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Title
AGGRESSION AND THE GUT-BRAIN AXIS
Creator
Kwiatkowski, Christine Carole
Date
2022
Collection
Electronic Theses & Dissertations
Description
Violence is a widespread public health and justice system problem with far-reaching consequences for victims, offenders, and their communities. Aggression, the cognitive and behavioral antecedent to violent action, is mainly understood in terms of the psychosocial risk factors that increase the likelihood of aggressive behavioral strategies. Neighborhood context is a principal risk factor for violent crime perpetration, but the mechanisms that mediate the effect of the environment on...
Show moreViolence is a widespread public health and justice system problem with far-reaching consequences for victims, offenders, and their communities. Aggression, the cognitive and behavioral antecedent to violent action, is mainly understood in terms of the psychosocial risk factors that increase the likelihood of aggressive behavioral strategies. Neighborhood context is a principal risk factor for violent crime perpetration, but the mechanisms that mediate the effect of the environment on individual-level aggression behavior are poorly understood, especially the biological factors that may contribute to our understanding of violent behavior. In order to gain a better understanding of mechanisms that precipitate violence in specific geographic contexts, this dissertation explores the relationship between aggression behavior and the gut microbiome, a spatially determined physiological system that affects human health and behavior. Preclinical experiments elucidate the role of the gut microbiome in territorial, reactive aggression behavior in mice. Results show significant differences in gut microbiome composition across the spectrum of murine aggression behavior. Moreover, manipulation of the gut microbiome via administration of short-term antibiotics and sodium butyrate, a short-chain fatty acid byproduct of microbial fermentation, increases aggression behavior. The overall goal of this research is to use basic science findings in mice to better understand how environmental exposures could influence human health and behavior, thus revealing how community health affects individuals and supplying a potential target for future intervention.
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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
An examination of between- and within-subject effects of stress on emotional eating over 49 consecutive days in women
Creator
Fowler, Natasha
Date
2021
Collection
Electronic Theses & Dissertations
Description
Objective: Stress is associated with emotional eating (EE) in women cross-sectionally (between-subject). However, few studies have examined stress longitudinally limiting our understanding of how within-subject variations in stress level influence risk for EE over time and whether stress is in fact a risk factor or consequence of EE (within-subject). This study used an intensive, longitudinal study design to examine between- and within-subject effects of major life stress, daily stress impact...
Show moreObjective: Stress is associated with emotional eating (EE) in women cross-sectionally (between-subject). However, few studies have examined stress longitudinally limiting our understanding of how within-subject variations in stress level influence risk for EE over time and whether stress is in fact a risk factor or consequence of EE (within-subject). This study used an intensive, longitudinal study design to examine between- and within-subject effects of major life stress, daily stress impact, and cortisol on EE in women. Methods: An archival sample of 477 women aged 15-30 years recruited from the Michigan State University Twin Registry provided daily ratings of EE and stress impact for 49 consecutive days, along with self-reports of major life stress in the last 12 months and hair cortisol concentration (HCC), a longitudinal measure of cortisol secretion. Mixed linear models examined main and interactive effects of each stress variable on EE. Results: Both between- and within-subject analyses showed that daily stress more strongly predicted EE than major life stress. Specifically, women engaged in higher levels of EE when they experienced higher levels of daily stress impact relative to other women (between-subject) and their own daily stress levels (within-subject). There was a tendency for lower HCC to predict increased levels of EE (between-subject). Discussion: Findings confirm longitudinal associations between daily stress impact and cortisol with EE in women. Results also highlight the importance of within-subject shifts in a woman’s stress level in her risk for EE and suggest that stress management techniques may a be useful tool for treatment.
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Title
An investigation of cerebellar morphology in childhood stuttering
Creator
Johnson, Chelsea Anna
Date
2022
Collection
Electronic Theses & Dissertations
Description
While many studies have connected structural and functional cerebellar differences to developmental stuttering, there are limited studies of cerebellar gray matter morphology in young children who stutter. These examinations include small sample sizes of children and use morphometry methods that might not be best suited for examining the cerebellum (e.g., Chang et al., 2008). This dissertation examines how the structure of specific cerebellar lobules differs in a larger cohort of children who...
