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Title: Neural mechanisms of female zebra finch mate choice : the role of the auditory perception sites, the social behavior network, and the reward system
Creator: Svec, Lace Ann
Date: 2009
Collection: Electronic Theses & Dissertations

Title: Interview of Dr. Deborah Wagenaar, professor in the Michigan State University Department of Psychiatry
Creator: Wagenaar, Deborah
Date: 2017-07-18
Collection: G. Robert Vincent Voice Library Collection
Description: Dr. Deborah Wagenaar DO, MS, professor in the Michigan State University Department of Psychiatry, talks about her career at MSU, specializing in geriatric psychiatry, and working with older adults and their multiple medical problems. Wagenaar says she was born and raised in Southeast Michigan and did her undergrad at Wayne State University. She describes the work environment in the College as "feeling like home." Wagenaar says she was initially reluctant to pursue psychiatry but it grew on...
Show moreDr. Deborah Wagenaar DO, MS, professor in the Michigan State University Department of Psychiatry, talks about her career at MSU, specializing in geriatric psychiatry, and working with older adults and their multiple medical problems. Wagenaar says she was born and raised in Southeast Michigan and did her undergrad at Wayne State University. She describes the work environment in the College as "feeling like home." Wagenaar says she was initially reluctant to pursue psychiatry but it grew on her over time. She says she has a goal of inspiring students to pursue geriatric psychiatry as a specialty and recommends exposing students to older patients early in their education. Wagenaar talks about the current state of psychiatric education and how the neurosciences are likely to change the field. She talks about some of the advances in the field for treating depression, dementia, and other maladies.
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Title: Determination of the role of ventral tegmental area SGK1 catalytic activity and phosphorylation in drug behavior
Creator: Doyle, Marie Althea
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Substance use disorder is a chronic, relapsing disease that affects 20.3 million people in the United States. Despite its prevalence, treatments remain inadequate in part due to our limited understanding of the neuroadaptations induced by drug use. Drugs of abuse are known to regulate the activity of the mesolimbic dopamine (DA) system, a key circuit for drug action and reward. Specifically, drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation have been...
Show moreSubstance use disorder is a chronic, relapsing disease that affects 20.3 million people in the United States. Despite its prevalence, treatments remain inadequate in part due to our limited understanding of the neuroadaptations induced by drug use. Drugs of abuse are known to regulate the activity of the mesolimbic dopamine (DA) system, a key circuit for drug action and reward. Specifically, drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation have been linked to behavioral outputs associated with addiction. Previous work determined that serum- and glucocorticoid-inducible kinase 1 (SGK1) mRNA expression, catalytic activity, and phosphorylation were increased by chronic administration of cocaine or morphine; however, it was unknown if these changes contributed to drug reward behaviors. In this thesis, I utilized transgenic and viral-mediated SGK1 manipulations to determine the impact of altered SGK1 expression and function on cocaine and morphine related-behaviors, primarily assessed by cocaine conditioned place preference (CPP) and voluntary morphine intake using a two-bottle choice task. I first established that that while SGK1 is transcriptionally upregulated and biochemically modified by chronic-drug administration, SGK1 deletion in either the VTA or in DA neurons was not capable of altering drug reward behaviors. Though SGK1 gene deletion did not alter reward, I next showed that viral-mediated overexpression of SGK1 mutants in the VTA of adult mice produced behaviorally relevant effects on cocaine and morphine reward. Specifically, intra-VTA infusion of a catalytically inactive SGK1 mutant (K127Q) significantly decreased cocaine CPP and morphine preference, suggesting that decreased VTA SGK1 activity is sufficient to impair drug reward. To more fully understand the role of VTA SGK1 in behaviors relevant to addiction, I manipulated SGK1 expression in a cell type-specific manner to determine whether SGK1 activity in VTA DA or GABA neurons drove the observed behavioral effects. Utilizing novel Cre-dependent viral constructs, I found that reduced SGK1 activity in VTA DA neurons significantly decreases cocaine CPP, while this same manipulation in VTA GABA neurons had no effect. Interestingly, this manipulation did not alter morphine preference. Future studies seek to determine a potential mechanism for these behavioral effects using ex vivo slice electrophysiology, and parallel studies currently explore the potential effects of a similarly regulated SGK1 phosphorylation site (Ser78) in drug-related behaviors. Altogether, these studies will allow for the identification of the specific cells and circuits that are critical for SGK1-mediated effects on drug reward and intake, a necessary step in assessing the feasibility of SGK1 inhibition as a novel therapeutic avenue for addiction.
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Title: Effects of early life stress and mast cells on brain function and behavior in the mouse and pig
Creator: Durga, Kaitlin
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Depression is a leading cause of disability worldwide, yet available treatments are ineffective for nearly half of treated patients. Depression has been linked to early life adversity and is exacerbated by stress, so uncovering how stress affects mood-related brain regions is critical to improve our understanding of depression etiology and potentially improving treatment. Depression patients often display reduced hippocampal volume, and many animal models of depression display a reduction in...
