Neurosciences Commons^™

The Effects Of Nmda Antagonism On Neuronal Activity And Neurovascular Coupling In Non-Human Primate Cortex, Benjamin Thomas Acland

Arts & Sciences Electronic Theses and Dissertations

The N-methyl-D-aspartate receptor (NMDAR) plays a variety of important roles in the development and function of primate central nervous systems. This thesis describes three nonhuman primate studies that, together, demonstrate that pharmacologically reducing NMDAR activity not only causes dramatic changes in neural activity in cortex, but also changes the relationship between that activity and a key signal often used as its proxy in human studies, the blood-oxygen-level-dependent (BOLD) signal. The first study reveals that NMDA antagonism is sufficient to induce powerful low-frequency modulation of spiking activity and extracellular local field potential (LFP) and discusses the implications of this finding for …

Contributions Of Specific Retinal Circuits And Their Respective Projections To Visual Behaviors, Jenna Mackenzie Krizan

Arts & Sciences Electronic Theses and Dissertations

The survival of a species is inextricably linked to its ability to successfully navigate and interact with its surroundings, whether to seek safety from predators or gain sustenance from prey. Both functions are performed by mice, guided by vision, and rely on intricate processing in the retina and subcortical targets in the brain. This dissertation addresses how specific features of the visual environment and specific retinal ganglion cell circuits that sample a particular space in the visual environment are used to guide efficient predation in mice.Recent studies have begun to link the ability to detect, track, and ultimately capture prey …

Sik3 & Wnk Signals Through Fray To Regulate Glial K+ Buffering And Seizure Susceptibility In Drosophila Models Of Hyperexcitability, Lorenzo Laronn Lones

Arts & Sciences Electronic Theses and Dissertations

K+ homeostasis is important for maintaining healthy, physiological levels of neuronal activity. Glial cells play a central role in maintaining homeostatic ion gradients. In previous work from our lab, we unravel a glial K+ buffering program that is centered on a key kinase, salt-inducible kinase 3 (SIK3). SIK3-HDAC4 signaling in glial regulates the transcription of channels and transporters involved in water and ion transport. Defects in this pathway lead to peripheral nerve edema, neuronal hyperactivity, and seizure sensitivity. In an hyperexcitability mutant, eag Shaker, we show this pathway is downregulated and genetic activation suppresses seizure behavior. In this thesis, I …

The Bidirectional Relationship Between The Circadian Clock And Alzheimer’S Disease, Patrick Sheehan

Arts & Sciences Electronic Theses and Dissertations

The circadian clock and inflammation have a well-described bidirectional relationship in the peripheral immune system: the circadian clock regulates inflammatory responses, but inflammation also impacts oscillatory gene transcription controlled by the clock. The purpose of this thesis work is to understand if manipulation of the circadian clock can impact Alzheimer’s disease pathology, and if pathology itself can alter the circadian clock and its outputs. Here, I show that astrocyte-specific disruption of the circadian clock via deletion of the clock gene Bmal1 surprisingly decreased intra-neuronal protein pathologies. Further investigation found that deletion of the circadian clock resulted in a transcriptomic profile …

Extensive Behavioral Phenotyping Of Williams Syndrome Locus Relevant Mouse Models To Assess Contributions Of Oxytocin And Gtf2ird1, Kayla Rose Nygaard

Arts & Sciences Electronic Theses and Dissertations

The Williams Syndrome Critical Region (WSCR) at chromosome 7q11.23 provides a unique opportunity to untangle the relationship between genotype and phenotype in complex behaviors, from fear and anxiety to sociability and sensorimotor processing. Copy number variations (CNVs) in this region result in two syndromes, Williams Syndrome (WS) and Duplication 7q11.23 Syndrome (Dup7), which display phenotypes that may align, indicating a common disruption of a system, or diverge, reflecting an underlying gene dosage-dependent effect. While case studies of atypical deletions resulting in WS have implicated telomeric genes Gtf2ird1 and Gtf2i in the cognitive and behavioral profiles of WS, proving causation requires …