Show moreWhile many studies have connected structural and functional cerebellar differences to developmental stuttering, there are limited studies of cerebellar gray matter morphology in young children who stutter. These examinations include small sample sizes of children and use morphometry methods that might not be best suited for examining the cerebellum (e.g., Chang et al., 2008). This dissertation examines how the structure of specific cerebellar lobules differs in a larger cohort of children who stutter and children who do not stutter as well as in persistent and recovered children who stutter. These data will provide evidence to better inform predictions of how the morphology of cerebellar areas are likely involved in aspects of speech motor control in developmental stuttering. In this study, gray matter morphology of the cerebellum was examined in children who do and do not stutter using voxel-based morphometry and a specialized toolbox and atlas for the cerebellum (Diedrichsen, 2006). Here we examined cerebellar gray matter volume (GMV) based on structural MRI data from children who stutter and children who do not stutter, 116 preschool-age children (stuttering N= 57) between the ages of 3-5 years, and a school-age cohort of 72 children (stuttering N=37) six years of age and up. This dissertation is the first study to examine cerebellar GMV in a large group of children who stutter using a specialized toolbox and atlas for the cerebellum. Results from this study showed that there were no overall significant group differences of lobular GMV between the stuttering and non-stuttering groups in any of the groups of children. There were significant age-related associations, however, that differentiated children who do and do not stutter in specific age ranges. In particular, the following cerebellar lobules differed significantly in GMV between children who do and do not stutter with age: 1) cerebellar lobule VII, which may correspond with cerebellar functions that support speech planning, 2) lobule VIII, which has been linked to various functions including corrections during perturbation studies, and 3) lobule IV which has been reported to be involved in feedforward control speech motor control processes. Notably, GMV of cerebellar lobule VI was associated negatively with Stuttering Severity Instrument (SSI) score in preschool-age persistent children who stutter. Associations between SSI score and GMV in cerebellar lobule VI may mean that feedforward control mechanisms are associated with the frequency of stuttering in children who stutter. In summary, significant findings of this investigation indicate that 1) children who do and do not stutter do not show an overall difference in cerebellar GMV, 2) GMV of the cerebellum is associated with SSI score, 3) age-related differences in GMV in the cerebellum differentiate children who do and do not stutter. The results from this study indicate that feedforward control is associated with disfluencies while age-related variations of cerebellar areas that may support both the feedback and feedforward control pathways are connected to aspects of stuttering, such as age.
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Title
Circuit-Specific Inhibition of Dopaminergic Signaling Associated with Phantom Gustatory Sensations in Disrupted-in-Schizophrenia-1 Mice
Creator
Fry, Benjamin R.
Date
2022
Collection
Electronic Theses & Dissertations
Description
Schizophrenia is a severe neuropsychiatric disorder characterized by a suite of symptoms occurring across cognitive (delayed processing, paraphasia, attentional deficits), negative (anhedonia, blunted affect, catatonia), and positive (hallucinations, delusions) domains. Antipsychotics are the most commonly prescribed medication to treat positive symptoms, however their use is complicated by substantial side-effects and inadequate efficacy. This reflects a lack of progress in understanding the...
Show moreSchizophrenia is a severe neuropsychiatric disorder characterized by a suite of symptoms occurring across cognitive (delayed processing, paraphasia, attentional deficits), negative (anhedonia, blunted affect, catatonia), and positive (hallucinations, delusions) domains. Antipsychotics are the most commonly prescribed medication to treat positive symptoms, however their use is complicated by substantial side-effects and inadequate efficacy. This reflects a lack of progress in understanding the precise neurobiological mechanisms underlying these symptoms, due in part to a lack of appropriate preclinical animal models. Here, I used an animal model of genetic vulnerability for neuropsychiatric illness known as Disrupted-in-schizophrenia-1 (DISC-1) to examine impaired reality testing, which reflects an aberrant internal representation of an absent event. In mice, this can be observed by an associatively evoked perception of an absent sweet taste. This effect is dopaminergically-dependent and associated with elevated activity in the insular cortex (IC). By combining sophisticated Pavlovian behavioral procedures with chemogenetic inhibition of dopamine neurons projecting from the ventral tegmental area (VTA) to the IC, I show that inactivation of the VTA --> IC dopaminergic circuitry leads to impaired reality testing in wild-type mice, and that DISC-1 mice have significantly less dopamine neurons which send projections to the IC, specifically. These data yield new insights with regard to the neurobiology underlying reality testing and the functional anatomical outcomes following perturbations of the DISC-1 genetic locus. My studies also suggest potential targets for the development of novel pharmacological treatments in humans with schizophrenia.
