Neuroscience and Neurobiology Commons^™

Mechanisms Of Calcium-Dependent Neurotransmission In Photoreceptors, Justin J. Grassmeyer

Theses & Dissertations

Rod and cone photoreceptors initiate vision by transforming light into graded membrane voltage changes that in turn dictate the rate of continuous Ca²⁺-dependent neurotransmission to postsynaptic neurons. Continuous release relies on synaptic ribbons at photoreceptor active zones, which organize exocytotic proteins and deliver vesicles to release sites near voltage-gated Ca²⁺ channels. Individual cones possess multiple ribbon synapses at which they contact postsynaptic neurons. We examined heterogeneity in signaling at individual ribbon synapses in salamander cones by measuring the voltage dependence of Ca²⁺ currents (I_Ca) and Ca²⁺ influx at individual ribbon release sites. Ca …

The Neurophysiological Changes Associated With Motor Learning In Adults And Adolescents, James E. Gehringer

Theses & Dissertations

One main purpose of this dissertation was to explore how sensorimotor cortical oscillations changed after practicing a novel ankle plantarflexion target matching task. We behaviorally quantified the speed, accuracy, reaction time, velocity, and variability of the participant’s performance of the task, while collecting their neurophysiological responses with magnetoencephalography (MEG). With these data, we assessed how the motor planning and execution stages of movement during a goal directed target matching task changed after practicing a task in typically developing young adults with their non-dominant ankle. We found that the cortical oscillations in the beta frequency range that were sourced from the …

The Opposing Roles Of Glun2c And Glun2d Nmda Receptor Subunits In Modulating Neuronal Oscillations, Zhihao Mao

Theses & Dissertations

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels consisting of two GluN1 subunits and two other subunits from among GluN2A-2D and GluN3A-3B subunits. NMDARs play critical roles in synaptic plasticity, learning and memory, and higher brain function such as cognition and perception. Dysfunction of NMDARs (hyper-function and hypo-function of NMDARs) are related to various diseases, including stroke, schizophrenia, Alzheimer’s disease, and others. However, to date, NMDARs antagonists have mostly failed in clinical trials due to adverse effects.

NMDARs antagonists replicate the core symptoms of schizophrenia which may underlie its ability to alter neuronal oscillations in the neural circuitry of different brain …

Arid1b And Macf1 In Murine Brain Development And Behavior, Jeffrey Jay Moffat

Theses & Dissertations

Intellectual disability (ID) and autism spectrum disorder (ASD) affect between one and three percent of the global population. These disorders represent a significant emotional and financial burden for affected individuals and their families. Treatment for these conditions remains limited because many of the key molecular factors and associated pathogenic mechanisms are still poorly understood.

In this report we examine two genes related to ASD and ID, AT-rich interactive domain-containing protein 1B (ARID1B) and Microtubule-actin crosslinking factor 1 (MACF1). ARID1B is a subunit of the mammalian BRG1/BRM associated factor (BAF) chromatin-remodeling complex, which broadly regulates gene expression. ARID1B also …

Neural Correlates Of Polysubstance Use: Differential And Interactive Effects Of Alcohol And Cannabis On The Adolescent Brain, Joseph Aloi

Theses & Dissertations

Two of the most commonly used and abused substances by adolescents in the United States are alcohol and cannabis, which are associated with adverse medical and psychiatric outcomes. Alcohol use and cannabis use during adolescence is also associated with an increased risk of alcohol use disorder (AUD) and/or cannabis use disorder (CUD) in adulthood as well as increased likelihood of relapse after successful treatment. Despite this, much of the previous work on the neurobiology of substance use disorders has focused on adult substance use. This work has shown that individuals with AUD and/or CUD show dysfunction within reward processing, emotion …

Electrophysiological Biomarkers Of Chemotherapy-Related Cognitive Impairment In Hematological Malignancy Patients, David E. Anderson

Theses & Dissertations

Multiple cancer populations frequently report cognitive impairment following treatment with chemotherapy agents (“chemo-brain”). Impaired neuropsychological performance is commonly reported in cognitive domains of attention and executive function. Understanding neural mechanisms underlying cognitive impairments is essential to developing prevention and rehabilitation strategies. Brain imaging studies frequently show chemotherapy-related impairments within the attentional control network, which is comprised of a constellation of cortical regions that govern reportedly impaired cognitive functions. In the current dissertation research, I developed a novel electrophysiology battery aimed at recording near-instantaneous neural activity within the attentional control network during cognitive task performance. Cancer patients diagnosed with hematological malignancy …

Molecular Mechanism Of Early Amyloid Self-Assembly Revealed By Computational Modeling, Mohtadin Hashemi

Theses & Dissertations

Protein misfolding followed by the formation of aggregates, is an early step in the cascade of conformational changes in a protein that underlie the development of several neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Efforts aimed at understanding this process have produced little clarity and the mechanism remains elusive.

