Neuroscience and Neurobiology Commons^™

Leveraging A Machine Learning Based Predictive Framework To Study Brain-Phenotype Relationships, Sage Hahn

Graduate College Dissertations and Theses

An immense collective effort has been put towards the development of methods forquantifying brain activity and structure. In parallel, a similar effort has focused on collecting experimental data, resulting in ever-growing data banks of complex human in vivo neuroimaging data. Machine learning, a broad set of powerful and effective tools for identifying multivariate relationships in high-dimensional problem spaces, has proven to be a promising approach toward better understanding the relationships between the brain and different phenotypes of interest. However, applied machine learning within a predictive framework for the study of neuroimaging data introduces several domain-specific problems and considerations, leaving the …

The Role Of Neurotrophin Signaling In Urinary Bladder Dysfunction With Cyclophosphamide-Induced Cystitis, Harrison Wood Hsiang

Graduate College Dissertations and Theses

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory pelvic pain syndrome characterized by urinary frequency and urgency, bladder discomfort, decreased bladder capacity, and pelvic pain. A positive feedback loop of bladder inflammation and afferent hypersensitization is currently thought to underlie IC/BPS. Inflammation increases bladder afferent excitability, which in turn releases inflammatory neuropeptides, growth factors, cytokines, and chemokines throughout the micturition pathway, leading to altered bladder function and sensation. There currently exists no effective therapy for IC/BPS.

While its etiology remains unknown, a large body of evidence suggests a role for changes in neurotrophin signaling, particularly that of nerve growth …

Context, Goals, And Operant Behavior: The Role Of The Prelimbic Cortex And Associated Neural Circuitry, Callum Mark Piper Thomas

Graduate College Dissertations and Theses

Operant (instrumental) conditioning is a laboratory model of voluntary behavior. In its simplest form, performing a particular response, such as a lever press, leads to delivery of a reinforcing outcome (e.g., a sucrose pellet). Operant behaviors can be associated with preceding stimuli (“habits”) or outcomes (“goal-directed actions”). A factor that influences performance of operant behaviors is the context in which they are learned. Contexts can be defined as background stimuli that are present during behavior. For example, eating dessert may occur in the context of a restaurant and the sated feeling of a finished meal. The context for eating dessert, …

Systems Approaches For Gene And Drug Discovery In Alzheimer’S Disease, Jeffrey Brabec

Graduate College Dissertations and Theses

Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder affecting all tissues and cell types of brain leading to emotional dysregulation and cognitive dysfunction. From genome-wide association studies (GWAS), to date we have identified forty-two genome-wide significant genes for AD that influence overall disease risk or endophenotypes, including neuroimaging and gene expression profiles. Nevertheless, the currently known AD genes do not account for a significant proportion of the heritability of disease risk, implying the existence of many weak-effect variants in potentially thousands of genes as drivers of AD outcomes. This genetic architecture, composed of many small effects, is partly due to …

Investigating The Mechanisms Linking Mutations In The Protein Synthesis Apparatus To Neurological Disease, Patrick Mullen

Graduate College Dissertations and Theses

The aminoacyl-tRNA synthetases (ARS) are a large family of enzymes that catalyze the aminoacylation reaction, in which an amino acid is attached to cognate tRNAs. This reaction is essential for the process of protein synthesis, as it allows tRNAs to carry amino acids to the ribosome during translation. In recent years, genome sequencing has revealed an association between ARS and inherited diseases of the nervous system. Dominant ARS mutations are linked to the inherited peripheral neuropathy Charcot-Marie-Tooth disease (CMT), while recessive ARS mutations cause multisystem disorders that often include severe neurodevelopmental defects. Additionally, bi-allelic mutations in 2 of the 3 …

Effects Of Imatinib Mesylate On Urinary Bladder Function And Inflammatory Mediators In Mice With Cyclophosphamide-Induced Cystitis, Megan Elizabeth Perkins

Graduate College Dissertations and Theses

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition of lower urinary tract (LUT) dysfunction, characterized by 6 ≤ weeks of LUT symptoms and pelvic pain or discomfort, with other discernable causes excluded. Few treatments exist and more therapeutic targets are needed. Progress is further compounded by the unknown etiology of IC/BPS.