Salience Coding In The Basal Forebrain And The Heterogeneous Underpinnings Underlying Novelty Computations, Kaining Zhang

McKelvey School of Engineering Theses & Dissertations

Humans and animals are consistently learning from the environment by interacting with it and getting feedback from their actions. In the environment, some objects are more important than others, because they are associated with reward, uncertainty, surprise, or novelty etc. These objects are salient to the animal. Salient objects attract attention and orientation, increase arousal, facilitate learning and memory, and affect reinforcement learning and credit assignment. However, the neural basis to support these effects is still not fully understood.We first studied how the basal forebrain, one of the principal sources of modulation of the neocortex, encodes salience events. We found …

Validation, Categorizing, And Prediction Of Upper Limb Outcomes After Stroke, Jessica Barth

Arts & Sciences Electronic Theses and Dissertations

The incidence and costs of stroke in the United States are projected to rise over the next decade because of the aging population. Declining stroke mortality over the past few decades means that more people survive stroke and live with physical, cognitive, and emotional disability. Stroke remains one of the leading causes of disability in the United States because very few survivors experience a full recovery of their upper limb. Upper limb recovery after stroke is critical to performing activities of daily living and physical and occupational therapies are one of the only treatment options to address these challenges. The …

Understanding The Influence Of Individual-Level Sources Of Pathology Variation On Neuroimaging Measures Of Alzheimer Disease, Austin Andrew Mccullough

Arts & Sciences Electronic Theses and Dissertations

The overall goal of this dissertation is to gain a better understanding of how current Alzheimer disease pathologic progression models interact with sources of individual-level variation in pathology to influence overall disease progression in a clinically meaningful way. Many sources of variation, both internal (e.g., genetic mutations, heterogeneity of tau pathology) and external (e.g., diet and exercise, sleep quality), are known to influence disease progression and symptom onset in AD. With the advent of therapies that have shown successful reduction of amyloid load in trials and the rapid progression of anti-tau therapies, we hypothesize that a better understanding of how …

Defining The Role Of Rare Genetic Variants That Drive Risk And Pathogenesis Of Alzheimer’S Disease, Matthew James Rosene

Arts & Sciences Electronic Theses and Dissertations

Alzheimer’s disease (AD) is the leading cause of dementia and is pathologically defined by the aggregation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Rare heritable mutations within the genes for amyloid precursor protein (APP) and presenilin 1 (PSEN1), and presenilin 2 (PSEN2) cause early onset AD and account for approximately 1% of AD cases. While the majority of AD cases are late-onset (LOAD), which is defined by a markedly more complex genetic architecture that is comprised of many genetic risk factors that influence AD through multiple cellular pathways. The advent of deep sequencing analyses have allowed for the identification …

Disuse-Driven Plasticity In The Human Brain, Dillan James Newbold

Arts & Sciences Electronic Theses and Dissertations

Brain circuits are shaped and maintained by active use. We blocked use of motor circuits in three adult participants by constraining the dominant upper extremity in a cast for two weeks, causing loss of strength and fine motor function. Daily resting-state functional magnetic resonance imaging (rs-fMRI) collected for 42-64 days before, during and after casting revealed two sets of changes in brain function. First, large, spontaneous pulses of activity occurred in the disused motor circuits. Pulses showed a consistent pattern of propagation through the disused circuits— occurring earliest in the dorsal anterior cingulate cortex (dACC) and supplementary motor area (SMA), …

Functional And Anatomical Characterization Of Descending Periaqueductal Gray (Pag) Projections And Their Role In Pain Modulation, Jose Gabriel Grajales