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Title
DEORPHANIZATION AND CHARACTERIZATION OF SEA LAMPREY OLFACTORY TRACE AMINE-ASSOCIATED RECEPTORS
Creator
JIA, LIANG
Date
2022
Collection
Electronic Theses & Dissertations
Description
The sense of smell plays an important role in mediating diverse behaviors in the animal kingdom. Odor detection in the sea lamprey is mediated by a limited number of odorant receptors (ORs) and trace amine-associated receptors (TAARs). Upon binding with odorants, the receptors are activated and subsequently activate the downstream neuronal signaling cascade that transforms the chemical information into electrophysiological signals. Odorous biogenic amines, when enriched in biological...
Show moreThe sense of smell plays an important role in mediating diverse behaviors in the animal kingdom. Odor detection in the sea lamprey is mediated by a limited number of odorant receptors (ORs) and trace amine-associated receptors (TAARs). Upon binding with odorants, the receptors are activated and subsequently activate the downstream neuronal signaling cascade that transforms the chemical information into electrophysiological signals. Odorous biogenic amines, when enriched in biological excretions, stimulate TAARs of the main olfactory epithelium and evoke innate behaviors in animals. I hypothesized that these biogenic amines are potent ligands for lamprey TAARs, and characterized the structural basis for amine recognition in these receptors. Chapter 1 describes discovery that spermine, an odorous polyamine in semen, serves as a sex pheromone in sea lamprey. Spermine potently stimulates the lamprey olfactory system, activates TAAR348 receptor, and attracts ovulated females. A novel antagonist to this receptor inhibits olfactory and female behavioral responses to spermine. This discovery elucidates a mechanism that male animals recruit mates through the release of chemical cues in ejaculates. In chapter 2, I demonstrated that two clades of independently evolved TAARs, represented by sea lamprey TAAR365 (sTAAR365) and mouse TAAR9 (mTAAR9), share a similar response profile. The results suggest a conserved mechanism whereby independently evolved TAAR receptors utilize convergent structural bases to detect various biogenic polyamines. In chapter 3, I found that a cadaverine-responsive sea lamprey TAAR receptor, TAAR346a, exhibits high basal activity when heterologously expressed in HEK293T cells. Triethylamine serves as an inverse agonist for TAAR346a that can specifically attenuate its high basal activity. These data support a model in which the inverse agonist recognizes only one of the two orthosteric sites used by the agonist as it elicits its inhibitory effect on the basal activity of the receptor. Further evidence was provided to highlight the importance of interhelical interactions in modulating ligand-independent activation of TAAR346a. Thus, this thesis contributes to a better understanding of sea lamprey olfaction and the structural basis of TAARs for amine recognition in vertebrate animals.
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Title
Delineation of Delta FosB's in vivo redox sensitivity
Creator
Lynch, Haley Marie
Date
2021
Collection
Electronic Theses & Dissertations
Description
Many neurodegenerative diseases, including Alzheimer’s disease (AD), are driven by altered reduction/oxidation (redox) balance in the brain. Moreover, cognitive decline in AD is caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expression. However, the mechanisms by which redox state controls gene expression in neurons are not well understood. Delta FosB is a neuronally enriched transcription factor critical for orchestrating...
