Michigan State University

MSU Libraries

Digital Repository

Search results

(1 - 17 of 17)
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.
Show less
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.
Show less
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.
Show less
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.
Show less
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.
Show less
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.
Show less
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.
Show less
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.
Show less
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.
Show less
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.
Show less
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
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.
Show less
Title
ROLE OF VENTRAL TEGMENTAL AREA NEUROTENSIN RECEPTOR-1 NEURONS IN ENERGY BALANCE
Creator
Perez-Bonilla, Patricia
Date
2021
Collection
Electronic Theses & Dissertations
Description
Dopamine (DA) neurons in the ventral tegmental area (VTA) modulate physical activity and feeding behaviors that are disrupted in obesity. Although the heterogeneity of VTA DA neurons has hindered determination of which ones might be leveraged to support weight loss, we have characterized a subset of VTA DA neurons that express NtsR1 (VTA NtsR1 neurons) that are involved in the coordination of energy balance. We hypothesized that 1) increased activity VTA NtsR1 neurons might promote weight...
Show moreDopamine (DA) neurons in the ventral tegmental area (VTA) modulate physical activity and feeding behaviors that are disrupted in obesity. Although the heterogeneity of VTA DA neurons has hindered determination of which ones might be leveraged to support weight loss, we have characterized a subset of VTA DA neurons that express NtsR1 (VTA NtsR1 neurons) that are involved in the coordination of energy balance. We hypothesized that 1) increased activity VTA NtsR1 neurons might promote weight loss behaviors, and that 2) deleting NtsR1 specifically from VTA DA neurons would promote weight gain by increasing food intake and decreasing physical activity. We first used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to activate VTA NtsR1 neurons in normal weight and diet-induced obese mice.Acute activation of VTA NtsR1 neurons (24hr) significantly decreased body weight in normal weight and obese mice by reducing food intake and increasing physical activity. Moreover, daily activation of VTA NtsR1 neurons in obese mice sustained weight loss over 7 days. Activating VTA NtsR1 neurons also suppressed how much mice worked to obtain sucrose rewards, even when there was high motivation to consume. However, VTA NtsR1 neural activation was not reinforcing, nor did it invoke anxiety, vasodepressor responses or hypothermia. We then used newly generated NtsR1 flox/flox mice to study NtsR1 deletion in both development and adulthood. Curiously, developmental deletion of VTA NtsR1 (by crossing DAT Cre mice with NtsR1 flox/flox mice) had no impact on feeding or body weight. Adult deletion of the receptor (by injecting adeno associated Cre into VTA of adult NtsR1 flox/flox mice), however, resulted in lower body weight and DA-dependent food intake. Altogether, these data suggest that modulating NtsR1 expression in the adult VTA may be useful to safely promote weight loss, and that NtsR1 is worth further exploration for managing obesity.
Show less
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.
Show less
Title
THE PERSISTENT AND MULTIDIMENSIONAL MICROGLIAL RESPONSE TO PATHOLOGICAL ALPHA-SYNUCLEIN AGGREGATION
Creator
Stoll, Anna C.
Date
2022
Collection
Electronic Theses & Dissertations
Description
Parkinson’s Disease, the second most common neurodegenerative disease, affects approximately 1 million people in the USA with 60,000 newly diagnosed people each year. Pathologically, PD is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies) and the progressive loss of the nigrostriatal dopamine (DA) neurons. While the exact cause of PD remains unknown, mounting evidence has suggested that neuroinflammation may play a significant role in PD...
Show moreParkinson’s Disease, the second most common neurodegenerative disease, affects approximately 1 million people in the USA with 60,000 newly diagnosed people each year. Pathologically, PD is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies) and the progressive loss of the nigrostriatal dopamine (DA) neurons. While the exact cause of PD remains unknown, mounting evidence has suggested that neuroinflammation may play a significant role in PD progression. The pathological features of PD can be recapitulated in vivo using the α-syn preformed fibril (PFF) model of synucleinopathy in rats. Specifically, in association with accumulation of phosphorylated α-syn (pSyn) inclusions in the SNpc, microglia increase soma size and MHC-II expression. This microglial response parallels pSyn inclusion formation, peaking at 2 months following intrastriatal PFF injection, months prior to the SNpc degeneration observed in the model. The overarching question of this dissertation is: does the microglial response to pathological α-syn accumulation contribute to degeneration? In Aim 1 of this dissertation an inhibitor of colony stimulating factor 1 receptor (CSF1R) was used to partially deplete microglia within the context