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Title: Structural connectivity of an interoception network in schizophrenia
Creator: Yao, Beier
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Interoception refers to the processing, integration, and interpretation of bodily signals by the brain. Interoception is key to not only basic survival, but also many cognitive processes, especially motivational and affective functioning. There is emerging evidence suggesting altered interoception in schizophrenia, but its neural underpinning has not been examined. The current study aims to investigate the structural connectivity of a putative interoception network in schizophrenia, and its...
Show moreInteroception refers to the processing, integration, and interpretation of bodily signals by the brain. Interoception is key to not only basic survival, but also many cognitive processes, especially motivational and affective functioning. There is emerging evidence suggesting altered interoception in schizophrenia, but its neural underpinning has not been examined. The current study aims to investigate the structural connectivity of a putative interoception network in schizophrenia, and its relationship with affective functioning and clinical symptoms. Thirty-five participants with schizophrenia (SZ) and 36 healthy control participants (HC) underwent diffusion tensor imaging (DTI) and performed tasks measuring emotional functioning. Probabilistic tractography was used to identify white matter tracts connecting the key hubs forming the interoception network (i.e., rostral and caudal anterior cingulate cortex, ventral anterior insula, dorsal mid and posterior insula, and amygdala). Microstructural integrity of these tracts was compared across groups and correlated with measures of emotional functioning and symptom severity. I found that SZ exhibited altered structural connectivity in the putative interoception network, compared to HC. The structural connectivity of the network was correlated with emotion recognition in HC, supporting a link between the interoception network and emotional functioning. However, this correlation was much weaker in SZ, suggesting less reliance on this network. I did not find a correlation between the structural connectivity and clinical symptoms in SZ. These findings suggest that altered interoception may play a role in illness mechanisms of schizophrenia, especially in relation to emotional deficits.
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Title: Sexual dimorphisms and androgen influence in medial posterodorsal amygdala astrocytes
Creator: Johnson, Ryan T.
Date: 2011
Collection: Electronic Theses & Dissertations
Description: The amygdala is a highly interconnected brain region involved in fear, anxiety, social and reproductive behaviors. In humans and laboratory species the amygdala exhibits sexual dimorphisms in neuroanatomy and function both in juveniles and adults. In rodents, the medial posterodorsal amygdala (MePD) is particularly sexually dimorphic and gonadal hormone sensitive, and while neurons have been examined in this region, few reports have examined the potential influence of gonadal hormones on...
Show moreThe amygdala is a highly interconnected brain region involved in fear, anxiety, social and reproductive behaviors. In humans and laboratory species the amygdala exhibits sexual dimorphisms in neuroanatomy and function both in juveniles and adults. In rodents, the medial posterodorsal amygdala (MePD) is particularly sexually dimorphic and gonadal hormone sensitive, and while neurons have been examined in this region, few reports have examined the potential influence of gonadal hormones on other cellular components of the MePD. Astrocytes are a subtype of glia involved in synapse formation and known to be plastic and dynamic cells sensitive to gonadal hormone influence in several brain regions. My dissertation reveals sexual dimorphisms in the number of astrocytes in the juvenile rat MePD and that this sexual dimorphism remains present in adult animals. I also found sex differences in the arbor complexity of astrocytes in adults that are not present prior to puberty. Astrocytes also respond to changes in circulating hormone levels in adulthood. Furthermore, while the sex difference in astrocyte numbers in juvenile animals is androgen receptor-independent, the sex differences found in adult astrocyte numbers and arbor complexity are both androgen receptor-dependent. Finally, I provide evidence that astrocytes in the MePD contain androgen receptors, suggesting that androgens may act directly on these cells. The influence of gonadal hormones on astrocytes in the MePD is likely an important part of pubertal development and has implications for our understanding of the cellular organization of the amygdala and its function.
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Title: The role of parkin in the recovery of central dopamine neurons from acute neurotoxicant exposure
Creator: Benskey, Matthew John
Date: 2013
Collection: Electronic Theses & Dissertations
Description: Parkinson Disease (PD) pathology is associated with the selective degeneration of nigrostriatal dopamine (NSDA) neurons, while the tuberoinfundibular DA (TIDA) neurons of the hypothalamus remain intact. The same pattern of selective degeneration has been observed following exposure to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyradine (MPTP), a mitochondrial complex I inhibitor which recapitulates many of the molecular pathologies associated with PD. The purpose of this dissertation is to...