Show moreMany neurodegenerative diseases, including Alzheimer’s disease (AD), are driven by altered reduction/oxidation (redox) balance in the brain. Moreover, cognitive decline in AD is caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expression. However, the mechanisms by which redox state controls gene expression in neurons are not well understood. Delta FosB is a neuronally enriched transcription factor critical for orchestrating gene expression underlying memory, mood, and motivated behaviors and is dysregulated in AD. Delta FosB regulates gene expression by dimerizing with JunD to form activator protein 1 (AP-1) which binds the promoter regions of target genes to control transcription. In controlled in vitro conditions, AP-1 complex formation and DNA binding are modulated by redox-sensitive disulfide bonds and related redox-sensitive conformational changes in Delta FosB. Here, we show that the redox-dependence of the structure-function relationship of Fos-family proteins found in vitro is also conserved in Delta FosB in cells and in the mouse brain. Under oxidizing conditions, Delta FosB cysteine residues can form disulfide bridges, including at C222 and C172, which can stabilize its interaction with a partner protein; however, these conditions reduce complex binding to AP-1 consensus sequence DNA, specifically when C172 is oxidized. We present evidence that this effect occurs in cells and in mouse brain, altering Delta FosB target gene expression during redox stress. This evidence supports Delta FosB as an important mediator of oxidative stress-driven changes in gene expression seen in neurological conditions and implicates Delta FosB as a possible therapeutic target for intervention in diseases of oxidative stress like AD.
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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
ENABLING REAL-TIME COMMUNICATION FOR HUMAN AUGMENTATION SYSTEMS VIA UNOBTRUSIVE HIGH BANDWIDTH MACHINE TO HUMAN ELECTROTACTILE PERIPHERAL NERVE STIMULATION
Creator
Parsnejad, Sina
Date
2022
Collection
Electronic Theses & Dissertations
Description
The advent of sensor technologies and the resulting abundance of information together with modern advanced processing capabilities makes improving human lives via human augmentation technologies ever more appealing. To establish a new effective form of human-machine-communication (M2HC) for augmentation, this dissertation explores non-invasive peripheral nerve stimulation via electrotactile waveforms. This dissertation conducts extensive convergence research between the fields of psychology,...
Show moreThe advent of sensor technologies and the resulting abundance of information together with modern advanced processing capabilities makes improving human lives via human augmentation technologies ever more appealing. To establish a new effective form of human-machine-communication (M2HC) for augmentation, this dissertation explores non-invasive peripheral nerve stimulation via electrotactile waveforms. This dissertation conducts extensive convergence research between the fields of psychology, electrical engineering, neuroscience and human augmentation and established innovations to create distinct sensations that can be utilized as iconic electrotactile M2HC. Existing electrotactile stimulation models deliver a limited range of distinct sensations, making iconic communication challenging. To address this issue, we created a software/hardware infrastructure, including novel electrotactile electrode arrays and improved stimulation circuitry, that allows for rapid prototyping and testing various electrotactile innovations. We created a model for electrotactile waveform generation (MEWS) wherein a train of high-frequency electrotactile pulses is shaped into electrotactile waveforms through a multi-layer on-off-keying modulation forgoing the need for constant frequency recalibration and making painful sensations less likely to happen. Using MEWS, we conducted multiple human trials on 15 volunteering participants stimulating a total of ~6000 electrotactile sensations which led us to create 13 distinct electrotactile waveform with an accuracy of 85.4%. To increase the number of messages that can be delivered by electrotactile stimulation, a model for creating varying electrotactile waveforms (MOVES) was created based on linguistic concept of phonemes and taking a semi-heuristic approach to creating electrotactile waveforms. Using MOVES we conducted multiple human trials on 21 volunteering participants stimulating a total of ~5000 electrotactile sensations. Our human trials proved that MOVES was able to create 24 distinct sensations with an accuracy of 89% that can be used to convey messages through iconic communication and has the potential to expand further beyond the 24 messages. The number of messages delivered by MOVES pentuples the best recorded number of distinct electrotactile sensations in literature.