Show moreDepression is a leading cause of disability worldwide, yet available treatments are ineffective for nearly half of treated patients. Depression has been linked to early life adversity and is exacerbated by stress, so uncovering how stress affects mood-related brain regions is critical to improve our understanding of depression etiology and potentially improving treatment. Depression patients often display reduced hippocampal volume, and many animal models of depression display a reduction in hippocampal neurogenesis that is reversed by chronic exposure to antidepressants. Using a pig and mouse model, we were able to examine the effects of early life adversity on adult neurogenesis, and mast cell FosB on behaviors respectively. Our examination of female, castrated male, and intact male pigs, who underwent either early weaning or late weaning allowed us to see not only the effects of early life adversity, but any possible sex-specific effects as well. We found that early weaned female pigs expressed a significantly reduced number of new neurons in their hippocampi compared to their late weaned counterparts. Using a transgenic mouse model which had FosB floxed out of all mast cells, we observed the behavioral outcomes in various assays, including social interaction, elevated plus maze, and sucrose preference. We found that male mice homozygous for the mutation had a significantly increased preference for sucrose compared to the wildtype mice.
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Title: Deep brain stimulation of the subthalamic nucleus increases brain-derived neurotrophic factor in the context of synucleinopathy
Creator: Miller, Kathryn M.
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Parkinson’s disease (PD) is the second most common neurodegenerative disorder behind Alzheimer’s disease, and is a major burden to society. PD is a progressive disorder resulting in a variety of symptoms including dementia, autonomic, and motor dysfunction; all contributing to a diminished quality of life for afflicted individuals. Current treatments help to restore motor function, however there are no disease-modifying treatments that halt or slow the progression of PD. The question of...
Show moreParkinson’s disease (PD) is the second most common neurodegenerative disorder behind Alzheimer’s disease, and is a major burden to society. PD is a progressive disorder resulting in a variety of symptoms including dementia, autonomic, and motor dysfunction; all contributing to a diminished quality of life for afflicted individuals. Current treatments help to restore motor function, however there are no disease-modifying treatments that halt or slow the progression of PD. The question of whether deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be disease-modifying in PD remains unanswered. Preclinical studies link STN DBS-mediated neuroprotection of nigrostriatal dopamine neurons to brain-derived neurotrophic factor (BDNF) signaling. However, the impact of STN DBS on α-synuclein (α-syn) aggregation, inclusion-associated neuroinflammation, and BDNF levels have yet to be examined in the context of synucleinopathy.In this dissertation I examine the effects of STN DBS on BDNF in the preformed fibril synucleinopathy model. PFF injection resulted in accumulation of phosphorylated α-syn (pSyn) inclusions in the substantia nigra pars compacta (SNpc) and cortical areas. SNpc pSyn inclusions were associated with significantly increased major histocompatibility complex-II immunoreactive (MHC-II-ir) microglia, and intensity, complexity, and length of astrocytes. Rats with pSyn inclusions had less tyrosine hydroxylase (THir) SNpc neurons (≈18-33% decrease) reflecting loss of TH phenotype. STN DBS did not alter any of these pSyn inclusion-associated effects, and also did not impact the size or intensity of individual pSyn inclusions within the SNpc. The presence of pSyn inclusions did not alter total levels of BDNF protein in any of the structures evaluated. However, the normally positive association between nigrostriatal and corticostriatal BDNF levels was negatively impacted in PFF treated rats. Despite this, rats receiving both PFF injection and STN DBS exhibited significantly increased BDNF protein in the striatum, which partially restored the normal corticostriatal BDNF relationship.The rat α-syn PFF model provides a relevant preclinical platform to examine the impact of STN DBS on multiple potentially disease-modifying factors. Our results demonstrate that pSyn inclusions may alter anterograde BDNF transport. However, STN DBS retains the ability to increase BDNF within the context of synucleinopathy. Future studies will examine whether long-term STN DBS can prevent the nigrostriatal degeneration associated with longer post PFF injection intervals.
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Title: The oxytocin receptor in vascular dementia
Creator: McKay, Erin
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Cognitive impairment following a stroke, known as vascular dementia (VaD), is a common outcome often overlooked in lieu of the motor and verbal impairments. Nonetheless, the executive and memory deficits in VaD can be drastically impairing. A successful treatment or intervention could improve the quality of life for millions of patients. Two aims were pursued in service of this goal. The first aim was to compare the gene expression profiles of frontal cortex tissue from diagnosed cases of VaD...