Show moreParkinson Disease (PD) pathology is associated with the selective degeneration of nigrostriatal dopamine (NSDA) neurons, while the tuberoinfundibular DA (TIDA) neurons of the hypothalamus remain intact. The same pattern of selective degeneration has been observed following exposure to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyradine (MPTP), a mitochondrial complex I inhibitor which recapitulates many of the molecular pathologies associated with PD. The purpose of this dissertation is to identify early molecular events that underlie TIDA neuron recovery from toxicant exposure and adapt these mechanisms in an attempt to rescue NSDA neurons from toxicity. NSDA neurons show loss of axon terminal DA concentrations following acute (20mg/kg; s.c.) and chronic (10 x 20mg/kg; s.c. over 35 days) MPTP administration and exhibit cell death following chronic MPTP administration. In contrast, TIDA neurons show no loss of axon terminal DA concentrations or cell death following acute or chronic MPTP exposure. The recovery of TIDA neurons is independent of extrinsic factors such as decreased toxicant exposure or hormonal activation. TIDA neuron recovery is associated with an increase in the PD-associated proteins, parkin and ubiquitin carboxy-terminal hydrolase L-1 (UCHL-1) within the arcuate nucleus (ARC) 24 h following MPTP. Additionally, parkin protein concentrations remain elevated in the ARC for up to 22 days following chronic MPTP administration. In contrast, the susceptibility of NSDA neurons is associated with decreased expression of both parkin and UCH-L1. The high correlation between the presence of the parkin protein and the recovery of DA neurons from MPTP toxicity is consistent with a role of parkin in DA neuron survival. In order to determine if parkin is necessary and sufficient in the recovery of TIDA neurons following MPTP, recombinant adeno-associated viral (rAAV) vectors containing parkin shRNA or a scrambled shRNA were created. Mice received stereotaxic ARC injections of rAAV containing either parkin shRNA or scrambled shRNA (250nl/side; 3.5x1013vg/ml), or remained naïve to surgery, and were administered a single injection of MPTP (20mg/kg; s.c.) 30 days following rAAV surgery. Twenty-four h post-MPTP, TIDA neurons were able to recover axon terminal DA concentrations following MPTP in control and scrambled shRNA treated animals. However, axon terminal DA was significantly reduced 24 hr following MPTP exposure following knockdown of parkin in TIDA neurons. To determine if parkin overexpression would protect NSDA neurons from MPTP toxicity, mice received unilateral stereotaxic injection of rAAV containing parkin into the substantia nigra (SN) (500nl; 3.4x1013vg/ml) and were administered a single injection of MPTP (20mg/kg; s.c.) 30 days following rAAV surgery. Twenty-four hours post-MPTP, parkin overexpression was unable to rescue MPTP-induced loss of DA in the striatum (ST), but did rescue MPTP-induced loss of tyrosine hydroxylase (TH) in the SN and ST. These findings are consistent with the following conclusions: 1) TIDA neuronal recovery from acute MPTP exposure is independent of extrinsic factors and is mediated by an intrinsic ability to increase expression of neuroprotective proteins, 2) The ability of TIDA neurons to up-regulate parkin is at least partially responsible for recovery of axon terminal DA following MPTP, 3) toxicant-induced loss of parkin contributes to MPTP toxicity within NSDA neurons.
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Title: 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: Employing Insect Antennal Lobe Olfactory Neural Signals for Non-Invasive Disease Detection
Creator: Farnum, Alexander J.
Date: 2023
Collection: Electronic Theses & Dissertations
Description: Gas-based chemical sensors have proven invaluable for investigating the underlying chemical configuration of a particular odorant. Technologies such as gas chromatography-mass spectrometry and hyphenated ion mobility spectrometry have elucidated numerous causal factors and biochemical pathways contributing to a variety of healthy and pathologic conditions. Nevertheless, these technologies face innate challenges that have precluded their adoption and implementation in the clinical environment....