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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
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
Heterogeneous Thalamic Reticular Nucleus Neurons and Their Functional Role in Thalamocortical Processing
Creator
Harding-Jackson, Laura
Date
2021
Collection
Electronic Theses & Dissertations
Description
The thalamic reticular nucleus (TRN) is an integral regulator of information flow between the thalamus and cortex. The TRN receives synaptic inputs from both cortical and thalamic regions and based upon this information it selectively inhibits thalamic activity. TRN neurons produce action potentials in two distinct modes: a fast, transient burst discharge from a hyperpolarized state, and a prolonged, tonic discharge from a relatively depolarized state. While previous studies have...
Show moreThe thalamic reticular nucleus (TRN) is an integral regulator of information flow between the thalamus and cortex. The TRN receives synaptic inputs from both cortical and thalamic regions and based upon this information it selectively inhibits thalamic activity. TRN neurons produce action potentials in two distinct modes: a fast, transient burst discharge from a hyperpolarized state, and a prolonged, tonic discharge from a relatively depolarized state. While previous studies have characterized burst discharge as a transient high frequency discharge (> 250 Hz), these electrophysiological studies reveal a highly variable range of burst frequencies (4- 342 Hz). In these studies, I aim to discover the mechanisms underlying these highly variable burst frequencies, as well as their functional role in thalamocortical processing.In chapter two, I found that bursts from TRN neurons with relatively higher frequency discharge (>100 Hz) contain more action potentials per burst. These neurons also have higher input resistances, broader action potentials, higher action potential thresholds, and larger somas. The amplitude of the T-type calcium channel-mediated low-threshold spike, which underlies the burst discharge, is positively correlated with both the burst discharge frequency and the number of action potentials per burst. I next investigated whether small conductance calcium-activated potassium channels (SK channels) could mediate the differences in burst firing rate and action potential number. Blocking SK channels increased the frequency and duration of the burst but did not increase the amplitude of the underlying T-type calcium current. Prior studies suggest that T-type calcium channels are distributed along the dendrites in TRN neurons with high frequency burst discharge. In chapter three, I examine the distribution of dendritic calcium activity within the lower frequency bursting neurons. While the calcium signal was lower in these neurons all along the dendrites, the calcium signal was evenly distributed across proximal, intermediate, and distal dendritic regions. Investigation of SK channel activity revealed significant location-specific effects. In lower frequency bursting neurons, SK channels had the greatest influence at proximal and distal locations. In higher frequency bursting neurons, SK channels had the greatest influence at proximal and intermediate dendritic locations. Heterogeneous TRN burst discharge frequencies may represent a diverse cell population with unique dendritic ion channel composition and distribution. These results may improve our understanding of the mechanisms of TRN neuron afferent synaptic integration as well as modulation of thalamocortical inhibition. In chapter four I investigate whether intrinsic properties of TRN neurons are altered in the Fmr1-KO mouse model of Fragile X Syndrome (FXS). Individuals with FXS experience a variety of comorbidities that could involve TRN function, such as altered sensory perceptions, sleep disorders, and epilepsy. Analysis of intrinsic cellular properties revealed no differences in TRN neuron properties. Further investigation of synaptic plasticity, which is an abnormal finding in several other brain regions in FXS, also revealed no pathology. These findings suggest that TRN dysfunction does not contribute to FXS pathology.
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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
Investigating Cognition in Howard Engel's Memory Book : Literary Interventions and Intercessions in Scientific Models of Memory
Creator
Cave, Kylene N.
Date
2022
Collection
Electronic Theses & Dissertations
Description
Crime fiction orbits around the concept of memory. At its core, crime narratives are concerned with reconstructing the past, bringing to light the events surrounding the criminal mystery. Memory also manifests in the genre’s detective figures, its modes of detection, and in the eyewitness testimonies used to solve the criminal mystery. In most crime narratives memory operates as a simplistic plot device used to temporarily complicate the mystery and, as such, it is rarely read beyond the...