A subpopulation of interstitial cells has been recently identified in the urinary bladder detrusor muscle and lamina propria (LP) and many express the platelet-derived growth factor receptor alpha (PDGFRα). Functionally, LP interstitial cells are theorized to act as intermediary sensors, transducing signals from the urothelium to the detrusor and/or …

Network And Cellular Effects Of The Mu Opioid Receptor In Cortical Interneurons, Adrian Dutkiewicz

Graduate College Dissertations and Theses

The µ opioid receptor (µOR) exerts a powerful excitatory effect in cortical circuits and cultured neurons by promoting glutamatergic activity after binding endogenous or exogenous opioids. While most research indicates that the receptor does this by decreasing activity or output of GABAergic interneurons that inhibit glutamate-releasing Pyramidal Neurons, other experiments suggest that the µOR directly upregulates excitatory Pyramidal Neurons instead. Thus, the cellular target of cortical opioid agonists remains unclear, and the µOR’s net excitatory mechanisms are not fully understood. Consequently, utilizing electrophysiology to detect µOR responses to the specific agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin (DAMGO) has yielded incomplete information on …

The Role Of Infralimbic Cortex In Switching Between An Instrumental Behavior’S Status As A Goal-Directed Action Or Habit, Matthew Broomer

Graduate College Dissertations and Theses

In instrumental learning, extensive training of a response typically generates a habit. The transition from goal-directed to habitual behavioral control is often considered unidirectional; however, recent evidence suggests this is not the case. Under certain conditions, goal-directed control may be restored to a behavior that was previously habitual. We identify the infralimbic cortex (IL) as a participant in this process and draw on both instrumental learning and fear extinction literatures to further our understanding of IL function.

Four experiments explored the role of IL in flexible behavior. Experiments 1a and 1b were instrumental learning experiments. Experiment 1a used a previously …

The Role Of Bdnf-Mediated Neuroplasticity In Cardiovascular Regulation Within The Hypothalamus And Brainstem, Daniella Johanna Thorsdottir

Graduate College Dissertations and Theses

The paraventricular nucleus of the hypothalamus (PVN) is an important cardiovascular and autonomic regulatory center. Activation of PVN neurons projecting to the brainstem and spinal cord elevates sympathetic activity and blood pressure. Brain derived neurotrophic factor (BDNF) plays a key role in stress-induced cardiovascular responses within the PVN and is also known to be upregulated in the PVN in response to stress and hyperosmolality. PVN overexpression or acute injection of BDNF also elevates blood pressure chronically. However, the mechanism behind BDNF-mediated cardiovascular regulation is not fully understood. BDNF is known to modulate excitatory/inhibitory signaling by altering the expression and membrane …

Brain-Behavior Connections Underlying Emotion And Theory Of Mind In Autism Spectrum Disorder, Yu Han

Graduate College Dissertations and Theses

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that af- fects nearly 1 in 54 children. Children with ASD struggle with social, communication, and behavioral challenges due to deficits in theory of mind (ToM). In addition, diag- nosis of ASD is complicated and there is an urgent need to identify ASD-associated biomarkers and features to help automate diagnostics and develop predictive ASD models. In this study, we conducted two experiments collecting behavioral and neu- roimaging data from 9 children with ASD and 19 neurotypical children (NT) between the age of 7 and 14 years.

The first experiment examined specific …

The Effects Of Interneuron Progenitor Cell Transplantation On Network Dynamics In An Animal Model Of Mesial Temporal Lobe Epilepsy, Willie Curry

Graduate College Dissertations and Theses

Epilepsy is associated with a very high incidence of cognitive and behavioral comorbidities that are detrimental to overall quality of life. Current treatments for epilepsy,namely anticonvulsant pharmacological agents, generally increase the amount of inhibitory drive in order to counteract the hyperexcitability observed in the disorder. However, administration of these agents, while effective for 70% of epilepsy sufferers, leave a residual 30% of patients who don’t become seizure-free. The concomitant adverse side effects of anticonvulsants - these can paradoxically include increased cognitive "fog" or confusion, automatisms, and even increased number of seizures - are a great additional concern, as is the …

Examining Sex Differences In Habit Formation: Effects Of Methamphetamine Sensitization And Contributions Of Ovarian Hormones, Hannah Schoenberg Book

Graduate College Dissertations and Theses

In the early stages of instrumental learning, behavior is goal-directed and sensitive to changes in the value of the instrumental outcome. As learning progresses, an association forms between the response and stimuli within the learning environment, such that after sufficient repetition, responding is evoked automatically in the presence of these stimuli and is insensitive to changes in outcome value. The reflexive nature of these types of behaviors has led to their classification as instrumental habits. The emergence of habitual behavior is thought to involve parallel processes that are mediated by distinct neural substrates. Regions of the prefrontal cortex, amygdala, and …

Mediators Of Bladder Dysfunction In A Rat Model Of Cyclophosphamide-Induced Cystitis, Katharine Beca