Show moreGas-based chemical sensors have proven invaluable for investigating the underlying chemical configuration of a particular odorant. Technologies such as gas chromatography-mass spectrometry and hyphenated ion mobility spectrometry have elucidated numerous causal factors and biochemical pathways contributing to a variety of healthy and pathologic conditions. Nevertheless, these technologies face innate challenges that have precluded their adoption and implementation in the clinical environment. As a result, a considerable amount of research and development has been geared towards fabricating cheap, easy-to-use, and highly portable electronic noses. These devices have demonstrated excellent potential for applications such as environmental monitoring, food analysis, and forensic science. Moreover, innovations in nanotechnology and other materials science fields have spurred the ideation and creation of highly efficient electronic noses. However, the broad range and low concentrations of chemical metabolites observed in breath profiles, hinders their use as medical diagnostics for complex diseases. Here, this work proposes a novel technology utilizing biologically based chemical biosensors to accurately characterize the volatile profiles associated with pathological disease states, especially that of cancer. The development of this powerful and efficient gas-sensing system has the potential for use in a variety of real-world contexts, including homeland security, law enforcement, and medicine.It is well known that the presence of disease alters underlying biochemical processes, thereby influencing metabolic byproducts and the volatile chemicals excreted via the breath. Existing manmade chemical sensors as medical diagnostics lack the ability to differentiate the breath profiles of healthy individuals from those with complex diseases. Chapter 1 investigates the field of volatolomics as a whole, including the gas-based identification of ‘simple’ diseases and the application of state-of-the-art sensor technologies to diagnose complex pathologies. In chapter 2, the methodology for all experiments involving this novel gas-based biosensor in the context of disease diagnosis is discussed. Chapters 3, 4, and 5 detail applied research which validates the biosensors’ powerful abilities to differentiate chemicals and chemical profiles. This work serves to establish its potential as a non-invasive medical diagnostic using biological matrices, such as breath profiles. Finally, chapter 6 discusses the current limitations of the proof-of-concept technology as well as modifications that will mitigate such limitations and aid in the creation of an effective state-of-the-art breath-based medical diagnostic.
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Title: Linking the Spatial Dimension to the Timing Control of Rhythmic Movements
Creator: KROGER, CAROLYN
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Rhythmically timed movements are integral to a wide range of human behaviors, including the production of fluent speech, music performance, dance, and sports, to name a few. Deficits in the timing of rhythmic movements have been observed in numerous neurological conditions, which can be devastating for an individual’s quality of life. One common method to investigate mechanisms underpinning the timing of rhythmic actions is a finger tapping task in which individuals synchronize finger taps...
Show moreRhythmically timed movements are integral to a wide range of human behaviors, including the production of fluent speech, music performance, dance, and sports, to name a few. Deficits in the timing of rhythmic movements have been observed in numerous neurological conditions, which can be devastating for an individual’s quality of life. One common method to investigate mechanisms underpinning the timing of rhythmic actions is a finger tapping task in which individuals synchronize finger taps with a series of tones that establish a target inter-tap interval (ITI) and then continue to produce the target interval after the tones stop. The data of interest in these studies have almost exclusively consisted of the time series of tap onsets and associated sequence of ITIs. Because all movements are inherently spatiotemporal, the thesis investigated herein is that our understanding of timing processes is incomplete because previous work ignores the contributions of spatial elements of an individual’s movements to their timing control. The experiments reported here fill this gap by using continuous motion tracking to measure the spatiotemporal dynamics of paced and unpaced rhythmic finger tapping and by considering the relation between spatiotemporal measures and timing accuracy and precision. Five experiments tested a series of hypotheses about contributions of spatiotemporal factors to the timing control of rhythmic movements. Experiment 1 tested a preferred velocity hypothesis that integrates amplitude and tempo for unpaced tapping. Participants completed unpaced tapping tasks that separately assessed preferred movement amplitude (finger height) and tempo (Mean ITI). In support of this hypothesis, participants produced similar amplitudes and tempi regardless of instructions for either preferred amplitude or tempo. Experiments 2 and 3 tested an amplitude control hypothesis for paced tapping where participants matched a wide range of target ITIs. Consistent with this hypothesis, individuals decreased tap amplitude with shorter target ITIs and variability in amplitudes predicted variability in ITIs. Further supporting this hypothesis, forcing participants to produce low and high amplitudes during paced tapping interfered with timing accuracy and precision in a manner consistent with amplitude as a parameter in timing control. The preferred velocity hypothesis was further supported by results showing that timing was less variable for conditions where participants tapped at target amplitudes and tempi that, in combination, were closer to their preferred velocity. Experiment 4 extended this line of work to timing control of tapping at slow tempi (near the temporal boundary where perceived rhythm breaks down). Of primary interest was a dwell time hypothesis, which proposes that at slow target ITI when amplitude cannot be increased further to lengthen intervals, participants increase dwell time (how long their finger rests on the table) to produce longer ITIs. Providing initial support for this hypothesis, participants kept tap amplitude constant and increased tap dwell time to produce longer ITIs. At the slowest target ITI, a bimodal distribution in tap dwell times also was observed, reflecting individual differences in dwell time strategy where some participants kept a constant proportion of dwell time to target ITI, while others increased the proportion of dwell time at slower tempi (longer ITIs). As a follow-up, Experiment 5 manipulated tap dwell time during paced tapping at comfortable and very slow tempi (ITIs). Participants successfully lengthened or shortened their dwell time at the slow ITI, regardless of their preferred dwell time. Timing accuracy and precision at the slow ITI were particularly poor when participants were instructed to produce short dwell times, suggesting that longer dwell times at slow tempi facilitate temporal accuracy and precision. Altogether, results provide novel evidence of contributions of spatial characteristics of rhythmic movements to their temporal control and lays the foundations for a new theory of timing and temporal control that links the dimensions of space and time.