Show moreCrime fiction orbits around the concept of memory. At its core, crime narratives are concerned with reconstructing the past, bringing to light the events surrounding the criminal mystery. Memory also manifests in the genre’s detective figures, its modes of detection, and in the eyewitness testimonies used to solve the criminal mystery. In most crime narratives memory operates as a simplistic plot device used to temporarily complicate the mystery and, as such, it is rarely read beyond the cursory scope of trauma. This dissertation, however, argues that crime narratives depicting extreme and rare cases of memory—like amnesia—help trace the boundaries around average functioning memory and reveal useful ways for conceptualizing how memory functions, and what disciplines have the impetus to do so. In this dissertation I argue that Howard Engel’s novel, Memory Book (2005), examines the complexities of memory by accomplishing three narratological tasks, distinguishing it from other crime fiction narratives and their more traditional handling of issues of memory and recall. The first task involves placing memory at the center of the narrative and elevating the mystery of the mind to the forefront of the plot. In placing memory at its center, the novel pushes back against traditional and widely popular scientific models of memory as merely the process of remembering and forgetting, advocating for a theory that is more complex and heterogenous. The second narratological task involves the novel’s ability to act as a literary intercessor on behalf of the sciences to translate and disseminate theories of memory to the layperson. Within this task, however, I assert that the novel not only passively intercedes, but actively intervenes in the study of memory by highlighting the inherent limitations of purely scientific or medical models of memory. In exposing these constraints, the novel also suggests a blended, transdisciplinary approach to conceptualizing human memory function and the mind. Lastly, the final task asserts that Memory Book is distinct because its narrative is infused with elements of lived experience, elements the scientific method is incapable of capturing in its probing of memory and cognition. Pointing specifically to Engel’s authorship and the circumstances surrounding the narrative’s composition following a stroke, I argue that the text intentionally blurs the boundaries between reality and fiction as a way of investigating the real-world implications of wrestling with memory loss and brain-injury based amnesia. Each of these narratological tasks is systematically analyzed by engaging with the Howard Engel’s memoir—The Man Who Forgot How to Read—deeply engaging with the novel’s paratextual elements, and through a detailed close reading of the novel.
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Title
MAPPING THE TAU PROTEIN INTERACTOME USING THE BIOID2 IN SITU LABELLING APPROACH
Creator
Atwa, Ahmed
Date
2022
Collection
Electronic Theses & Dissertations
Description
Pathological inclusions composed of tau protein are hallmarks of neurodegenerative diseases collectively known as tauopathies, of which the most common is Alzheimer’s Disease (AD). Tau is most well-known as a microtubule-associated protein involved in regulating microtubule dynamics, but accumulating evidence suggests tau is involved in many biological functions. Deciphering the tau protein interactome is critical for better understating the physiological and pathological roles of tau. This...
Show morePathological inclusions composed of tau protein are hallmarks of neurodegenerative diseases collectively known as tauopathies, of which the most common is Alzheimer’s Disease (AD). Tau is most well-known as a microtubule-associated protein involved in regulating microtubule dynamics, but accumulating evidence suggests tau is involved in many biological functions. Deciphering the tau protein interactome is critical for better understating the physiological and pathological roles of tau. This work aimed to identify tau interacting partners using the in situ protein labelling BioID2 method by creating fusion proteins between full-length human tau and either BioID2 on the N-terminus (BioID2-Tau) or C-terminus (Tau-BioID2). A total of 372 proteins were identified, of which 269 interacted with Tau-BioID2, 169 with BioID2-Tau, and 66 proteins overlapped between both tau proteins. Gene Ontology (GO) cellular component analysis mapped protein interactions in the mitochondria, cytoskeleton, dendrites, nucleus, synaptic vesicles, and the ribonucleoprotein complex. While GO molecular function pathways identified proteins involved in RNA binding, translation regulation, ubiquitin ligase activity, kinase binding, mitochondrial oxidoreductase, and peroxidase activity. KEGG pathway analysis identified proteins associated with neurodegenerative diseases, including AD, Parkinson’s disease, Huntington’s disease, and Amyotrophic lateral sclerosis. Thus, this approach can identify members of the tau interactome via in situ labeling, that may help shed light on tau’s functional roles and provide novel therapeutic strategies for neurodegenerative diseases.