Graduate College Dissertations and Theses

The urinary bladder relies on complex and interconnected neural circuits in the peripheral and central nervous systems to properly coordinate micturition. Local sensory signals in the bladder produce neurochemical changes that are relayed and integrated to allow a switch from the storage phase to the elimination phase of the micturition reflex. These local signals can result from mechanical distension that occurs during bladder filling or can be the result of maladaptive neurotransmission due to noxious stimuli and/or inflammation. The latter occurs frequently in individuals with a chronic pain pathology called interstitial cystitis (IC)/bladder pain syndrome (BPS). Patients with IC/BPS typically …

Regulation Of Neuroinflammation After Ischemic Stroke By Astroglial Endothelin Receptor Type-B Signaling, John Mcinnis

Graduate College Dissertations and Theses

A large body of neuroscientific research has focused on reactive gliosis and glial scar formation because these are among the most prominent features of the cellular response to central nervous system (CNS) injury. Despite much progress in our understanding, controversy remains regarding the relative balance between the protective nature of the astroglial scar and its anti-regenerative features. Recent work suggests that astrocytes are heterogeneous in their resting state and in their reactivity. In traumatic injuries such as stroke and spinal cord injury, proliferative reactive astrocytes protect CNS tissue. By contrast, under neuroinflammatory and/or neurodegenerative conditions, neurotoxic astrocyte phenotypes may contribute …

Bed Nucleus Of The Stria Terminalis Pituitary Adenylate Cyclase Activating Peptide Projections To The Central Nervous System Regions, Lauren Lepeak

Graduate College Dissertations and Theses

Pituitary adenylate cyclase activating peptide (PACAP) is a pleiotropic neuropeptide that has vast functions, ranging from behavioral, to endocrine, cardiovascular, and cellular, in which often these effects are biphasic. This paper will focus on the effects of PACAP within the central nervous system (CNS), specifically in response to stress and anxiety. PACAP has been extensively researched in terms of its effect on the stress response and is well-known for its effects in inducing anxiety-like behaviors. PACAP induces such effects through working in regions of the CNS such as the amygdala, hypothalamus, and bed nucleus of the stria terminalis (BNST). Research …

Finding Brain Predictors Of Psychostimulant Medication Use In Adhd Using Machine Learning, Zoe Irene Hulce

Graduate College Dissertations and Theses

Psychostimulant medication is the first line of treatment for Attention deficit/hyperactivity disorder (ADHD). Despite the prevalence of ADHD, there is a lack of understanding of the underlying neurophysiological mechanisms of the disorder and its pharmacological treatments. Existing neuroimaging research shows some consistent structural differences in ADHD, but it can be difficult to discern what is relevant. Machine learning algorithms present a novel way of analyzing a large amount of data by making predictions based on pattern detection.

The present study applied an elastic-net logistic machine learning model to structural magnetic resonance imaging (sMRI) data from the Adolescent Brain Cognitive Development …

Altered Fast Synaptic Transmission In An In Vitro Mouse Model Of Epileptic Encephalopathy, Matthew Mccabe

Graduate College Dissertations and Theses

Epileptic encephalopathies (EEs) are severe seizure disorders that occur in infants and young children, characterized by developmental delay, and cognitive decline. Recent efforts have identified a wide variety of genetic variants that cause EEs. Among these, variants in the DNM1 gene have emerged as definitive causes of EEs, including Infantile Spasms and Lennox-Gastaut syndrome. A mouse model of Dnm1-associated EE, known as “Fitful” (Dnm1Ftfl), recapitulates key features of the disease, including spontaneous seizures, developmental delay, and neuronal degeneration. Previous work showed that Dnm1 is a key regulator of synaptic vesicle (SV) endocytosis and synaptic transmission, and suggested that inhibitory neurotransmission …

Exosomes Isolated From Murine Astroglial Cells And Human Blood Samples Contain The Notch 1 Intracellular Domain, Nicholas Toker

Graduate College Dissertations and Theses

Notch 1 is an evolutionarily conserved cell signaling receptor with important functions ranging from control of stem cell proliferation and differentiation to regulation of angiogenesis. Accordingly, Notch 1 expression affects a diverse assortment of protein targets. Here, we explore the role that Notch 1 and related signaling molecules play in astrocyte cell biology. Specifically, we investigate exosomes and the transduction of Notch signaling in astrocytes. Exosomes are small (10-150 nm) vesicles secreted by most cell types and have been found to contain cargo ranging from small RNA species to full length transmembrane receptors. We report, for the first time to …

Assessing The Effectiveness Of A Luminally Restricted 5-Ht4 Agonist For The Treatment Of Colitis And Constipation, Molly C. Hurd

