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The Subplate And Its Role In The Gaba System In The Prefrontal Cortex, Gaeul Kyla Lee

Electronic Thesis and Dissertation Repository

During early brain development, the subplate relays thalamocortical afferents. Lesions to the subplate have been implicated in developmental abnormalities of cortical GABAergic circuits. This thesis examined the effects of subplate lesions in the prefrontal cortex of rats on the expression of GABA markers (parvalbumin and GAD67) and GABA synapse maturation [potassium-chloride cotransporter (KCC2) and sodium-potassium- chloride cotransporter (NKCC1)] with relevance to the characterization of a rat model for schizophrenia. Lesions were made on postnatal day 1 (P1). Lesioned and control rats were sacrificed between P5 and P90 and immunolabelled for parvalbumin, GAD67, KCC2, and NKCC1. We found decreased parvalbumin expression …

Examining The Structure Of Symbolic Number Representations In The Parietal Cortex: An Rsa Study, Aymee Alvarez Rivero

Electronic Thesis and Dissertation Repository

Previous studies using fMRI adaptation to investigate the neural substrate of symbolic number processing have found ratio-dependent responses in regions of the parietal cortex, suggesting that number symbols are coded by overlapping neuronal populations: the larger the ratio between two numerals, the more their representation overlap. The current study analyzed the distributed patterns of activation associated with numerals presented during this task. I could not find substantial evidence supporting the ratio-dependent structure of the similarity space predicted by the univariate adaptation analyses. I also failed to find evidence in favor of the alternative model that similarities were driven by lexical …

Elucidating The Consequence And Cause Of Microrna Dysregulation In Amyotrophic Lateral Sclerosis (Als), Zachary C. E. Hawley

Electronic Thesis and Dissertation Repository

Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neurodegenerative disorder with an average life expectancy of 2-5 years post-diagnosis. Common pathological features associated with ALS are the formation of cytoplasmic inclusions of intermediate filaments and RNA-binding proteins within motor neurons. The formation of intermediate filament cytoplasmic inclusions is believed to be driven by a loss of stochiometric expression between five neuronal intermediate filament proteins—NFL, NFM, NFH, INA and PRPH—where there is a selective suppression of the steady-state levels of NEFL, INA and PRPH mRNA. Further, three RNA-binding proteins—TDP-43, FUS and RGNEF—have been shown to co-aggregate with each other in …

Computational Unfolding Of The Human Hippocampus, Jordan M. K. Dekraker

Electronic Thesis and Dissertation Repository

The hippocampal subfields are defined by their unique cytoarchitectures, which many recent studies have tried to map to human in-vivo MRI because of their promise to further our understanding of hippocampal function, or its dysfunction in disease. However, recent anatomical literature has highlighted broad inter-individual variability in hippocampal morphology and subfield locations, much of which can be attributed to different folding configurations within hippocampal (or archicortical) tissue. Inspired in part by analogous surface-based neocortical analysis methods, the current thesis aimed to develop a standardized coordinate framework, or surface-based method, that respects the topology of all hippocampal folding configurations. I developed …

Cognitive Resources Are Recruited Consistently Across People During Story Listening, Matthew T. Bain

Electronic Thesis and Dissertation Repository

Degraded speech encoding as a result of hearing loss increases cognitive load and makes listening effortful. Standard hearing assessment does not capture this cognitive impact of hearing impairment. Speech-in-noise testing measures intelligibility for isolated sentences that are typically not engaging and lack meaningful context. These materials may not capture the processes involved in everyday listening situations, in which people are often intrinsically motivated to comprehend the speech they are hearing. The current study explored a novel approach using natural, spoken stories. We first characterized time courses of executive load during story listening in young individuals with normal hearing using a …

Investigating Cognitive Impairment In Tdp-43 Mouse Models Of Ftd-Als Using Automated Touchscreens, Keon Coleman

Electronic Thesis and Dissertation Repository

TAR-DNA-binding protein 43 (TDP-43) misfolding and aggregation is a major pathological hallmark of frontotemporal dementia-amyotrophic lateral sclerosis (FTD/ALS). FTD/ALS is characterized by motor and cognitive impairment, with cognitive impairment frequently reported before the onset of classical motor symptoms. Yet, treatment for cognitive decline in FTD/ALS is lacking, and robust cognitive phenotypes related to TDP-43 proteinopathy have not been established for most mouse models of FTD/ALS. Herein, we used automated touchscreen technology to assess executive function (affected in FTD/ALS) in male TDP-43^Q331Klow and ^-G348C FTD/ALS transgenic mice. The touchscreen pairwise visual discrimination task revealed impairments in 4-5-month-old TDP-43^Q331Klow and …