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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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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
NOVEL IMPACTS OF HOST-ENVIRONMENT INTERACTIONS IN ENTERIC GLIA THROUGH SEQUENCING AND IN-SITU EXPRESSION
Creator
Ponnampalam, Christine Dharshika
Date
2021
Collection
Electronic Theses & Dissertations
Description
The enteric nervous system (ENS) is comprised of enteric neurons and glia that facilitate essential gastrointestinal (GI) function including motility, visceral sensation, absorption, and gut permeability. Enteric neurons and glia are responsive to environmental cues and stressors ranging from the local gut microenvironment to the host’s psychosocial state and understanding how the ENS integrates these cues to modulate local and systemic function is critical. Novel roles for enteric neurons in...
Show moreThe enteric nervous system (ENS) is comprised of enteric neurons and glia that facilitate essential gastrointestinal (GI) function including motility, visceral sensation, absorption, and gut permeability. Enteric neurons and glia are responsive to environmental cues and stressors ranging from the local gut microenvironment to the host’s psychosocial state and understanding how the ENS integrates these cues to modulate local and systemic function is critical. Novel roles for enteric neurons in host-environmental interactions have been discovered using specialized sequencing technologies but these tools have not yet readily investigated enteric glia. The goal of this dissertation was to develop and utilize genetic technologies to characterize enteric glial responses to environmental mediators. First we adapted existing genetic tools to study molecular changes in the ENS and specifically enteric glia. We developed effective means of characterizing enteric glial expression within complex in vivo models using the RiboTag model with RNA-sequencing and subsequently visualized changes in gene expression within enteric ganglia in situ. We then utilized these techniques to investigate sex-specific responses to early life stress in enteric glia. Enteric glia from male and female mice have contrasting expression profiles including differences in GPCR signaling that could contribute to sex-specific ENS signaling mechanisms and ultimately GI disease outcomes. This supports recent findings of sexual dimorphism in glial functional connectivity and may highlight a critical difference in the way enteric glia communicate with other cell types between males and females. Additionally enteric glia from male mice ‘feminize’ following iiiearly life stress through altered expression of GI and neurological disease genes including mechanisms of glial-immune communication like type I interferon signaling. Together these data highlight striking differences in the physiologic molecular patterns and nature of stress response in enteric glia between males and females that likely contribute to sexually dimorphic GI disease patterns and symptom presentation. Next we investigated ENS type I interferon responses through the stimulator of interferon genes (STING) pathway. STING responds to both microbial and host mediators to contribute to GI inflammation. However the role of STING signaling in the gut is complex and can either exacerbate or ameliorate inflammation likely dependent on complex microenvironmental factors. We provide the first known investigation of STING expression and signaling within the ENS. STING is expressed in both enteric neurons and glia but IFNB is only expressed in enteric neurons. ENS STING is activated by its canonical ligands toproduce type I interferons. However this is likely primarily mediated through canonical activation of enteric neuronal STING and the contribution of enteric glial STING to type I IFN response is minor. Additionally enteric glial STING does not alter gastrointestinal outcomes during acute colitis within the DSS colitis model. Taken together these findings suggest enteric glia do not utilize STING for canonical type I IFN signaling or contribute to disease pathology in acute DSS colitis. Enteric glial STING may instead utilize primordial and specialized signaling pathways that more selectively alter local function. Together our data provide novel genetic tools and data to further uncover molecular functions in enteric glia and their role in GI and systemic health. Using these we discovered entirely novel molecular interaction effects between sex and early life stress that shift the framework of these risk factors in GI disease. Furthermore we highlight a novel potential mediator of ENS-microbe communication with STING. Our findings further characterize the molecular patterns used by glia in response to complex environmental factors and highlight unique heterogeneity in glial intercellular communication.