Graduate College Dissertations and Theses

The 5-hydroxytryptamine receptor 4 (5-HT4 receptor) is highly expressed in the gastrointestinal system on colonic epithelial cells and has been identified as a potential therapeutic target in altered bowel function and pain. 5-HT4 receptors influence propulsive motility, decrease sensitivity and visceral pain, increase enteric neuron survival, increase mucus secretion and mediate epithelial cell proliferation. Previous work in the Mawe laboratory has demonstrated that intraluminal application of the 5-HT4 receptor agonist, tegaserod, exerts protective actions in animal models of colitis as well as accelerate recovery from active colitis. The first aim of this study was to test a newly developed luminally …

Effects Of Chronic Stress On The Pituitary Adenylate Cyclase Activating Polypeptide (Pacap) In The Bed Nucleus Of The Stria Terminalis (Bnst), Mahafuza Aktar

Graduate College Dissertations and Theses

Exposure to chronic stressors can produce maladaptive behavioral and physiological consequences. Previous work has demonstrated that chronic variant stress exposure enhances anxiety-like behavior and increases pituitary adenylate cyclase activating polypeptide (PACAP) and PAC1 receptor transcripts in the anterolateral bed nucleus of the stria terminalis (BNST) in rats. The studies described here demonstrate that treatment with a chronic variant stress paradigm produced anxiety-like behavior in transgenic PACAP-Cre mice. Additionally, the stressed group did not gain weight during the 14 days of chronic stressor exposure compared to control mice. Furthermore, fewer PACAP-expressing neurons were observed in the posterior BNST and lateral hypothalamus …

Neurodevelopmental Roles Of Semaphorin6a/Plexina2 Signaling In Zebrafish, Sarah Elizabeth Emerson

Graduate College Dissertations and Theses

ABSTRACT

A multitude of complex cellular changes are required throughout development in order for a single cell to transform into a fully functioning organism. Cellular events including proliferation, migration, and differentiation have to be carefully controlled in order for development to proceed correctly. In order to study such dynamic processes, in vivo models are often utilized. Using the zebrafish (Danio rerio) as a model system, we have investigated the role of an axon guidance signaling pair, Semaphorin6A (Sema6A) and PlexinA2 (PlxnA2), in neurodevelopment.

A previous investigation into the developmental expression patterns of sema6A and plxnA2 in zebrafish, revealed overlapping expression …

Biochemical And Functional Characterization Of Semaphorin6a-Plexina Signaling In Zebrafish Eye Development, Riley St. Clair

Graduate College Dissertations and Theses

During embryonic development, cells respond to extracellular signals to establish proper tissue organization. Semaphorins (Semas) are a large class of secreted and transmembrane proteins that signal through Plexin (Plxn) receptors to guide migrating cells to their correct position and thus play critical roles in the development of various tissues including the nervous and cardiovascular systems. We have previously shown that Sema6A-PlxnA2 signaling is essential for visual system development, as decreasing endogenous Sema6A or PlxnA2 in zebrafish results in decreased cohesion of the early eye field, impaired retinal lamination, and smaller eye size. However, the molecular mechanisms governing these phenotypes are …

Biobehavioral Predictors Of Cannabis Use In Adolescence, Philip Aaron Spechler

Graduate College Dissertations and Theses

Cannabis use initiated during adolescence may precipitate lasting consequences on the brain and behavioral health of the individual. However, research on the risk factors for cannabis use during adolescence has been largely cross-sectional in design. Despite the few prospective studies, even less is known about the neurobiological predictors. This dissertation improves on the extant literature by leveraging a large longitudinal study to uncover the predictors of cannabis use in adolescent samples collected prior to exposure. All data were drawn from the IMAGEN study and contained a large sample of adolescents studied at age 14 (N=2,224), and followed up at age …

Risk Profiles For Adolescent Internalizing Problems, Kelsey Elizabeth Hudson

Graduate College Dissertations and Theses

Objective: Internalizing problems are commonly diagnosed during adolescence, and are associated with distress, impairment, and negative mental health outcomes in adulthood. Thus, there is a critical need to characterize adolescents who are at the highest risk for escalating to clinical levels of internalizing problems while extending current literature and incorporating both biological and environmental predictors. This study aimed to characterized risk profiles for fourteen-year-old adolescents who developed clinical levels of internalizing (High Internalizing [HI]) problems by age nineteen, using brain, genetic, personality, cognitive, life history, psychopathology, and demographic measures. The study also examined whether there were functional and structural brain …