Dnajc7, A Molecular Chaperone Protein That Modulates Protein Misfolding In Amyotrophic Lateral Sclerosis (Als), Meaghan Kathleen Stoltz

Electronic Thesis and Dissertation Repository

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease associated with protein misfolding and dysregulated cellular protein quality control mechanisms. Molecular chaperones, and heat shock proteins (Hsp), are key players in maintaining cellular protein quality control. DNAJC7 is an understudied cytosolic Hsp40 that works together with Hsp70 and Hsp90 to regulate proper protein folding or degradation. Of note, mutations in the gene encoding DNAJC7 were discovered to cause familial ALS. We asked whether ALS-associated mutations in DNAJC7 compromise its function as a chaperone, which may cause the toxic accumulation of misfolded proteins. This study attempts to uncover the functions of DNAJC7 …

Optimizing Preprocessing Of Fmri Data To Maximize Correspondence Of Functional Anatomy Across Individuals, Nargess Ghazaleh

Electronic Thesis and Dissertation Repository

In movie-activation fMRI, intersubject correlation (ISC) indicates a functional correspondence across viewers. Brains di↵er in shape; spatial normalization and smoothing enhance inter-subject functional overlap. We compare three normalization methods and six smoothing levels to discover which method yields the best functional overlap, indexed by ISC. This is key to optimizing data analysis in clinical studies using movie-activation fMRI in future. In a 3T scanner, 44 healthy subjects watched an 8-min movie. Both normalization and smoothing a↵ected the strength and extent of the ISC. ISC values were more robust for ANTs and DARTELthanforSPM12andwere(asymptotically)thestrongestat12mmsmoothing. When image data are preprocessed with high-dimensional volumetric …

Early Markers Of Dysfunction In Frontotemporal Dementia, Tamara P. Tavares

Electronic Thesis and Dissertation Repository

Frontotemporal Dementia (FTD) is a neurodegenerative disorder that results in atrophy within the frontal and/or temporal lobes. Clinically, patients with FTD present with progressive deterioration in behaviour and/or language abilities. FTD has a strong genetic component with approximately 40% of patients reporting a family history. Specifically, mutations in microtubule-associated protein tau (MAPT), progranulin (GRN) and expanded repeats in the chromosome 9 open reading frame 72 (C9orf72) are the main genetic causes of FTD. Currently, no disease-modifying treatments exist, and off-label medications have been used for symptomatic management of behaviours. Substantial progress has been made to …

The Role Of The Leucine-Rich (Leur) Domain Of Rho Guanine Nucleotide Exchange Factor (Rgnef) In The Regulation Of Amyotrophic Lateral Sclerosis (Als) Associated Protein Tar Dna-Binding Protein Of 43 Kda (Tdp-43), Hind Amzil

Electronic Thesis and Dissertation Repository

The presence of neuronal cytoplasmic inclusions (NCIs) composed of RNA-binding proteins (RBPs) and neurofilaments is considered to be ALS’s neuropathological hallmark. RGNEF has been previously shown to interact with TDP-43 and to have a regulatory effect on the expression levels of NEFL mRNA and NFL protein in vitro. Here, I examined the mechanism of the RGNEF N-terminus, leucine-rich domain (LeuR) domain’s interaction with TDP-43. I observed that the minimal domain required is 110 amino acids (LeuR110), that the Ankyrin domain adjacent to LeuR110 does not participate, and that LeuR110 forms of a high molecular weight complex with TDP-43 in …

The Effect Of Nitric Oxide On Microglia Function And Activity: Implications On Transient Receptor Potential Channels, Matthew J-E. Maksoud

Electronic Thesis and Dissertation Repository

Microglia proliferation and phagocytosis is critical for proper development and maintenance of the central nervous system (CNS), whereas dysregulated proliferation and phagocytosis contributes to various CNS pathologies. Specifically, in response to pathology or tissue injury, microglia transform to an activated state characterized by elevated inducible nitric oxide synthase (iNOS) expression, increased nitric oxide (NO) production, active phagocytosis, and decreased proliferation. Importantly, microglial phagocytosis and proliferation are tightly regulated by intracellular calcium levels. As non-excitable cells, microglia rely on calcium entry through transient receptor potential (TRP) channels to carry out phagocytosis and proliferation. However, the role of iNOS/NO signaling in regulating …