Arts & Sciences Electronic Theses and Dissertations

Endogenous analgesic pathways embody a potential target for the development for chronic pain therapies. Previous studies have demonstrated the role of the ventrolateral periaqueductal gray (vlPAG) in descending pain modulation. It has been proposed that tonic GABAergic neurotransmission at the level of the vlPAG serves to inhibit efferent excitatory projections that mediate descending analgesia. Disinhibition of these projection neurons allows subsequent activation of rostral ventromedial medulla (RVM) neurons that inhibit nociception at the level of the spinal cord. However, lack of cell-type specificity in these studies has prevented the determination of the role of specific subsets of vlPAG neurons in …

Vcp: A Gatekeeper For Intracellular Proteopathic Seeding, Jiang Zhu

Arts & Sciences Electronic Theses and Dissertations

Protein inclusions such as β-amyloid, tau, α-synuclein, and TDP-43 are considered the pathologic hallmarks of many neurodegenerative diseases. These proteins are prone to misfold, aggregate, and template new aggregates. Accumulating evidence suggests that those proteins in their high-molecular-weight forms can serve as a "seed", spread through an interconnected brain network, and induce new inclusions. Therefore, it is essential to understand the mechanism of proteopathic seeding. In this dissertation, we performed a whole genomic CRISPR-Cas9 KO screening to identify gene modifiers of αS seeding. Within the screening, we found several hits of endolysosomal function and trafficking, including VCP. VCP is a …

An Investigation Of Sensory Percepts Elicited By Macro-Sieve Electrode Stimulation Of The Rat Sciatic Nerve, Nikhil Shiva Chandra

McKelvey School of Engineering Theses & Dissertations

Intuitive control of conventional prostheses is hampered by their inability to replicate the rich tactile and proprioceptive feedback afforded by natural sensory pathways. Electrical stimulation of residual nerve tissue is a promising means of reintroducing sensory feedback to the central nervous system. The macro-sieve electrode (MSE) is a candidate interface to amputees’ truncated peripheral nerves whose unique geometry enables selective control of the complete nerve cross-section. Unlike previously studied interfaces, the MSE’s implantation entails transection and subsequent regeneration of the target nerve. Therefore, a key determinant of the MSE’s suitability for this task is whether it can elicit sensations at …

Influence Of Focal Activity On Macroscale Brain Dynamics In Health And Disease, Zachary Pollack Rosenthal

Arts & Sciences Electronic Theses and Dissertations

Macroscopic recordings of brain activity (e.g. fMRI, EEG) are a sensitive biomarker of the neural networks supporting neurocognitive function. However, it remains largely unclear what mechanisms mediate changes in macroscale networks after focal brain injuries like stroke, seizure, and TBI. Recently, optical neuroimaging in animal models has emerged as a powerful tool to begin addressing these questions. Using widefield imaging of cortical calcium dynamics in mice, this dissertation investigates the mechanisms by which focal disruptions in activity alter brain-wide functional dynamics. In two chapters, I demonstrate 1) that focal sensory stimulation elicits state-dependent, global slow waves propagating from primary somatosensory …

Causal Function And Bias Correlation Of The Orbitofrontal Cortex In Economic Choices, Shi Weikang

Arts & Sciences Electronic Theses and Dissertations

Economic choices entail two mental processes, value calculation and value comparison (Niehans, 1990). Studies in the last twenty years have shown that neurons in the orbitofrontal cortex (OFC) could support both processes. Namely, in the studies in which monkeys chose between two juice options with various amounts, three functional cell groups had been found in the OFC: offer value cells encode the value of individual juices, chosen juice cells encode the choice in a binary way and chosen value cells encode the value of the chosen juice (Padoa-Schioppa and Assad, 2006). These results suggest a decision circuit within OFC with …

The Role Of Neuronal Atp-Sensitive Potassium Channels In Learning And Memory, Shaul Vladimir Yahil

Arts & Sciences Electronic Theses and Dissertations

ATP-sensitive potassium (KATP) channels link cellular metabolism and membrane excitability in many tissues, including brain and pancreas. Gain-of-function (GOF) mutations to KATP channels cause neonatal diabetes, with some patients exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Diabetic symptoms have been attributed to loss of membrane excitability and insulin secretion in pancreatic β-cells, though the origin of neurological deficits and the effects of neuronal KATP-GOF mutations more generally remain elusive. In this dissertation, I will present evidence that mice expressing KATP-GOF mutations pan-neuronally (nKATP-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hKATP-GOF mice exhibited predominantly learning and memory deficits. …

