traits, and working memory abilities. Both MBSR and SE groups showed decreased amygdala-sensorimotor and frontal pole-insula connectivity which correlated with reduced depression. Study 3 consisted of an EEG spectral power analysis at high-frequency brainwaves associated with default mode network (DMN) activity. Results showed MBSR-specific and nonspecific decreases in beta- and gamma-band power, with effects being generally more robust in the MBSR group; additionally, MBSR-specific decreases in posterior gamma correlated with anxiolytic effects. Collectively, these studies suggest: 1) social support is sufficient for improvements in depression, anxiety, and autistic traits; 2) MBSR provides additional benefits related to mindfulness traits and working memory; and 3) distinct and shared neural mechanisms of mindfulness training in adults with ASD, implicating the salience and default mode networks and high-frequency neurophysiology. Findings bear relevance to the development of personalized medicine approaches for psychiatric co-morbidity in ASD, provide putative targets for neurostimulation research, and warrant replication and extension using advanced multimodal imaging approaches.
ContributorsPagni, Broc (Author) / Braden, B. Blair (Thesis advisor) / Newbern, Jason (Thesis advisor) / Davis, Mary (Committee member) / Brewer, Gene (Committee member) / Arizona State University (Publisher)
Created2022