Show moreCognitive impairment following a stroke, known as vascular dementia (VaD), is a common outcome often overlooked in lieu of the motor and verbal impairments. Nonetheless, the executive and memory deficits in VaD can be drastically impairing. A successful treatment or intervention could improve the quality of life for millions of patients. Two aims were pursued in service of this goal. The first aim was to compare the gene expression profiles of frontal cortex tissue from diagnosed cases of VaD, intermediate Alzheimer's disease (AD), and no cognitive impairment. Gene expression products that were differentially expressed in VaD cases versus AD and controls were to be investigated for biological significance and therapeutic potential. Further validation studies were also used to identify targets worth pursuing further. The oxytocin receptor (OXTR) was identified as differentially upregulated in the frontal cortex in cases of VaD, and localization to astrocytes surrounding areas of infarction was noted. The second aim was designed to test the therapeutic potential of the OXTR in an animal model of VaD. Administration of the potent vasoconstrictor endothelin-1 (ET-1) into the prefrontal cortex of spontaneous hypertensive stroke prone rats (SHRSP) was used to create a model of focal stroke with a pre-morbidity leading to cognitive deficits without obstructing motor deficits. A pre-injury intervention of an adeno-associated virus expressing either the OXTR or green fluorescent protein (GFP) linked with the astrocytic promoter glial fibrillary acidic protein (GFAP) was applied. The animals were then subjected to a battery of cognitive tests to confirm deficits induced by the ischemic lesion and assess potential rescue by the pre-upregulation of the OXTR in astrocytes. OXTR upregulation improved performance in the novel object task compared to control, suggesting a rescue of working memory function that is mediated by the prefrontal cortex. Tissue processing assessed infarct size, white matter density, and viral expression, which showed no difference in white matter density but a reduction in the size of the infarct by the pre-upregulation of the receptor in the perimeter of the targeted prefrontal cortex site. An additional sub-aim of aim two was devised to compare the effects on known molecular participants in the pathway of ischemic injury within animals expressing ectopic OXTR or GFP in separate hemispheres to ET-1 or saline treated animals. At the 24 hour time point chosen, no difference was observed in either reactive oxygen species generation or the profiles of cytokines implicated in the course of ischemic injury. The results from the human tissue studies in aim one suggest that a specific peri-infarct specific upregulation of the OXTR on astrocytes is a hallmark of ischemic VaD. Rescue studies in a rat model in aim two suggest that this upregulation may be a compensatory response acting to salvage penumbra tissue and reduce the ensuing behavioral deficits. However, the specific mechanism remains undefined at this time. Further preclinical mechanistic studies are needed, particularly at different time points, to more rigorously evaluate the relative efficacy of targeting the OXTR as an intervention for VaD.
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Title: Early Axonal Tau Pathology in the Human Hippocampus and the Molecular Consequences of AT8 Tau Phosphorylation
Creator: Christensen, Kyle Robert
Date: 2018
Collection: Electronic Theses & Dissertations
Description: Tau is a microtubule-associated protein that is classically thought to play a role in stabilizing microtubules and the pathological accumulation of tau protein is a hallmark of several diseases collectively known as tauopathies, including Alzheimer’s disease (AD). Despite the clear implications for tau playing a critical role in tauopathies, many questions regarding its deposition in disease and mechanisms of toxicity remain unanswered. This dissertation was aimed at addressing two key...
Show moreTau is a microtubule-associated protein that is classically thought to play a role in stabilizing microtubules and the pathological accumulation of tau protein is a hallmark of several diseases collectively known as tauopathies, including Alzheimer’s disease (AD). Despite the clear implications for tau playing a critical role in tauopathies, many questions regarding its deposition in disease and mechanisms of toxicity remain unanswered. This dissertation was aimed at addressing two key questions in the field. 1) Does tau deposition occur first in the axons of affected neurons before proceeding to the somatodendritic compartment? 2) Does pathological modification of tau cause abnormalities in the ability of tau to modulate protein phosphatase 1 (PP1)? A long-held hypothesis on the progressive deposition of tau pathology in AD is that pathological tau accumulates first in axons of neurons and then progresses back into the cell bodies to form neurofibrillary tangles, however, studies have not directly analyzed this relationship in human tissue. In the early phases of tau deposition, both AT8 phosphorylation and exposure of the amino terminus of tau occur in tauopathies, and these modifications are linked to mechanisms of synaptic and axonal dysfunction. Here, the hippocampus of 44 well-characterized human samples from cases ranging between non-demented and mild cognitively impaired were examined for AT8 phosphorylation, amino terminus exposure, and amyloid- (Aβ) pathology in the axons and neuronal cell bodies within strata containing the CA3-Schaffer collateral and dentate granule-mossy fiber pathways. We show that tau pathology first appears in the axonal compartment of affected neurons in the absence of observable tau pathology in the corresponding cell bodies and independent of the presence of Aβ pathologies. Using the axonal marker, SMI-312, we confirmed that the majority of tau pathology-positive neuropil threads were axonal in origin. These results support the hypothesis that AT8 phosphorylation and PAD exposure are early pathological events and that the deposition of tau pathology occurs first in the axonal compartment prior to observable pathology in the cell bodies of affected neuronal pathways. The functional implications of AT8 and PAD-exposed tau deposition early in the axons of affected neurons is important because of a recently identified mechanism where these pathogenic forms of tau activate a PP1-dependent signaling pathway and lead to disruption of axonal functions. However, the connection between tau and PP1 was not defined. Here, we performed detailed studies on the interaction between tau and PP1 and subsequent effects on PP1 activity. Wild-type tau interacts with and activates PP1α and γ, but shows little to no interaction with PP1β, and this effect depends primarily on the microtubule binding repeats in tau. Additionally, AT8 tau increased the interactions with and activity of PP1γ, while deletion of PAD in the presence of AT8 reduced this interaction. These results suggest that tau’s function likely extends beyond stabilizing microtubules to include regulation of PP1 signaling cascades, and disease-associated tau phosphorylation may alter this function. Collectively, this work suggests forms of pathological tau, such as AT8 phospho-tau, that alter PP1 signaling and disrupt axonal function deposit in the axons of affected hippocampal neurons early during disease pathogenesis and prior to their appearance in the somatodendritic compartment of neurons.