Here, we demonstrate that the hairpin fold, a structure found in the early folding intermediates of amyloid b, induces morphological and stability changes in the aggregates of Aβ(14-23) peptide. We structurally characterized the interactions of monomer and hairpin using extended molecular dynamics (MD) simulations, which revealed a novel intercalated type complex. …

T Cell Mediated Cytotoxicity In The Mptp Mouse Model Of Parkinson's Disease, Rebecca A. Wilshusen

Theses & Dissertations

Increasing evidence suggests that neurotoxic inflammatory activities affect the pathogenesis and progression of PD. Neuroinflammatory processes also produce oxidized and modified self-central nervous system (CNS) proteins which lead to dysfunction, mis-folding, aggregation, and retention of those oxidized products. In PD, nitrated α-synuclein (N-α-syn) is found aggregated within the cytoplasm and Lewy bodies of dopaminergic neurons within the substantia nigra and is released to the extraneuronal environment by dying and damaged neurons. Previous studies have shown that after 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) intoxication, adoptive transfer of effector T cells (Teff) exacerbates microglial-mediated neuroinflammation and amplifies dopaminergic neurodegeneration with accelerated and prolonged …

Novel Therapeutic Approaches For Juvenile Neuronal Ceroid Lipofuscinosis (Cln3), Megan Elizabeth Bosch

Theses & Dissertations

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by autosomal recessive mutations in CLN3. Neuronal loss is thought to occur via glutamate excitotoxicity; however, little is known about neuron-astrocyte glutamate regulation in JNCL. We discovered that Cln3^Δex7/8 astrocytes have significantly lower basal spontaneous Ca²⁺ oscillations and decreased responses to glutamate, indicating a disrupted signaling network. Cln3^Δex7/8 astrocytes also displayed significantly lower basal mitochondrial respiration and ATP production, suggesting impaired metabolic functions. Concurrent with diminished astrocyte metabolism and Ca²⁺ signaling, Cln3^Δex7/8 neurons were hyper-responsive to glutamate stimulation. These studies suggest that CLN3 …

Effects Of Gm-Csf On Dendritic Cells And Regulatory T Cells In Parkinson’S Disease Patients And Models Of Parkinson’S Disease, Charles Schutt

Theses & Dissertations

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Pathologically, loss of nigrostriatal neurons and dopamine released by these neurons are responsible for PD motor symptoms. During PD, activation of resident microglia and infiltrating lymphocytes leads to progressive neuroinflammation and reduction in the number and function of regulatory immune cells. Neuroinflammation contributes to progressive neurodegeneration and declining motor function. Reducing neuroinflammation is the target for novel PD therapeutics. Our goal is to increase the number and function of regulatory T cells (Tregs) in PD patients to decrease neuroinflammation and reduce PD symptoms. One potential therapy is granulocyte-macrophage colony stimulating …

A Role For Δ-Catenin In Synaptic Regulation, Li Yuan

Theses & Dissertations

The cadherin-catenin complex regulates cell-cell adhesion and signal transduction in epithelial cells. It is becoming increasingly evident that components of the complex regulate various aspects of neuronal architecture and function. δ-catenin is a cytosolic component of the cadherin-catenin complex and is predominantly expressed in the central nervous system. Loss of CTNND2, which encodes δ-catenin, is associated with intellectual disability and mutations in CTNND2 have been identified in autism, suggesting that δ-catenin is a critical component of the molecular machinery underlying neural circuit function. We have previously demonstrated that δ-catenin regulates multiple aspects of synaptic and dendritic development, including dendritic …

Pattern Recognition Receptors, Immune Proteins, And Nf-Κb Signaling Regulate Behaviors Associated With Aging Phenotypes, Nicholas W. Dekorver

Theses & Dissertations

The aging process is accompanied by functional impairments, including reduced locomotor function, fragmentation of active states, and alterations in energy balance. Our lab has demonstrated that immune proteins are increased in specific regions of the mouse brain that correlate with strain specific deficits. These immune proteins include toll-like receptors (Tlr), class I major histocompatibility complex proteins (MHC I), and complement proteins. There is an increasing appreciation for the role of immune proteins in neurodevelopment; however, their involvement in age-associated deficits is poorly understood. Here, we present data demonstrating that 1) activation of a specific immune receptor (Tlr2) leads to changes …

Inflammasome Activation By Methamphetamine Potentiates Lipopolysaccharide Stimulation Of Il-1Β Production In Microglia, Enquan Xu

Theses & Dissertations

Methamphetamine (Meth) is a psychostimulant drug that is widely abused all around the world. The administration of Meth causes a strong instant euphoria effect, and long-term of abuse is correlative of drug-dependence and neurotoxicity. The neuroimaging studies demonstrated that the long-term abuse of Meth is associated with the reduction of the dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) in the striatum. Neuroinflammation is well-accepted as an important mechanism underlying the Meth-induced neurotoxicity. The over-activated microglia were found both in Meth human abusers and animal models.

NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is the most predominant Nod-like …

Basal And Experience Dependent Ampar And Synapse Dynamics: Alterations In A Mouse Model Of Fragile X Syndrome, Anand Suresh

Theses & Dissertations

Dendritic spines are the principal sites of excitatory synapses in the neurons of mammalian central nervous system. Spine are plastic, undergoing structural and functional changes under basal and experience dependent conditions. Spine properties are altered in a number of neurodevelopmental disorders including the Fragile X syndrome (FXS) which is the most common inherited form of intellectual disability. The structural reorganization of dendritic spines is thought to be associated with synaptic plasticity mechanisms that are deficient in FXS. A number of synaptic plasticity mechanisms involve modulation of synaptic strength via insertion or removal of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). However, the link …

Target Validation And Pharmacological Characterization Of Novel Nmdar Modulators, Kiran Sapkota

Theses & Dissertations

The N-methyl-D aspartate receptors (NMDARs) are ligand-gated ion channels, which play important roles in learning and memory. Excessive activity of NMDARs is implicated in damage due to stroke and neurodegenerative diseases, whereas hypoactivity of NMDARs contributes to schizophrenia. The initial goal of my dissertation is to evaluate the potential role of the GluN2D-containing NMDARs in neuropathological, behavioral and cognitive alterations associated with schizophrenia and characterize the pharmacology and mechanisms of action of NMDAR modulators which could potentially be used to modulate these receptors in schizophrenia.

A subanesthetic dose of the NMDAR antagonist ketamine elicits symptoms of schizophrenia. This property led …

Motor Control In Individuals With Multiple Sclerosis, David Arpin

Theses & Dissertations

This dissertation explored motor control in individuals with multiple sclerosis (MS) by quantifying the behavioral and neurophysiological deficits present in these individuals. We behaviorally quantified the precision of the ankle plantarflexor musculature of individuals with MS. Our results indicated that the individuals with MS had a greater amount of variability in the precision of the isometric ankle torques, and that this greater variability was related to decreased walking performance. To further explore whether these motor control deficits were due to aberrant cortical activity associated with planning motor actions, we used magnetoencephalography to assess the motor planning and execution stages of …

Global Gene Expression Profiling Of Healthy Human Brain And Its Application In Studying Neurological Disorders, Simarjeet K. Negi

Theses & Dissertations

The human brain is the most complex structure known to mankind and one of the greatest challenges in modern biology is to understand how it is built and organized. The power of the brain arises from its variety of cells and structures, and ultimately where and when different genes are switched on and off throughout the brain tissue. In other words, brain function depends on the precise regulation of gene expression in its sub-anatomical structures. But, our understanding of the complexity and dynamics of the transcriptome of the human brain is still incomplete. To fill in the need, we designed …

Mitogen And Morphogen Signaling Dysregulation: Pathophysiological Influence In Pancreatic Cancer And Alzheimer’S Disease, Eric Cruz

Theses & Dissertations

Although the etiology of a particular disease will vary, there are genetic and epigenetic bottlenecks that frequently converge resulting in dysregulation of mitogenic and morphogenetic signaling. This propensity is acutely experienced in malignancy and neurodegenerative disease.

Here, we have first investigated the role of dysregulated signaling in the context of pancreatic cancer (PC). Morphogenetic signaling has been regarded as a pleiotropic pathway with the potential to promote and inhibit metastatic features. Our investigation of bone morphogenetic protein 2 (BMP-2), an archetypical member of the BMP superfamily, has revealed the presence of extracellular, intracellular, and long non-coding RNA products. Our findings …

Voltage-Gated K+ Channels And Hiv-1-Induced Neural Injury: Implications For Pathogenesis Of Hiv-1-Associated Neurocognitive Disorders, Han Liu

Theses & Dissertations

Human immunodeficiency virus-1 (HIV-1)-associated neurocognitive disorder (HAND) is a subcortical disease involving neuronal loss and myelin damage. Myelin is deposited by oligodendrocytes through a complex process including oligodendrocyte progenitor cell (OPC) proliferation and maturation. Oligodendrocytes/OPCs are susceptible to viral proteins such as Tat and that myelin damage is associated with oligodendrocyte number decrease. It has been shown that activation of voltage-gated K⁺ (K_V) channels mediates apoptosis in various cell types. K_V1.3 is the most predominant K_V channel expressed in OPCs/oligodendrocytes and potentially involved in OPC developmental regulation. We studied the involvement of K_{V …}