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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
PERTURBATION OF ASTROCYTIC KEAP1-NRF2-ARE PATHWAY AND GLUTAMATE TRANSPORTER EXPRESSION IN SPINAL ASTROCYTIC DEGENERATION
Creator
Wiwatratana, Duanghathai
Date
2021
Collection
Electronic Theses & Dissertations
Description
Several cellular mechanisms are known to be involved in methylmercury (MeHg) induced central nervous system (CNS) toxicity, including the dysregulation of intracellular Ca2+, redox, and glutamate homeostasis. However, the factors that make particular neurons susceptible to MeHg toxicity, and the latency period of neurological signs and symptoms, have not yet been clearly delineated. For example, the spinal dorsal root ganglia (DRG) is the primary target of MeHg. Mercury (Hg) granules are...
Show moreSeveral cellular mechanisms are known to be involved in methylmercury (MeHg) induced central nervous system (CNS) toxicity, including the dysregulation of intracellular Ca2+, redox, and glutamate homeostasis. However, the factors that make particular neurons susceptible to MeHg toxicity, and the latency period of neurological signs and symptoms, have not yet been clearly delineated. For example, the spinal dorsal root ganglia (DRG) is the primary target of MeHg. Mercury (Hg) granules are first detected in spinal cord motor neurons (SMNs) in the non-symptomatic phase, whereas Hg granules are detected in glia later, following with neurological symptoms (Møller-Madsen, 1991). This finding suggested that the latent period (non-symptomatic phase) is associated with Hg accumulation in neurons, while the symptomatic phase occurs following Hg accumulation in glia, and the susceptibility is not associated with Hg granule accumulation in cells (Møller-Madsen, 1991). Astrocytes generally provide glutathione (GSH) for neurons to detoxify toxic insult. In the spinal cord, MeHg might perturb the antioxidant pathway, Keap1-Nrf2-ARE pathway in the spinal cord astrocytes (SCAs) consequently contribute to DRG or SMN susceptibility to MeHg toxicity. In this study, the comparative responses of different SCAs maturity to a non-toxic MeHg concentration (0.1 μM) suggested that the fully mature SCAs (Day in vitro 30; DIV30), were more susceptible to MeHg than SCAs on DIV14. The perturbation of the Keap1-Nrf2-ARE pathway in SCAs (DIV 30) during exposure to sub-toxic MeHg concentration (0.50 μM) caused a biphasic increase in antioxidant genes such as Keap1, Nrf2, Gclc, Abcc1 mRNAs expression. The concomitant increase of glutamate transporter Slc7a11 encoded for the system Xc-, and Slc1a3 encoded for EAAT1, and Slc1a2 encoded for EAAT2 expression during MeHg exposure might suggest the cooperative expression or function of these glutamate transporters. This concomitant expression was further demonstrated in studies using Nrf2-knockout (Nrf2-KO) derived SCAs. The increase of basal Slc7a11 mRNA, was concurrent to the increase of basal Slc1a3 and Slc1a2 mRNA expressions in Nrf2-KO derived SCA. The function of time of MeHg exposure indicated that Nrf2-KO derived SCAs were more susceptible to MeHg than the wild-type (WT)-derived SCAs. The pronounced susceptibility of Nrf2-KO derived SCAs was mainly due to the loss of GSH) metabolism and transport genes Gclc, GPx1, GPx4, and Abcc1 mRNAs in this genotype. MeHg significantly reduced these mRNA expressions in both genotypes. However, not all Nrf2-ARE regulated genes were affected by MeHg in similar ways in these genotypes. For example, MeHg induced the increase of Slc7a11 mRNA expression in WT-derived SCAs, but it appears to cause the reduction of this mRNA expression in Nrf2 KO-derived SCAs. Administration of antioxidant N-acetyl-L-cystine (NAC) in pretreatment (NP), co-treatment (CO), and post-treatment of MeHg (MP) prevented the reduction of SCAs metabolic functions for over 160h. The mechanism of NAC action in preventing MeHg induced SCAs degeneration is primarily due to its thiol antioxidant property.In conclusion, this study suggests that age and genetic predisposition contribute to SCAs susceptibility to MeHg toxicity. The dysregulation of the antioxidant pathways and glutamate homeostasis in SCAs potentially contributes to SMNs or DRG susceptible to MeHg.
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