Feeling-Of-Knowing Experiences Breed Curiosity, Gregory Brooks

Electronic Thesis and Dissertation Repository

It is well-established that curiosity has benefits for learning. Less is known about potential links between curiosity and memory retrieval. In theoretical work on metacognition it has been argued that retrieval experiences that occur during memory search can exert control over behaviour. States of curiosity, which can be defined as behavioural tendencies to seek out information, may play a critical role in this control function. We conducted two experiments to address this idea, focusing on links between feeling-of knowing (FOK) experiences, memory-search duration, and subsequent information-seeking behaviour. We administered an episodic FOK paradigm that probed memory for previously studied arbitrary …

The Impact Of Multiliteracies And Multimodality On Esl Learners: Using Neuroimaging Technologies, Wenyu Huang

Electronic Thesis and Dissertation Repository

Educational neuroscience has become an important role in understanding education and the association with brain development. However, few previous studies have applied neuroimaging techniques to multiliteracies research, which is an important literacy pedagogy addressing multimodal learning and cultural and linguistic diversity. This study used functional near infrared spectroscopy (fNIRS) to investigate the association of multiliteracies learning on adult English Second Language (ESL) students’ performance through multimodal tasks.

Students’ multimodality background was collected through a technology questionnaire. Behavioural and fNIRS data were collected before and after multiliteracies learning. Results showed that there was no significance change in behavioural responses while the …

The Impact Of Emotional Information On Task Performance In Unimodal Vs. Cross-Modal Paradigms, Emma K. Stewart

Electronic Thesis and Dissertation Repository

Emotional stimuli can disrupt or enhance task performance, and this may depend on the sensory modality involved. In unimodal paradigms (e.g. visual task-irrelevant stimuli during a visual task) emotional stimuli frequently produce distraction effects; it is unclear how emotion affects task performance in cross-modal paradigms (e.g. auditory stimuli during a visual task). This project explored task performance as a function of sensory modality and emotional valence. In Study 1, participants (N=50) completed a visual task in the presence of task-irrelevant negative and neutral images and sounds. Response times and accuracy were disrupted in the presence of visual but not auditory …

Assessment Of Autistic-Like Behaviour Of Mice Lacking Atrx In Forebrain Glutamatergic Neurons, Nicole A. Martin-Kenny

Electronic Thesis and Dissertation Repository

Mutations in ATRX, which encodes a chromatin remodeling protein, have been identified in patients with autism and are associated with ATR-X syndrome, a genetic disorder characterized by cognitive deficits, developmental delays, and autistic-like behaviour. Despite the relationship between ATRX and autism, it is not yet known how mutations lead to autistic behaviour. To investigate this relationship, we generated two mouse models displaying distinct timing of Atrx inactivation in forebrain excitatory neurons. With these models, we performed behavioural paradigms to assess behaviour related to autism. Behavioural testing revealed that the conditional deletion of Atrx in differentiated forebrain neurons during …

Functional And Structural Brain Reorganization After Unilateral Prefrontal Cortex Lesions In Macaques, Ramina Adam

Electronic Thesis and Dissertation Repository

Visually exploring the surrounding environment relies on attentional selection of behaviourally relevant stimuli for further processing. The prefrontal cortex contributes to target selection as part of a frontoparietal network that controls shifts of gaze and attention towards relevant stimuli. Evidence from stroke patients and nonhuman primate lesion studies have shown that unilateral damage to the prefrontal cortex commonly impairs the ability to allocate attention toward stimuli in the contralesional visual hemifield. Although these impairments often exhibit a gradual improvement over time, the neural plasticity that underlies recovery of function remains poorly understood. The main objective of this dissertation was to …

Understanding The Effects Of Physical Activity On Executive Functioning And Psycho-Emotional Well-Being In Children With Adhd, Hannah B. Bigelow