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Title: Masking : the acute effects of light on the brain and behavior
Creator: Shuboni, Dorela Doris
Date: 2013
Collection: Electronic Theses & Dissertations
Description: Masking of behavior by external stimuli works with the circadian system to ensure that animals are active during the correct time-of-day. Light for diurnal and nocturnal species produces different masking responses, enhancing activity for diurnal species and suppressing activity for nocturnal species. Few studies have examined the neural mechanisms of masking; none these experiments use animals active during the day. The first experiment of this dissertation uses the protein of the immediate...
Show moreMasking of behavior by external stimuli works with the circadian system to ensure that animals are active during the correct time-of-day. Light for diurnal and nocturnal species produces different masking responses, enhancing activity for diurnal species and suppressing activity for nocturnal species. Few studies have examined the neural mechanisms of masking; none these experiments use animals active during the day. The first experiment of this dissertation uses the protein of the immediate-early gene cFOS to compare activation of brain regions to light between nocturnal mice and diurnal grass rats during a time-point where they showed a distinct behavioral dichotomy in response. Grass rats showed a consistent increase in activation in areas that receive retinal innervation or were related to sleep/arousal, while mice showed either no difference or a decrease in activation with the exception of the SCN. This study demonstrates the differences in behavioral and neurological responses to masking pulse of light between a nocturnal and diurnal rodent species.We next examined the functional role of the ventral subparaventricular zone (vSPZ) on masking to light in the grass rat. The vSPZ uniquely responded to light in diurnal grass rats, receives direct retinal innervation from the eye and after ablation showed a possible alteration in masking. Schwartz et al. (2009)showed that grass rats with damage to the vSPZ had bouts of arrhythmia in LD conditions, indicating that the masking system may be altered. In Chapter 3, we tested the functional for of the region by bilateral lesioning the vSPZ and directly testing the effects of light on masking. Animals with complete ablations still increased activity in response to light in two different masking protocols. In Chapter 4, we examined another brain structure that could have played a role in masking, the pineal gland. Melatonin is a hormone produced by the pineal gland that plays a role in circadian rhythms and seasonality. The expression of melatonin is sensitive to light exposure, additionally, the presence of the hormone also feedbacks and influences the effects of light on the brain. Additionally, pinealectomy in rats alters the behavior profile of activity in LD conditions. Removal of the pineal gland in the grass rats did not influence the ability of animals to mask to light or the animal's circadian rhythm of activity.In summary, the work presented in this dissertation demonstrates the immediately impact of light on behavior and the possible brain regions that may play a functional role in the masking response. We established that two neural structures when ablated or removed do not impact the grass rat's ability to respond to light with an increase in activity. Here we broaden the scope of research into the neural mechanisms of masking to include a diurnal species, beginning the journey toward understanding the neural changes needed for a species to transition between temporal niches.
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Title: Pathology at the neuromuscular junction in mouse models of spinal bulbar muscular atrophy
Creator: Poort, Jessica Erin
Date: 2014
Collection: Electronic Theses & Dissertations
Description: Spinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease that results in muscle weakness and atrophy, as well as motoneuron death in men. While pathology at the neuromuscular junction (NMJ) is noted in numerous neurodegenerative diseases, disease-related changes at the NMJ in SBMA have not been explored. Characterizing such changes is not only important for determining whether the NMJ has any role in the functional changes underlying motor dysfunction, but also...
Show moreSpinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease that results in muscle weakness and atrophy, as well as motoneuron death in men. While pathology at the neuromuscular junction (NMJ) is noted in numerous neurodegenerative diseases, disease-related changes at the NMJ in SBMA have not been explored. Characterizing such changes is not only important for determining whether the NMJ has any role in the functional changes underlying motor dysfunction, but also in determining how such potential pathology at the NMJ develops as disease progresses. If for example, pathology emerges first at the NMJ followed by motoneuron death, then the NMJ offers future promise as a therapeutic target for preventing or reversing symptoms of SBMA before motoneurons are lost. We evaluated three different mouse models of SBMA, one overexpressing a wildtype androgen receptor (AR) exclusively in muscle fibers (so called "myogenic" model), a second which expressed the endogenous AR gene with the first exon of the human mutant AR gene "knocked in" (the so called "knock-in" model), and a final model that broadly expresses a full length human AR transgene harboring the SBMA mutation (the so called "97Q" model). Using both confocal microscopy and electron microscopy, I found that all three mouse models show a pathological fragmentation of the NMJ suggestive of functionally weakened synapses. Other changes at the neuromuscular synapse suggesting decreases in synaptic strength that were found in some but not all models include a decline in the number of docked vesicles ready for release in nerve terminals, a widening of synaptic clefts, simplified postsynaptic folds, and an abnormal accumulation of synaptic vesicle and neurofilament proteins. Retrograde axonal transport of endosomes was also characterized in the 97Q model using live imaging confocal microscopy. Despite previously published data, I found no evidence for a disease-related defect in retrograde transport in the 97Q model. The strikingly abnormal morphology of NMJs in all three models raises the possibility that synaptic function is impaired. Such synaptic dysfunction may contribute to or underlie the impairments in motor function associated with SBMA.