Slo2.1 Channels: A New Molecular Mechanism To Regulate Uterine Excitability, Juan Jose Ferreira

Arts & Sciences Electronic Theses and Dissertations

At the end of pregnancy, the uterus transitions from a non-contractile state to a highly contractile state. Two processes primarily drive this transition. First, from the 28th week of pregnancy until labor, the resting membrane potential of uterine (myometrial) smooth muscle cells (MSMCs) gradually becomes more positive (depolarizes) (Parkington et al. 1999). Second, at the end of pregnancy, MSMCs express more oxytocin receptors and become more sensitive to oxytocin (Kimura et al. 1996). However, the detailed mechanisms by which these processes occur have not been determined. My central hypothesis was that the Na+-activated K+ channel SLO2.1 plays a key role …

On Arousal And The Internal Regulation Of Brain Function: Theory And Evidence Across Modalities And Species, Ryan Raut

Arts & Sciences Electronic Theses and Dissertations

The brain is an organ. It is subject to the same physiological regulatory processes that engage the rest of the body’s organs, sculpted over hundreds of millions of years to sustain life so effectively. The central message of this thesis is that the holistic functioning of the brain, rather than operating at some level above or independent from these systemic regulatory processes, is deeply related to them. In short, as our limited attention spans might suggest: brain function is internally regulated. I propose that this internal regulation is a primary function of intrinsic brain activity. Chapter 2 provides a theoretical …

Influence Of Aging And Cerebrovascular Disease On Neuroimaging Measures Of Alzheimer Disease, Lauren Nicole Koenig

Arts & Sciences Electronic Theses and Dissertations

The overall goal of this dissertation is to gain a better understanding of how Alzheimer disease relates to normal aging and cerebrovascular disease to impact neuroimaging measures in a clinically meaningful way. Both aging and cerebrovascular disease are known to influence measures of Alzheimer disease, making it difficult to separate what changes are attributable specifically to Alzheimer disease. We hypothesize that a better understanding of these relationships will allow future studies to appropriately take these factors into account. In Chapters 2 and 3 we attempt to separate out the influences of normal aging and Alzheimer disease on measures of atrophy. …

Genetic Risk Factors For Neurodevelopmental Disorders: Insights From Hipsc-Cerebral Organoids, Michelle L. Wegscheid

Arts & Sciences Electronic Theses and Dissertations

Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder (NDD) characterized by remarkable phenotypic variability, where affected children manifest a spectrum of central nervous system (CNS) abnormalities, including brain tumors, impairments in attention, behavior, learning disabilities, and an increased incidence of autism spectrum disorder (ASD). A significant barrier to the implementation of precision medicine strategies for children with NF1 is a lack of prognostic risk factors to guide clinical management. However, emerging population-based genotype-phenotype association studies have suggested that the germline NF1 gene mutation may represent one clinically actionable risk factor for NF1-associated neurodevelopmental abnormalities. As a critical step in …

Mapping Neural Responses Onto Innate And Acquired Behavior: From Insect Olfaction To Realizing A Bio-Hybrid Chemical Recognition System, Rishabh Chandak

McKelvey School of Engineering Theses & Dissertations

In many organisms, the sense of smell, driven by the olfactory system, serves as the primary sensory modality that guides a plethora of behaviors such as foraging for food, finding mates, and evading predators. Using an array of biological sensors, the olfactory system converts volatile chemical inputs from an organism’s environment into well-patterned neural responses that inform downstream motor neurons to drive appropriate behaviors (e.g., moving towards food or away from danger). For many external cues, the elicited neural responses are often determined by the genetic makeup of the organism, which assigns an innate preference, or valence, for these different …