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Title: SEX AND PHENOTYPIC DIFFERENCES OF OBESITY-INDUCED GHSR VENTRAL HIPPOCAMPAL DISRUPTIONS IN THE CONTROL OF APPETITE
Creator: KONDILIS, ATHANASIOS
Date: 2022
Collection: Electronic Theses & Dissertations
Description: The gastric hunger signal, ghrelin, influences feeding behavior via activation of the growth hormone secretagogue receptor (GHSR). GHSR’s are abundantly expressed in cells in the ventral hippocampus (VHPC) where they function to regulate food intake. In this study, we used a GHSR-IRES-Cre mouse to examine whether feeding behaviors driven by GHSR cells in the VHPC are influenced by vulnerability to dietary obesity. Both males and females were exposed to 8 weeks of a high fat diet (HFD)—the top...
Show moreThe gastric hunger signal, ghrelin, influences feeding behavior via activation of the growth hormone secretagogue receptor (GHSR). GHSR’s are abundantly expressed in cells in the ventral hippocampus (VHPC) where they function to regulate food intake. In this study, we used a GHSR-IRES-Cre mouse to examine whether feeding behaviors driven by GHSR cells in the VHPC are influenced by vulnerability to dietary obesity. Both males and females were exposed to 8 weeks of a high fat diet (HFD)—the top and bottom quartiles of weight gainers from each respective sex were designated as diet-induced obese (DIO) and diet resistant (DR), respectively. These mice received targeted injections of an excitatory (hM3Dq) or inhibitory DREADD (hM4Di) virus. This enabled chemogenetic control of GHSR-expressing cells in the VHPC as mice engaged in consumption of lab chow or HFD. Only DR female mice displayed the expected increase in food intake when tested with lab chow following DREADD stimulation, indicating that female mice that are resistant to dietary obesity maintain typical function for GHSR’s in VHPC. Surprisingly, in males, DREADD stimulation decreased meal intake, which for chow occurred in DIO mice, whereas for HFD testing this was observed in DR mice. On the other hand, DREADD inhibition attenuated chow intake only in female mice. In the final series of studies, I used licking microstructure to examine the pre-ingestive (e.g., orosensory, palatability) and post-ingestive (e.g., gastrointestinal negative feedback) variables that regulate GHSR-dependent food intake. Multiple findings were revealed, including that the increased consumption of food in female mice following GHSR stimulation reflects a reduction in gastrointestinal negative feedback. Overall, my findings stress the need to implement a rigorous examination of a host of variables with refined analyses of meal intake to determine a role for how feeding signals in the brain impact ingestive behavior.
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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: Directed information for complex network analysis from multivariate time series
Creator: Liu, Ying
Date: 2012
Collection: Electronic Theses & Dissertations
Description: Complex networks, ranging from gene regulatory networks in biology to social networks in sociology, havereceived growing attention from the scientific community. The analysis of complex networks employs techniquesfrom graph theory, machine learning and signal processing. In recent years, complex network analysis tools havebeen applied to neuroscience and neuroimaging studies to have a better understanding of the human brain. In thisthesis, we focus on inferring and analyzing the complex...