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Title: Directed information for complex network analysis from multivariate time series
Creator: Liu, Ying
Date: 2012
Collection: Electronic Theses & Dissertations
Description: Complex networks, ranging from gene regulatory networks in biology to social networks in sociology, havereceived growing attention from the scientific community. The analysis of complex networks employs techniquesfrom graph theory, machine learning and signal processing. In recent years, complex network analysis tools havebeen applied to neuroscience and neuroimaging studies to have a better understanding of the human brain. In thisthesis, we focus on inferring and analyzing the complex...
Show moreComplex networks, ranging from gene regulatory networks in biology to social networks in sociology, havereceived growing attention from the scientific community. The analysis of complex networks employs techniquesfrom graph theory, machine learning and signal processing. In recent years, complex network analysis tools havebeen applied to neuroscience and neuroimaging studies to have a better understanding of the human brain. In thisthesis, we focus on inferring and analyzing the complex functional brain networks underlying multichannelelectroencephalogram (EEG) recordings. Understanding this complex network requires the development of a measureto quantify the relationship between multivariate time series, algorithms to reconstruct the network based on thepairwise relationships, and identification of functional modules within the network.Functional and effective connectivity are two widely studiedapproaches to quantify the connectivity between two recordings.Unlike functional connectivity which only quantifies the statisticaldependencies between two processes by measures such as crosscorrelation, phase synchrony, and mutual information (MI), effectiveconnectivity quantifies the influence one node exerts on anothernode. Directed information (DI) measure is one of the approachesthat has been recently proposed to capture the causal relationshipsbetween two time series. Two major challenges remain with theapplication of DI to multivariate data, which include thecomputational complexity of computing DI with increasing signallength and the accuracy of estimation from limited realizations ofthe data. Expressions that can simplify the computation of theoriginal definition of DI while still quantifying the causalityrelationship are needed. In addition, the advantage of DI overconventionally causality measures such as Granger causality has notbeen fully investigated. In this thesis, we propose time-laggeddirected information and modified directed information to addressthe issue of computational complexity, and compare the performanceof this model free measure with model based measures (e.g. Grangercausality) for different realistic signal models.Once the pairwise DI between two random processes is computed,another problem is to infer the underlying structure of the complexnetwork with minimal false positive detection. We propose to useconditional directed information (CDI) proposed by Kramer to addressthis issue, and introduce the time-lagged conditional directedinformation and modified conditional directed information to lowerthe computational complexity of CDI. Three network inferencealgorithms are presented to infer directed acyclic networks whichcan quantify the causality and also detect the indirect couplingssimultaneously from multivariate data.One last challenge in the study of complex networks, specifically in neuroscience applications, is to identifythe functional modules from multichannel, multiple subject recordings. Most research on community detection inthis area so far has focused on finding the association matrix based on functional connectivity, instead ofeffective connectivity, thus not capturing the causality in the network. In addition, in order to find a modularstructure that best describes all of the subjects in a group, a group analysis strategy is needed. In thisthesis, we propose a multi-subject hierarchical community detection algorithm suitable for a group of weightedand asymmetric (directed) networks representing effective connectivity, and apply the algorithm to multichannelelectroencephalogram (EEG) data.
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Title: Altered Metabotropic Glutamate Receptor Function in the Neocortex of a Fragile X Mouse
Creator: Fenn, Jacqueline Ann
Date: 2017
Collection: Electronic Theses & Dissertations
Description: Fragile X Syndrome (FXS) is the leading cause of inherited intellectual disability. It is characterized by a wide array of symptoms, including cognitive impairments, attention deficit and hyperactivity disorder (ADHD), hypersensitivity to sensory stimuli, autistic features, mood lability, and seizures. Since the creation of the Fmr1 KO mouse more than 20 years ago, a wealth of studies have uncovered a role for group I metabotropic glutamate receptors (mGluRs) in mediating many FXS phenotypes,...