Identification Of Multi-Tissue Protein Quantitative Trait Loci And Causal Inference Of Protein Effects In Neurological And Other Complex Human Diseases Via Mendelian Randomization, Chengran Yang

Arts & Sciences Electronic Theses and Dissertations

Alzheimer disease (AD) is the most common neurodegenerative disease, affecting 6.2 million people mostly aged 65 years or older in the United States as of early 2021. AD has been widely studied and characterized worldwide, but there is still no effective treatment or cure. Even the latest FDA-approved treatment, Aducanumab, cannot stop decline or improve cognition. To develop a truly effective treatments, researchers keep discovering genetic and molecular mechanisms underlying the disease. Protein biomarkers are keys to bridge the mechanisms to disease. Here, I first used a high-throughput proteomic dataset from three tissues (CSF, plasma, and brain) with array-based genotype …

Role Of 4r Tau In Astrocyte-Mediated Neuronal Toxicity And The Progression Of Neurodegenerative Disease, Lubov Alexandra Ezerskiy

Arts & Sciences Electronic Theses and Dissertations

The microtubule-binding protein tau is associated with neurodegenerative diseases, including Alzheimer’s disease, progressive supranuclear palsy, and a subset of frontotemporal dementias. In these tauopathies, tau becomes hyperphosphorylated and forms intracellular neurofibrillary tau tangles, contributing to synaptic dysfunction, neuronal death, and severe astrogliosis. Tau can be classified as having a 3-repeat (3R) or 4-repeat (4R) structure, resulting from alternative splicing of exon 10 within the MAPT gene. While the higher deposition of 4R tau characterizes many primary tauopathies, the role of 4R tau in neurodegenerative disease pathogenesis remains unclear. To investigate the role of tau isoforms in disease, we created tau …

Phenotyping And Preclinical Meta-Analysis Of Behavioral Outcomes From Complete Freund’S Adjuvant-Induced Inflammatory Pain In The Rodent Hind-Paw, Dominika J. Burek

Arts & Sciences Electronic Theses and Dissertations

Pain and opioid use disorder prevalence, diagnoses of mental health disorders, and rate of suicide have all skyrocketed over the last 30 years as a matrix of public health crises. Each reduces quality of life and installs risk of the others; together, they have burdened our country with nearly unmanageable healthcare challenges. Although the critical demand for novel and more effective therapeutics has been clear for decades, relatively little progress has been made to address pain and its comorbidities. Repeated clinical trial failures have called into question the preclinical evidence upon which they are based. Preclinical models of pain-induced negative …

Investigating Localization And Activity-Dependent Translation Of Astrocyte Mrna, Rohan Khazanchi

Senior Honors Papers / Undergraduate Theses

Over the past two and a half years, I have studied fundamental aspects of astrocyte biology by investigating the existence and mechanism of astrocyte local translation peripherally around tripartite synapses consisting of pre- and post-synaptic neuron terminals and an associated astrocyte. Astrocytes are critical components of central nervous system synapses (which are predominately tripartite in nature); thus, it is important to consider how astrocyte dysregulation and dysfunction could contribute to the pathogenesis of diseases of synaptic connectivity such as autism spectrum disorders, Alzheimer’s disease, seizure disorders, and more. Overall, my projects involved the development of novel methods to identify astrocyte-specific …

Relationships Between Age And White Matter Integrity In Children With Phenylketonuria, Erika M. Wesonga

Arts & Sciences Electronic Theses and Dissertations

Objective: Phenylketonuria (PKU) is a hereditary metabolic disorder associated with cognitive compromise. Diffusion tensor imaging (DTI) has allowed detection of poorer microstructural white matter integrity in children with PKU, with decreased mean diffusivity (MD) in comparison with healthy children. However, very little research has been conducted to examine the trajectory of white matter development in this population. The present study investigated potential differences in the developmental trajectory of MD between children with early- and continuously-treated PKU and healthy children across a range of brain regions.

Methods: Children with PKU (n = 31, mean age = 12.2 years) were …