Electronic Thesis and Dissertation Repository

A short bout of physical activity has been shown to improve executive functioning in children. However, the implications for children with Attention Deficit Hyperactivity Disorder (ADHD) has been understudied. We examined the impact of a 10min bout of physical activity on executive functioning and psycho-emotional well-being in children with ADHD. Participants engaged in two lab-based sessions separated by 1-week: a physical activity session and a control session. The physical activity session included a 10min bout of moderate-intensity biking, with a pre-post battery of cognitive and psycho-emotional assessments. The control session consisted of 10mins of silent reading. We used functional imaging …

Investigating Humor Processing In Parkinson's Disease, Margaret T.M. Prenger

Electronic Thesis and Dissertation Repository

Dopamine has a demonstrated role in humor processing. Humor comprehension (i.e., “getting the joke”) relies on dorsal striatum (DS) mediated problem-solving mechanisms, whereas humor appreciation (i.e., “funniness”) relies on ventral striatum (VS) mediated reward processing. Despite this, relatively little research has been conducted on potential deficits in humor processing in Parkinson’s disease (PD). The present study investigated the comprehension (i.e., categorization as jokes or non-jokes) and appreciation (i.e., funniness ratings) of verbal jokes and non-jokes in PD patients and healthy age-matched controls while ON and OFF levodopa medication. Relative to controls, PD patients demonstrated reduced humor comprehension in the form …

Frontoparietal Networks Underlying Saccadic Eye Movements In The Common Marmoset, Maryam Ghahremani

Electronic Thesis and Dissertation Repository

Common marmosets (Callithrix jacchus) are small-bodied New World primates that are increasingly popular as model animals for neuroscience research. Their lissencephalic cortex provides substantial advantages for the application of high-density electrophysiological techniques to enhance our understanding of local cortical circuits and their cognitive and motor functions. The oculomotor circuitry underlying saccadic eye movements has been a popular system to study cognitive control. Most of what we know about this system, comes from electrophysiological studies on macaques, but most of their cortical oculomotor areas are buried within sulci and harder to access for high-density recordings. In contrast, marmosets provide greater advantages …

The Role Of Histone Demethylases In Learning And Memory In The Mushroom Body Of Drosophila Melanogaster, Crystal Keung

Electronic Thesis and Dissertation Repository

Intellectual disability (ID) is a neurodevelopmental disorder associated with many epigenetic regulators and chromatin modifying enzymes like histone lysine methyltransferases (KMTs) and demethylases (KDMs). Here, I systematically investigate the role of 7 KDMs: Su(var)3-3, KDM2, Lid, CG2982, UTX, KDM4B, JHDM2, and 1 KMT: trr in the context of learning and memory using Drosophila melanogaster. Genetic knockdown of each gene in the mushroom body (MB) of flies are tested for short- and long-term memory impairment using courtship conditioning. Knockdown of 6 KDMs and trr resulted in memory loss. MB morphology was analyzed to determine potential cause of memory loss. …

Assessment Of Intrinsic Hand Neuromuscular Physiology, Philemon Tsang

Electronic Thesis and Dissertation Repository

Alterations to the peripheral nervous system and neuromuscular physiology may impact hand function in a typical or clinical population, such as individuals with ulnar neuropathy. The mechanisms that influence these positive and negative changes are still not well understood. The three studies within my thesis aim to validate the reliability of decomposition-based quantitative electromyography (DQEMG) measurements and explore the changes in intrinsic hand neuromuscular physiology in a typical aging population and individuals recovering from a surgical intervention for severe ulnar neuropathy.

The purpose of the first study was to determine the test-retest reliability of near-fibre (NF) jiggle, a measure of …

Oculomotor Task-Switching Performance Improves And Persists Following A Single Bout Of Aerobic Exercise, Diksha Shukla

Electronic Thesis and Dissertation Repository

Executive function includes the core components of response inhibition, working memory, and cognitive flexibility. Interestingly, an accumulating evidence has reported that inhibitory control and working memory improve following a single bout of exercise. It is, however, largely unclear whether cognitive flexibility elicits a similar post-exercise benefit. Accordingly, Chapter Two of my thesis examined whether 20-min of aerobic exercise provides an immediate post-exercise ‘boost’ to cognitive flexibility. Chapter Three examined for how long a putative post-exercise benefit persists. Cognitive flexibility was examined via an AABB task-switching paradigm wherein participants alternated between a well-practiced and a novel oculomotor task pre- and post-exercise. …

The Effects Of Chronic Inflammatory Demyelinating Polyneuropathy On The Neuromuscular System In Humans, Kevin J. Gilmore

Electronic Thesis and Dissertation Repository

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is an inflammatory autoimmune peripheral nerve disorder. CIDP is associated with demyelination, slow motor nerve-conduction velocity, and distal muscle weakness. CIDP is under-recognized due to its heterogeneous presentation and the limitations of clinical diagnostic criteria. Using a combination of electrophysiology and muscle imaging techniques the four studies outlined in this thesis systemically investigate the impacts of this demyelinating disease on motor nerves and their innervated muscles.