Show moreFragile X Syndrome (FXS) is the leading cause of inherited intellectual disability. It is characterized by a wide array of symptoms, including cognitive impairments, attention deficit and hyperactivity disorder (ADHD), hypersensitivity to sensory stimuli, autistic features, mood lability, and seizures. Since the creation of the Fmr1 KO mouse more than 20 years ago, a wealth of studies have uncovered a role for group I metabotropic glutamate receptors (mGluRs) in mediating many FXS phenotypes, leading to development of "The mGluR Theory of Fragile X". However, studies supporting this theory have focused on impairments in the hippocampus, amygdala, and other structures of the allocortex. The isocortex remains largely uninvestigated, despite its major role in sensory integration, attentional processes, and executive function. MgluRs are also highly expressed in the neocortex, where they can modulate neuronal excitability and synaptic transmission. Using electrophysiological methods, I investigated the role of group I and group II mGluRs in modulating neocortical circuits in primary visual cortex. Humans with FXS show severe visual-motor deficits, and perform poorly on global motion tasks. Autopsy studies also reveal abnormal dendritic spine morphologies in layer 5/6 of the visual neocortex, and this is substantiated in the Fmr1 KO mouse. Using whole cell patch clamp recordings of different neuron subtypes in layer 5/6 of primary visual cortex, I found that Fmr1 KO layer 5/6 somatostatin expressing neurons (SST+) have a significant decrease in input resistance compared to wild type (WT), indicating that they are less intrinsically excitable than WT SST+ neurons. Further, I show that activation of group II mGluRs leads to disinhibition of excitatory pyramidal neurons. I also discover that suppression of GABAergic transmission by group II mGluRs is normal in the Fmr1 KO, leading to my hypothesis that increased disinhibition of pyramidal neurons by group II mGluRs is due to their altered modulation of fast glutamatergic transmission onto layer 5/6 interneurons in the Fmr1 KO mouse. Using recordings from fluorescently labeled interneurons in layer 5/6 visual neocortex, I discover that group II mGluR-mediated suppression of fast excitatory glutamatergic transmission onto inhibitory neurons is exaggerated in the Fmr1 KO mouse. I show that this effect is cell specific, as it only occurs in SST+ interneurons and not parvalbumin expressing interneurons. Finally, I show that this deficit in excitatory drive onto SST+ interneurons is mediated by presynaptic mGluRs, and that these defects are specific to layer 5/6 visual neocortex. Both the decreased excitability of SST+ interneurons and exaggerated group II-mGluR mediated suppression of excitatory drive onto these cells would lead to neocortical circuit hyperexcitability in the Fmr1 KO mouse. A hyperexcitable neocortical circuit would be anticipated to negatively impact sensory integration, a requirement for both stimulus encoding and attentional processes. Lastly, a hyperexcitable neocortical network could give rise to epileptiform activity. The results of these studies are fascinating, as group II mGluRs have not previously been implicated in studies of the neocortical pathogenesis in the Fmr1 KO mouse. This investigation also showed that group I mGluR-mediated modulation of membrane excitability and fast synaptic transmission is unaltered in the Fmr1 KO mouse, suggesting that "The mGluR theory of Fragile X" may in fact be more or less valid contingent on the brain region under investigation. It is my hope that these circuit studies will inform scientific investigations on autism spectrum disorders and epilepsy syndromes, as both show high comorbidity in individuals with FXS.
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Title: The role of parkin in the recovery of central dopamine neurons from acute neurotoxicant exposure
Creator: Benskey, Matthew John
Date: 2013
Collection: Electronic Theses & Dissertations
Description: Parkinson Disease (PD) pathology is associated with the selective degeneration of nigrostriatal dopamine (NSDA) neurons, while the tuberoinfundibular DA (TIDA) neurons of the hypothalamus remain intact. The same pattern of selective degeneration has been observed following exposure to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyradine (MPTP), a mitochondrial complex I inhibitor which recapitulates many of the molecular pathologies associated with PD. The purpose of this dissertation is to...
Show moreParkinson Disease (PD) pathology is associated with the selective degeneration of nigrostriatal dopamine (NSDA) neurons, while the tuberoinfundibular DA (TIDA) neurons of the hypothalamus remain intact. The same pattern of selective degeneration has been observed following exposure to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyradine (MPTP), a mitochondrial complex I inhibitor which recapitulates many of the molecular pathologies associated with PD. The purpose of this dissertation is to identify early molecular events that underlie TIDA neuron recovery from toxicant exposure and adapt these mechanisms in an attempt to rescue NSDA neurons from toxicity. NSDA neurons show loss of axon terminal DA concentrations following acute (20mg/kg; s.c.) and chronic (10 x 20mg/kg; s.c. over 35 days) MPTP administration and exhibit cell death following chronic MPTP administration. In contrast, TIDA neurons show no loss of axon terminal DA concentrations or cell death following acute or chronic MPTP exposure. The recovery of TIDA neurons is independent of extrinsic factors such as decreased toxicant exposure or hormonal activation. TIDA neuron recovery is associated with an increase in the PD-associated proteins, parkin and ubiquitin carboxy-terminal hydrolase L-1 (UCHL-1) within the arcuate nucleus (ARC) 24 h following MPTP. Additionally, parkin protein concentrations remain elevated in the ARC for up to 22 days following chronic MPTP administration. In contrast, the susceptibility of NSDA neurons is associated with decreased expression of both parkin and UCH-L1. The high correlation between the presence of the parkin protein and the recovery of DA neurons from MPTP toxicity is consistent with a role of parkin in DA neuron survival. In order to determine if parkin is necessary and sufficient in the recovery of TIDA neurons following MPTP, recombinant adeno-associated viral (rAAV) vectors containing parkin shRNA or a scrambled shRNA were created. Mice received stereotaxic ARC injections of rAAV containing either parkin shRNA or scrambled shRNA (250nl/side; 3.5x1013vg/ml), or remained naïve to surgery, and were administered a single injection of MPTP (20mg/kg; s.c.) 30 days following rAAV surgery. Twenty-four h post-MPTP, TIDA neurons were able to recover axon terminal DA concentrations following MPTP in control and scrambled shRNA treated animals. However, axon terminal DA was significantly reduced 24 hr following MPTP exposure following knockdown of parkin in TIDA neurons. To determine if parkin overexpression would protect NSDA neurons from MPTP toxicity, mice received unilateral stereotaxic injection of rAAV containing parkin into the substantia nigra (SN) (500nl; 3.4x1013vg/ml) and were administered a single injection of MPTP (20mg/kg; s.c.) 30 days following rAAV surgery. Twenty-four hours post-MPTP, parkin overexpression was unable to rescue MPTP-induced loss of DA in the striatum (ST), but did rescue MPTP-induced loss of tyrosine hydroxylase (TH) in the SN and ST. These findings are consistent with the following conclusions: 1) TIDA neuronal recovery from acute MPTP exposure is independent of extrinsic factors and is mediated by an intrinsic ability to increase expression of neuroprotective proteins, 2) The ability of TIDA neurons to up-regulate parkin is at least partially responsible for recovery of axon terminal DA following MPTP, 3) toxicant-induced loss of parkin contributes to MPTP toxicity within NSDA neurons.