of the α-syn PFF rat model in order to determine whether degeneration of the nigrostriatal system can be attenuated. Despite significant microglial depletion, increased soma size and expression of major-histocompatibility complex-II (MHC-II) on microglia within the α-syn inclusion bearing substantia nigra pars compacta (SNpc) was maintained. Further, partial microglia depletion did not impact degeneration of dopaminergic neurons in the SNpc. Paradoxically, long term partial microglial depletion increased the soma size of remaining microglia in both control and PFF rats was associated with widespread MHC-IIir expression in extranigral regions. These results suggest that partial microglial depletion is not a promising anti-inflammatory therapeutic strategy for PD and that this approach may induce a heightened proinflammatory state in remaining microglia. Aim 2 of this dissertation built on a previous study RNA-Seq dataset that identified multiple upregulated innate and adaptive immune transcripts in the inclusion bearing SNpc in the PFF model. Complementary approaches of fluorescent in situ hybridization (FISH) and droplet digital PCR (ddPCR) were used. FISH results identified an a-syn aggregate associated microglial (a-SAM) phenotype that is characterized by upregulation of CD74, CXCl10, RT1-A2, GRN, CSF1R, Tyrobp, C3, C1qa and Fcer1g. ddPCR results identified additional neuroinflammatory genes, Cd4, Stat1, Casp 1, Axl and IL18, that are significantly upregulated in inclusion bearing nigral tissue. Collectively these findings implicate that the deposition of pathological α-syn inclusions in the SNpc is associated with perturbations in immune functions related to complement, inflammasome and T cell activation, phagocytosis, and interferon gamma signaling. Collectively, the findings of these dissertation experiments demonstrate that the microglial response to pathological α-syn aggregation is persistent and multifaceted. This comprehensive understanding of the multidimensional response of microglia to pathological α-syn aggregates may help to uncover novel therapeutic targets that could facilitate future anti-inflammatory, disease-modifying strategies for PD.
Show less
Title
THE ROLE OF α-SYNUCLEIN IN CHOLINERGIC NEUROTRANSMISSION IN THE ENTERIC NERVOUS SYSTEM
Creator
Yelleswarapu, Narayana KrishnaChaithanya
Date
2021
Collection
Electronic Theses & Dissertations
Description
Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder that is manifested by significant motor impairments that decrease the quality of life and increase mortality in our elderly population. Non-motor symptoms in PD are common in patients and occur up to 2 decades prior to the onset of motor symptoms. Gastrointestinal (GI) complications, specifically constipation, is seen in over 50% of patients with PD and can be debilitating and result in malnutrition and weight loss....
Show moreParkinson’s disease (PD) is a slowly progressive neurodegenerative disorder that is manifested by significant motor impairments that decrease the quality of life and increase mortality in our elderly population. Non-motor symptoms in PD are common in patients and occur up to 2 decades prior to the onset of motor symptoms. Gastrointestinal (GI) complications, specifically constipation, is seen in over 50% of patients with PD and can be debilitating and result in malnutrition and weight loss. There is a need to elucidate the underlying mechanisms the lead to gut dysmotility in PD. Moreover, the pathologic event that causes cell death of dopaminergic neurons within the central nervous system (CNS) is observed with the enteric nervous system (ENS) decades prior to pathology in the CNS. This pathologic event is the toxic conversion and aggregation of a presynaptic terminal protein, α-synuclein (αSyn), into Lewy bodies. αSyn plays an important functional role in various cellular processes, including but not limited to, mitochondrial, lysosomal, synaptic vesicle regulation, and protease function. Therefore, we can predict the cascade of events that occur when this protein is no longer functional. Within the ENS, acetylcholine is the primary vesicular neurotransmitter involved in smooth muscle contractions. In this work I aimed to elucidate the role of pathologic αSyn on slow colonic transit disrupting cholinergic neurotransmission. In Chapter 2, we used two mouse models of hαSyn overexpression to target ENS pathology. In Chapter 3, we used a gene knockout of αSyn to further establish a functional role for the protein in cholinergic neurotransmission. We performed immunofluorescence, fecal pellet output, whole gut transit, colonic migrating motor complexes, studied longitudinal smooth muscle contractions, and junctional potentials to put together a thorough picture connecting phenotype to circuitry within the ENS. Our findings discussed in this dissertation shed light on 1) αSyn’s role in cholinergic neurotransmission, and 2) whether αSyn is necessary for normal colonic function and motility. Overall, cholinergic neurotransmission warrants a closer inspection in the ENS in PD. Strong evidence has continued to associate αSyn pathology to cholinergic neurons. Understanding this mechanism may allow for development of therapeutics that may alleviate GI symptoms in the PD population and help focus on discovering an early biomarker in diagnosing PD.
Show less
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.
Show less