The first two studies examine the neuronal consequences of demyelination caused by CIDP and the following two studies investigate how skeletal muscle is affected by these neuronal complications. Specifically, …

Thyroxine-Dependent And -Independent Effects On Premature Aging And Myelination In Atrx Mutant Mice, Megan E. Rowland

Electronic Thesis and Dissertation Repository

ATRX is an ATP-dependent chromatin remodeler required to safeguard genomic integrity. Conditional deletion of Atrx in the mouse embryonic forebrain and anterior pituitary in Atrx^Foxg1Cre mice phenocopies mouse models of progeria which display increased DNA damage, coupled with reduced lifespan, growth and subcutaneous fat. These mice also have severely low circulating levels of insulin like growth factor 1 (IGF-1) and (T4) which have been reported in models of premature aging. Based on evidence that Igf1 is activated by the ligand-bound thyroid hormone receptor, I tested whether T4 supplementation could restore IGF-1 levels and ameliorate premature aging phenotypes in Atrx …

Mushroom Body-Specific Gene Regulation By The Swi/Snf Chromatin Remodeling Complex, Kevin Cj Nixon

Electronic Thesis and Dissertation Repository

Over the lifetime of an organism, neurons must establish, remodel, and maintain precise connections in order to form neural circuits that are required for proper nervous system functioning. Disruptions in these processes can lead to neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder. Mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex have been implicated in ID, yet the role of this complex in neurons is poorly understood. In this project, I established cell-type specific methods to examine the effect of SWI/SNF subunit knockdowns on gene transcription and chromatin structure in the memory-forming neurons of …

Using An Internal Auditory Stimulus To Activate The Developing Primary Auditory Cortex: A Fetal Fmri Study, Estee Goldberg

Electronic Thesis and Dissertation Repository

Insight into the rapidly developing brain in utero is scarce. Fetal functional magnetic resonance imaging (fMRI) is a technique used to gain awareness into the developmental process. Previous auditory task-based fMRI studies employed an external sound stimulus directly on the maternal abdomen. However, there has since been recommendation to cease doing so. We sought to investigate a reliable paradigm to study the development of fetal brain networks and postulate that by using an internal stimulus, such as the mother singing, it would result in activation of the fetal primary auditory cortex. Volunteers carrying singleton fetuses with a gestational age of …

Putting 'Dopamine Overdose' To The Test: A Psychopharmacological Investigation In Parkinson's Disease And Healthy Volunteers, Andrew Vo

Electronic Thesis and Dissertation Repository

Dopaminergic therapy prescribed to address motor symptoms in Parkinson’s disease (PD) is done at the expense of some cognition functions. It has been hypothesized that whether a given function is improved or impaired by medication depends on the baseline dopamine levels within underlying brain regions. Areas most affected by PD and severely dopamine depleted are predicted to benefit from dopaminergic therapy. Regions with less dopamine deficiency are predicted to worsen from excessive dopamine stimulation. This theoretical framework is known as the dopamine overdose hypothesis. The central aim of this thesis was to critically test the straightforward predictions put forward by …

Behavioural And Molecular Consequences Of Postnatal Stress In A Mouse Model Of Fetal Alcohol Spectrum Disorder, Bonnie Alberry

Electronic Thesis and Dissertation Repository

Fetal alcohol spectrum disorders (FASD) are caused by prenatal alcohol exposure (PAE) and affect 1‑5% of the North American population. Children born with FASD often face maternal separation throughout childhood. How this early life stress (ELS) affects the severity of FASD-related deficits is poorly understood. Using a mouse model, this dissertation establishes that behavioural deficits accumulate following prenatal alcohol exposure and early life stress, assessed using tests for activity, anxiety-like behaviour as well as learning and memory. Hippocampal gene expression was evaluated using RNA-seq followed by clustering of expression profiles through weighted gene co-expression network analysis (WGCNA). A set of …