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Title: Sexual dimorphisms and androgen influence in medial posterodorsal amygdala astrocytes
Creator: Johnson, Ryan T.
Date: 2011
Collection: Electronic Theses & Dissertations
Description: The amygdala is a highly interconnected brain region involved in fear, anxiety, social and reproductive behaviors. In humans and laboratory species the amygdala exhibits sexual dimorphisms in neuroanatomy and function both in juveniles and adults. In rodents, the medial posterodorsal amygdala (MePD) is particularly sexually dimorphic and gonadal hormone sensitive, and while neurons have been examined in this region, few reports have examined the potential influence of gonadal hormones on...
Show moreThe amygdala is a highly interconnected brain region involved in fear, anxiety, social and reproductive behaviors. In humans and laboratory species the amygdala exhibits sexual dimorphisms in neuroanatomy and function both in juveniles and adults. In rodents, the medial posterodorsal amygdala (MePD) is particularly sexually dimorphic and gonadal hormone sensitive, and while neurons have been examined in this region, few reports have examined the potential influence of gonadal hormones on other cellular components of the MePD. Astrocytes are a subtype of glia involved in synapse formation and known to be plastic and dynamic cells sensitive to gonadal hormone influence in several brain regions. My dissertation reveals sexual dimorphisms in the number of astrocytes in the juvenile rat MePD and that this sexual dimorphism remains present in adult animals. I also found sex differences in the arbor complexity of astrocytes in adults that are not present prior to puberty. Astrocytes also respond to changes in circulating hormone levels in adulthood. Furthermore, while the sex difference in astrocyte numbers in juvenile animals is androgen receptor-independent, the sex differences found in adult astrocyte numbers and arbor complexity are both androgen receptor-dependent. Finally, I provide evidence that astrocytes in the MePD contain androgen receptors, suggesting that androgens may act directly on these cells. The influence of gonadal hormones on astrocytes in the MePD is likely an important part of pubertal development and has implications for our understanding of the cellular organization of the amygdala and its function.
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Title: ENTERIC GLIAL MODULATION OF IMMUNE ACTIVATION DURING INFLAMMATORY STRESS
Creator: Chow, Aaron Kin Yeung
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Gastrointestinal (GI) disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome, and other functional GI disorders are major health concerns and account for about $26.4 billion in yearly costs in the United States alone. Many of these GI disorders manifest symptoms such as GI dysmotility, intestinal secretion and absorption dysfunction, and abdominal pain. Inflammation plays a major role in the pathogenesis of these diseases, and current therapies for many GI disorders aim...
Show moreGastrointestinal (GI) disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome, and other functional GI disorders are major health concerns and account for about $26.4 billion in yearly costs in the United States alone. Many of these GI disorders manifest symptoms such as GI dysmotility, intestinal secretion and absorption dysfunction, and abdominal pain. Inflammation plays a major role in the pathogenesis of these diseases, and current therapies for many GI disorders aim to regulate the activation and progression of the inflammatory cascade. However, due to a gap in knowledge in how the immune system is regulated within the GI tract, there remains a lack of effective treatments for these common GI disorders. Interactions between the nervous system and immune system point to neurons having important roles in immune modulation, but the mechanisms of neuro-immune regulation in the gut is not completely understood.The enteric nervous system (ENS) consists of enteric neurons and enteric glia arranged in plexuses embedded in the gut wall. This neural network is responsible for the normal secretomotor functioning of the GI tract, and the disruption of the ENS network alters GI functioning and underlies pathological GI symptoms. As part of the ENS, enteric glia work in tandem with enteric neurons to coordinate GI functions. In addition to their contributions to maintain normal secretomotor functioning of the GI tract, enteric glia are activated by immunomodulatory signals, they can secrete and respond to cytokines, can exert immunosuppressive effects, and share characteristics with antigen presenting cells. Therefore, we hypothesize that enteric glia play an active role in immune regulation in the ENS. In this dissertation, we specifically examine the role enteric glial cells play as an antigen presenting cell to regulate immune activation. Our results show that enteric glia have the machinery necessary to act as an antigen presenting cell and can express major histocompatibility complex (MHC) type II molecules during inflammatory stress to interact with T-lymphocytes. Enteric glial MHC II expression has functional relevance, as it modulates the activation in Th17 and Treg subtypes, but not Th1 or Th2 T-lymphocyte subtypes. Although MHC II molecules are typically associated with the expression of phagocytosed extracellular antigens, our results show that enteric glia do not readily phagocytose extracellular antigens. Instead, MHC II expression in enteric glia is mediated by autophagy. The activation of autophagic pathways is necessary, but not sufficient in eliciting enteric glial MHC II expression. Finally, although enteric glia regulate T-lymphocyte activation, cytokine levels at the whole organism or regional tissue levels remain unchanged, suggesting that enteric glial cytokine effects primarily operate at the local microenvironment level. Our findings provide support for enteric glial cells having an active role as an immunomodulator. Specifically, we show that enteric glia modulate T-lymphocyte activation via autophagy-mediated MHC II expression and propose a novel mechanism of neuro-immune modulation in the gut.