Show moreComplex networks, ranging from gene regulatory networks in biology to social networks in sociology, havereceived growing attention from the scientific community. The analysis of complex networks employs techniquesfrom graph theory, machine learning and signal processing. In recent years, complex network analysis tools havebeen applied to neuroscience and neuroimaging studies to have a better understanding of the human brain. In thisthesis, we focus on inferring and analyzing the complex functional brain networks underlying multichannelelectroencephalogram (EEG) recordings. Understanding this complex network requires the development of a measureto quantify the relationship between multivariate time series, algorithms to reconstruct the network based on thepairwise relationships, and identification of functional modules within the network.Functional and effective connectivity are two widely studiedapproaches to quantify the connectivity between two recordings.Unlike functional connectivity which only quantifies the statisticaldependencies between two processes by measures such as crosscorrelation, phase synchrony, and mutual information (MI), effectiveconnectivity quantifies the influence one node exerts on anothernode. Directed information (DI) measure is one of the approachesthat has been recently proposed to capture the causal relationshipsbetween two time series. Two major challenges remain with theapplication of DI to multivariate data, which include thecomputational complexity of computing DI with increasing signallength and the accuracy of estimation from limited realizations ofthe data. Expressions that can simplify the computation of theoriginal definition of DI while still quantifying the causalityrelationship are needed. In addition, the advantage of DI overconventionally causality measures such as Granger causality has notbeen fully investigated. In this thesis, we propose time-laggeddirected information and modified directed information to addressthe issue of computational complexity, and compare the performanceof this model free measure with model based measures (e.g. Grangercausality) for different realistic signal models.Once the pairwise DI between two random processes is computed,another problem is to infer the underlying structure of the complexnetwork with minimal false positive detection. We propose to useconditional directed information (CDI) proposed by Kramer to addressthis issue, and introduce the time-lagged conditional directedinformation and modified conditional directed information to lowerthe computational complexity of CDI. Three network inferencealgorithms are presented to infer directed acyclic networks whichcan quantify the causality and also detect the indirect couplingssimultaneously from multivariate data.One last challenge in the study of complex networks, specifically in neuroscience applications, is to identifythe functional modules from multichannel, multiple subject recordings. Most research on community detection inthis area so far has focused on finding the association matrix based on functional connectivity, instead ofeffective connectivity, thus not capturing the causality in the network. In addition, in order to find a modularstructure that best describes all of the subjects in a group, a group analysis strategy is needed. In thisthesis, we propose a multi-subject hierarchical community detection algorithm suitable for a group of weightedand asymmetric (directed) networks representing effective connectivity, and apply the algorithm to multichannelelectroencephalogram (EEG) data.
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Title: Altered Metabotropic Glutamate Receptor Function in the Neocortex of a Fragile X Mouse
Creator: Fenn, Jacqueline Ann
Date: 2017
Collection: Electronic Theses & Dissertations
Description: Fragile X Syndrome (FXS) is the leading cause of inherited intellectual disability. It is characterized by a wide array of symptoms, including cognitive impairments, attention deficit and hyperactivity disorder (ADHD), hypersensitivity to sensory stimuli, autistic features, mood lability, and seizures. Since the creation of the Fmr1 KO mouse more than 20 years ago, a wealth of studies have uncovered a role for group I metabotropic glutamate receptors (mGluRs) in mediating many FXS phenotypes,...
Show moreFragile X Syndrome (FXS) is the leading cause of inherited intellectual disability. It is characterized by a wide array of symptoms, including cognitive impairments, attention deficit and hyperactivity disorder (ADHD), hypersensitivity to sensory stimuli, autistic features, mood lability, and seizures. Since the creation of the Fmr1 KO mouse more than 20 years ago, a wealth of studies have uncovered a role for group I metabotropic glutamate receptors (mGluRs) in mediating many FXS phenotypes, leading to development of "The mGluR Theory of Fragile X". However, studies supporting this theory have focused on impairments in the hippocampus, amygdala, and other structures of the allocortex. The isocortex remains largely uninvestigated, despite its major role in sensory integration, attentional processes, and executive function. MgluRs are also highly expressed in the neocortex, where they can modulate neuronal excitability and synaptic transmission. Using electrophysiological methods, I investigated the role of group I and group II mGluRs in modulating neocortical circuits in primary visual cortex. Humans with FXS show severe visual-motor deficits, and perform poorly on global motion tasks. Autopsy studies also reveal abnormal dendritic spine morphologies in layer 5/6 of the visual neocortex, and