The Metabotropic Glutamate Receptor Mglur1 Regulates The Voltage-Gated Potassium Channel Kv1.2 Through Agonist-Dependent And Agonist-Independent Mechanisms, Sharath Chandra Madasu

Graduate College Dissertations and Theses

The voltage gated potassium channel Kv1.2 plays a key role in the central nervous system and mutations in Kv1.2 cause neurological disorders such as epilepsies and ataxias. In the cerebellum, regulation of Kv1.2 is coupled to learning and memory. We have previously shown that blocking Kv1.2 by infusing its specific inhibitor tityustoxin-kα (TsTX) into the lobulus simplex of the cerebellum facilitates eyeblink conditioning (EBC) and that EBC itself modulates Kv1.2 surface expression in cerebellar interneurons. The metabotropic glutamate receptor mGluR1 is required for EBC although the molecular mechanisms are not fully understood. Here we show that infusion of the mGluR1 …

The Role Of Pituitary Adenylate Cyclase Activating Polypeptide In The Dentate Gyrus In Regulating Behavior And Neurophysiology, Gregory Charles Johnson

Graduate College Dissertations and Theses

Fear and anxiety disorders are potentially crippling conditions that often stem from past experience of trauma and chronic stress. One clear feature of these disorders is the failure to use proximate spatial and contextual information presented in the environment to regulate reflexive physiological threat responses. The central nervous system networks that govern spatial navigation and contextual learning and memory are a series of complex circuitries in which the hippocampus is integrally involved. Deficits in hippocampal function have been linked to severe anterograde and mild retrograde amnesia of semantic and episodic memory, and specific deficits in contextual processing. These deficits manifest …

The Role Of The Prelimbic, Infralimbic, And Cerebellar Cortices In Operant Behavior, Megan Laura Shipman

Graduate College Dissertations and Theses

Operant (instrumental) conditioning is a laboratory method for investigating voluntary behavior and involves training a particular response, such as pressing a lever, to earn a reinforcer. Operant behavior is generally divided into two categories: actions and habits. Actions are goal-directed and controlled by response-outcome (R-O) associations. Habits are stimulus-driven and controlled by stimulus-response associations (S-R). Behavior is determined to be goal-directed or habitual by whether or not it is sensitive (action) or insensitive (habit) to reinforcer/outcome devaluation. Many brain regions have been linked to the learning and/or expression of actions and/or habits. This dissertation investigates a few different brain regions …

Examining The Roles Of Sex, Methamphetamine, And Degree Of Training In Habit Formation In Rats, Hannah Schoenberg

Graduate College Dissertations and Theses

Addiction is characterized by a progressive loss of executive control over drug-seeking and consumption, and may be associated with a behavioral shift from instrumental goal-directed actions to stimulus-response habits. Sex differences in drug addiction have been linked to changing hormone levels across the estrous cycle, and females exhibit a particular vulnerability to psychostimulants such as cocaine and amphetamines. Psychostimulants and estrogen both influence dopaminergic activity in the dorsal striatum, a region of the brain in which dopamine activity is thought to mediate the shift from action to habit. In the present set of experiments, we examined the roles of sex, …

Protective Actions Of Luminally Restricted 5-Ht4 Receptor Agonist In Dextran Sodium Sulfate Induced Colitis, Alisha Anne Linton

Graduate College Dissertations and Theses

Background: The 5-hydroxytrptamine receptor 4 (5-HT4 receptor) is heavily expressed on colonic epithelial cells and has been targeted as a therapeutic for functional bowel symptoms and pain; however, adverse cardiac events related to 5-HT4 agonist treatment limited their therapeutic use. Previous studies in the Mawe laboratory have demonstrated that intraluminal application of a 5-HT4 agonist exerts protective epithelial actions in animal models of colitis, and accelerates recovery from colitis. The aim of this study was to test the effects of a luminally restricted 5-HT4 agonist in a mouse model of experimental colitis.

Methods: The luminally restricted 5-HT4 agonist (Takeda Pharmaceuticals; …

Neural Preparation For Step Initiation In Unpredictable Conditions With Age And Parkinson's Disease, Roman Popov

Graduate College Dissertations and Theses

Mobility is essential for the independent lifestyle. However, as the US population ages, challenges to mobility start to arise, among them just the aging itself which leads to decreased postural stability, falls and the second most common neurodegenerative disease, that is Parkinson’s disease (PD). We decided to investigate step initiation as it is crucial to mobility: walking is not possible without the first step.

Step initiation is impaired in PD. However, the impact of PD on the neural mechanisms of step initiation when some of the step parameters are unpredictable remains unexplored. Cortical preparation for step initiation can be assessed …