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Title: BIOMATERIAL AND GENETIC TOOLS TO INFLUENCE NEURONAL NETWORK FORMATION, EXCITABILITY, AND MATURITY AT THE ELECTRODE INTERFACE
Creator: Setien-Grafals, Monica B.
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Understanding brain function remains a grand challenge of our time. Likewise, when neurodegeneration occurs, repair efforts are limited due to the highly heterogeneous and interconnected nature of the cerebral cortex. The drive to better understand normal brain function and pathological states has intensified demand for new technologies which can interrogate the nervous system with enhanced spatiotemporal resolution. Implanted brain electrodes are being used and developed to provide a deeper...
Show moreUnderstanding brain function remains a grand challenge of our time. Likewise, when neurodegeneration occurs, repair efforts are limited due to the highly heterogeneous and interconnected nature of the cerebral cortex. The drive to better understand normal brain function and pathological states has intensified demand for new technologies which can interrogate the nervous system with enhanced spatiotemporal resolution. Implanted brain electrodes are being used and developed to provide a deeper understanding for neurological injury and neurodegeneration. However, issues with biological integration come into play and potentially interfere with signal stability over time. Here, this work provides innovative tools that can be used to interface and control the tissue-electrode interface. In particular, we are interested in exploring surface chemistries, genetic tools, and electrode materials which favor neural regeneration around implanted electrodes. The research presented in this dissertation describes the exploration of biomaterial and genetic tools for interfacing the tissue-electrode interface: (1) characterization of surface chemistries presented to differentiating neural progenitors, and an understanding of the conditions which promote neurite outgrowth and electrophysiological maturation, (2) a blue-light inducible gene expression system, which could potentially be used to control gene expression at the implanted electrode interface, and (3) testing the impacts of “next-generation” electrode materials, such as diamond, as candidates for neural interfacing. Chapter 2 uncovers the study of various common substrates and their effects on rat neural progenitor cells, which can be used to create unique morphologies. Chapter 3 explores the use of an optogenetic system from a bacterial transcription factor (EL222) that allows for blue light-dependent transcriptional activation. Here, we validated the use of EL222 for spatial patterning of fluorescent reporter genes and developed stable expression in HEK293 cells, which can be used long-term for developing approaches for light-driven regeneration of neural circuitry. Chapter 4 reveals material and genetic factors that can affect cell structure and function. Here, we report the results of an initial characterization of the biocompatibility of the novel diamond-based materials, including conductive boron-doped polycrystalline diamond (BDD) and insulating polycrystalline diamond (PCD). The results presented will inform the transfer of the novel diamond substrate materials to sensing applications in the in vivo environment, where we expect to leverage the positive performance characteristics of the diamond materials displayed in vitro. Taken together, these chapters offer significant development of material and biological tools and that will help manage and mitigate challenges presented at the tissue-electrode interface. Future directions aim at exploring synergistic effects of electrode material and optogenetic control for controlling excitability and identity of cells at the interface, effectively bridging the divide between electronics and tissue.
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Title: MIND-BODY STATE LITERACY : A PEDAGOGICAL APPROACH THAT USES MINDFULNESS AND BRAIN LITERACY TO SUPPORT LEARNING AND RELATIONAL NARRATIVE WORK
Creator: Schaefer, Erin Elizabeth
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Mind-Body State Literacy: A Pedagogical Approach that uses Mindfulness and Neuroscience to Support Learning and Relational Narrative Work describes the literacies necessary to develop the habits of minds presented in the Framework for Success in Postsecondary Writing: “curiosity, openness, engagement, creativity, persistence, responsibility, flexibility and metacognition” (WPA, NCTE, & NWP, 2011, par. 2). Such habits, because they deal with students’ openness in the learning process, are key...
Show moreMind-Body State Literacy: A Pedagogical Approach that uses Mindfulness and Neuroscience to Support Learning and Relational Narrative Work describes the literacies necessary to develop the habits of minds presented in the Framework for Success in Postsecondary Writing: “curiosity, openness, engagement, creativity, persistence, responsibility, flexibility and metacognition” (WPA, NCTE, & NWP, 2011, par. 2). Such habits, because they deal with students’ openness in the learning process, are key to students’ ability to receive a liberal education. I suggest that before instructors or students can develop these habits, they need to learn to develop an open mind-body state, defined as the ability to let one’s narrative incorporate other narratives/perspectives through listening. The Mind-Body State model is comprised of three facets: brainwaves, narratives, and emotions. The Mind-Body State Literacy (MBSL) approach suggests that students develop literacies related to these three facets, drawing primarily from mindfulness practices and philosophies the center the body and compassion. I anchor my presentation of the MBSL by suggesting why it might be especially relevant as students engage in personal narrative writing in the Rhetoric and Writing classroom.
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