this is substantiated in the Fmr1 KO mouse. Using whole cell patch clamp recordings of different neuron subtypes in layer 5/6 of primary visual cortex, I found that Fmr1 KO layer 5/6 somatostatin expressing neurons (SST+) have a significant decrease in input resistance compared to wild type (WT), indicating that they are less intrinsically excitable than WT SST+ neurons. Further, I show that activation of group II mGluRs leads to disinhibition of excitatory pyramidal neurons. I also discover that suppression of GABAergic transmission by group II mGluRs is normal in the Fmr1 KO, leading to my hypothesis that increased disinhibition of pyramidal neurons by group II mGluRs is due to their altered modulation of fast glutamatergic transmission onto layer 5/6 interneurons in the Fmr1 KO mouse. Using recordings from fluorescently labeled interneurons in layer 5/6 visual neocortex, I discover that group II mGluR-mediated suppression of fast excitatory glutamatergic transmission onto inhibitory neurons is exaggerated in the Fmr1 KO mouse. I show that this effect is cell specific, as it only occurs in SST+ interneurons and not parvalbumin expressing interneurons. Finally, I show that this deficit in excitatory drive onto SST+ interneurons is mediated by presynaptic mGluRs, and that these defects are specific to layer 5/6 visual neocortex. Both the decreased excitability of SST+ interneurons and exaggerated group II-mGluR mediated suppression of excitatory drive onto these cells would lead to neocortical circuit hyperexcitability in the Fmr1 KO mouse. A hyperexcitable neocortical circuit would be anticipated to negatively impact sensory integration, a requirement for both stimulus encoding and attentional processes. Lastly, a hyperexcitable neocortical network could give rise to epileptiform activity. The results of these studies are fascinating, as group II mGluRs have not previously been implicated in studies of the neocortical pathogenesis in the Fmr1 KO mouse. This investigation also showed that group I mGluR-mediated modulation of membrane excitability and fast synaptic transmission is unaltered in the Fmr1 KO mouse, suggesting that "The mGluR theory of Fragile X" may in fact be more or less valid contingent on the brain region under investigation. It is my hope that these circuit studies will inform scientific investigations on autism spectrum disorders and epilepsy syndromes, as both show high comorbidity in individuals with FXS.
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Title: Pathology at the neuromuscular junction in mouse models of spinal bulbar muscular atrophy
Creator: Poort, Jessica Erin
Date: 2014
Collection: Electronic Theses & Dissertations
Description: Spinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease that results in muscle weakness and atrophy, as well as motoneuron death in men. While pathology at the neuromuscular junction (NMJ) is noted in numerous neurodegenerative diseases, disease-related changes at the NMJ in SBMA have not been explored. Characterizing such changes is not only important for determining whether the NMJ has any role in the functional changes underlying motor dysfunction, but also...
Show moreSpinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease that results in muscle weakness and atrophy, as well as motoneuron death in men. While pathology at the neuromuscular junction (NMJ) is noted in numerous neurodegenerative diseases, disease-related changes at the NMJ in SBMA have not been explored. Characterizing such changes is not only important for determining whether the NMJ has any role in the functional changes underlying motor dysfunction, but also in determining how such potential pathology at the NMJ develops as disease progresses. If for example, pathology emerges first at the NMJ followed by motoneuron death, then the NMJ offers future promise as a therapeutic target for preventing or reversing symptoms of SBMA before motoneurons are lost. We evaluated three different mouse models of SBMA, one overexpressing a wildtype androgen receptor (AR) exclusively in muscle fibers (so called "myogenic" model), a second which expressed the endogenous AR gene with the first exon of the human mutant AR gene "knocked in" (the so called "knock-in" model), and a final model that broadly expresses a full length human AR transgene harboring the SBMA mutation (the so called "97Q" model). Using both confocal microscopy and electron microscopy, I found that all three mouse models show a pathological fragmentation of the NMJ suggestive of functionally weakened synapses. Other changes at the neuromuscular synapse suggesting decreases in synaptic strength that were found in some but not all models include a decline in the number of docked vesicles ready for release in nerve terminals, a widening of synaptic clefts, simplified postsynaptic folds, and an abnormal accumulation of synaptic vesicle and neurofilament proteins. Retrograde axonal transport of endosomes was also characterized in the 97Q model using live imaging confocal microscopy. Despite previously published data, I found no evidence for a disease-related defect in retrograde transport in the 97Q model. The strikingly abnormal morphology of NMJs in all three models raises the possibility that synaptic function is impaired. Such synaptic dysfunction may contribute to or underlie the impairments in motor function associated with SBMA.
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Title: 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: 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

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