Molecular Mechanisms Involved In Neurotoxicity Mediated By Hiv Proteins And Drug Abuse, Yu Cai

Theses & Dissertations

While the advancement of highly active antiretroviral therapy (HAART) has transformed the course of HIV/AIDS from a death sentence to a manageable chronic condition, the prevalence of a constellation of neurological disorders collectively termed as HIV-associated neurocognitive disorders (HAND) continues to persist in these patients. HAND is characterized by cognitive dysfunction, depression, impaired memory and/or deficits in motor skills. The underlying factors leading to HAND have been the subject of extensive research and are thought to be associated with HIV infection in the CNS combined with robust immune activation of resident cells of the CNS. In addition, there is a …

Expression And Function Of Inflammation-Associated Micrornas In Traumatic Brain Injury, Emily Harrison

Theses & Dissertations

MicroRNAs (miRNAs) are important regulators of gene expression. Many neurological diseases, including traumatic brain injury alter expression of miRNAs in the brain. However, the function of these molecules in the context of TBI is largely unknown. Here we report multiple potential roles for miRNAs in TBI, some of which extend beyond the traditional model of post-transcriptional regulation, highlighting that these RNA molecules may have broader implications for the neurobiology of disease. We found that miR-155 plays an essential role in interferon expression after CCI and that miR-155 contributes to TBI induced anxiety, potentially through regulation of interferons. Expression of miR-155 …

Compensatory Mechanisms And T Cell Migration In Mouse Models Of Dopaminergic Loss, Kristi M. Anderson

Theses & Dissertations

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and second most common neurodegenerative disorder. PD is characterized by the selective loss of dopaminergic neurons and dopamine neurotransmitter within the substantia nigra and termini in the striatum. Progressive loss of dopaminergic neurons occurs over many years in PD, and by the time movement disorder symptoms manifest, up to 50-70% of dopaminergic neurons have been lost. Several aspects of PD pathology have been described in detail, but a better understanding of PD progression is needed to develop more efficient treatments.

Motor symptoms associated with PD do not manifest until significant …

Development Of Manganese-Enhanced Magnetic Resonance Imaging (Memri) Methods To Study Pathophysiology Underlying Neurodegenerative Diseases In Murine Models, Aditya N. Bade

Theses & Dissertations

Manganese-enhanced magnetic resonance imaging (MEMRI) opens the great opportunity to study complex paradigms of central nervous system (CNS) in freely behaving animals and reveals new pathophysiological information that might be otherwise difficult to gain. Due to advantageous chemical and biological properties of manganese (Mn²⁺), MEMRI has been successfully applied in the studies of several neurological diseases using translational animal models to assess comprehensive information about neuronal activity, morphology, neuronal tracts, and rate of axonal transport. Although previous studies highlight the potential of MEMRI for brain imaging, the limitations concerning the use of Mn²⁺ in living animals and …

Characteristics Of Exocytosis And Endocytosis In Photoreceptors, Karlene M. Cork

Theses & Dissertations

Photoreceptors signal changes in light intensity to downstream retinal neurons through the exocytosis of glutamate-containing synaptic vesicles. The maintenance of the vesicle exocytosis and endocytosis process is essential for ongoing synaptic signaling. This study investigated the properties of exocytosis and endocytosis in photoreceptors and their role in ongoing neurotransmission.

I used electrophysiology and imaging techniques to study the properties of vesicle exocytosis and endocytosis in photoreceptors. First, we examined baseline release in photoreceptors that occurs in the absence of depolarizing stimulation. We measured mEPSCs in whole cell patch clamp recordings from horizontal cells. After inhibiting Ca²⁺ influx and efflux …

Effects Of Maternal Immune Activation And Repeated Maternal Separation On Postpartum Behaviors In The Female Rat Offspring, Shinnyi Chou

Theses & Dissertations

Early life stress can induce persistent brain and behavioral alterations. As a lifetime history of clinical symptoms similar to those caused by early adversities may predict postpartum dysfunctions, these stressors likely contribute to their etiology. Postpartum neuropsychiatric disorders (e.g. postpartum depression, anxiety and depression) are costly, yet due to the complex neuronal reorganization during this period, insights into how early adversities-induced CNS functional changes affect postpartum processes remain limited, especially under multiple stressors. Thus, there is a need to determine postpartum functions altered by early stress, in order to increase understandings of risks associated with postpartum maladaptations. Accordingly, this work …