Medical Neurobiology Commons^™

Autologous Peripheral Nerve Grafts To The Brain For The Treatment Of Parkinson's Disease, Andrew Welleford

Theses and Dissertations--Neuroscience

Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that …

Cell Specific Control Of The Pallidostriatal Pathway, Shubha Verma '19

Student Publications & Research

Parkinson’s Disease is a neurodegenerative disorder of the basal ganglia. The main cause for Parkinson’s Disease is the depletion of dopamine, a neurotransmitter. The basal ganglia contains four major nuclei: the substantia nigra, the subthalamic nucleus, the external globus pallidus, and the striatum. These nuclei communicate with each other by the use of neurons.

Heat Shock Protein 40 And Immune Function In Altered Gravity, Amber M. Paul, Brooke D. Shepard, Sharmila Bhattacharya

Publications

In space, astronauts are more susceptible to pathogens, viral reactivation and immunosuppression, which poses limits to their health and the mission. Interestingly, during space flight, stress-inducible heat shock proteins (HSP) are robustly induced, and the overexpression of HSPs have been implicated in immune dysregulation, therefore HSPs may be critically involved in regulating immune homeostasis. HSP40/DNAJ1 plays a major role in proper protein translation and folding. Its loss of function has been implicated in susceptibility to microbial infection, while its overexpression has been implicated in autoimmunity, collectively suggesting its complicated, but necessary, role in maintaining immunological function. To determine the role …

The Role Of Developmental Timing Regulators In Progenitor Proliferation And Cell Fate Specification During Mammalian Neurogenesis, Jennifer S. Romer-Seibert

Graduate School of Biomedical Sciences Theses and Dissertations

Developmental timing is a key aspect of tissue and organ formation in which distinct cell types are generated through a series of steps from common progenitors. These progenitors undergo specific changes in gene expression that signifies both a distinct progenitor type and developmental time point that thereby specifies a particular cell fate at that stage of development. The nervous system is an important setting for understanding developmental timing because different cell types are produced in a certain order and the switch from stem cells to progenitors requires precise timing and regulation. Notable examples of such regulatory molecules include the RNA-binding …

Spinal Cord Trauma: An Overview Of Normal Structure And Function, Primary And Secondary Mechanisms Of Injury, And Emerging Treatment Modalities, Daniel Morin

Senior Honors Theses

The structures of the spinal cord and vertebral column are designed to provide flexibility, while still providing ample protection for the spinal cord deep within. While it does offer remarkable protection against most routine trauma, the spinal cord is still vulnerable to high-force etiologies of trauma and may become damaged as a result. These events are referred to as primary injury. Following the initial injury, the body’s own physiological responses cause a cascade of deleterious effects, known as secondary injury. Secondary injury is a major therapeutic target in mitigating the effects of spinal cord injury (SCI), and much research is …

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 …

Thiamine Deficiency And Neurodegeneration: The Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, And Autophagy, Dexiang Liu, Zunji Ke, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Thiamine (vitamin B1) is an essential nutrient and indispensable for normal growth and development of the organism due to its multilateral participation in key biochemical and physiological processes. Humans must obtain thiamine from their diet since it is synthesized only in bacteria, fungi, and plants. Thiamine deficiency (TD) can result from inadequate intake, increased requirement, excessive deletion, and chronic alcohol consumption. TD affects multiple organ systems, including the cardiovascular, muscular, gastrointestinal, and central and peripheral nervous systems. In the brain, TD causes a cascade of events including mild impairment of oxidative metabolism, neuroinflammation, and neurodegeneration, which are commonly observed in …

Rat Hind Limb Nociceptive Withdrawal Response To Heat And Mechanical Stimuli Depends On Initial Position Of The Paw But Not Stimulus Location, Giavanna Verdi

Senior Honors Projects, 2010-2019

Mammals rapidly withdraw their hind limb in response to noxious stimulation, which is a protective movement known as the nociceptive withdrawal response (NWR). The NWR has been previously studied in spinalized, decerebrated and anesthetized non-human and human mammals; however, there is minimal information on the NWR in intact, unanesthetized non-human mammals.

The first specific aim was to identify the factors that determine the direction and magnitude of the NWR in intact, unanesthetized rats. Based on previous studies, we hypothesized that the location of stimulation and the initial position of the paw preceding the NWR will influence the direction and magnitude …

Encoding Of Saltatory Tactile Velocity In The Adult Orofacial Somatosensory System, Rebecca Custead

College of Education and Human Sciences: Dissertations, Theses, and Student Research

Processing dynamic tactile inputs is a key function of somatosensory systems. Spatial velocity encoding mechanisms by the nervous system are important for skilled movement production and may play a role in recovery of motor function following neurological insult. Little is known about tactile velocity encoding in trigeminal networks associated with mechanosensory inputs to the face, or the consequences of movement.

High resolution functional magnetic resonance imaging (fMRI) was used to investigate the neural substrates of velocity encoding in the human orofacial somatosensory system during unilateral saltatory pneumotactile inputs to perioral hairy skin in 20 healthy adults. A custom multichannel, scalable …

Neurocalcin ẟ Response To Calcium: Which Ef Hand Matters The Most?, Trokon Fiawoo

Graduate School of Biomedical Sciences Theses and Dissertations

Changes in intracellular calcium levels play a very important role in cell signaling, in turn, affecting neuronal functions such as memory, learning and cell death. A class of proteins called Neuronal Calcium Sensor (NCS) proteins serves to modulate the functioning of the neuronal cells in response to changes in calcium levels. Structurally, all NCS proteins have 4 calcium-binding EF hand motifs, although EF I does not bind to calcium in many members. All NCS proteins are myristoylated at the N-terminus. Neurocalcin delta (NCALD) is an NCS protein, and shares 95% similarity in primary amino acid sequence with another major NCS …

Cannabinoid Receptor Interacting Protein Suppresses Agonist-Driven Cb1 Receptor Internalization And Regulates Receptor Replenishment In An Agonist-Biased Manner, Lawrence C. Blumes, Sandra Leone-Kabler, Deborah J. Luessen, Glenn S. Marrs, Erica Lyons, Caroline E. Bass, Rong Chen, Dana E. Selley, Allyn C. Howlett

Neurology Publications

Cannabinoid receptor interacting protein 1a (CRIP1a) is a CB1 receptor (CB1R) distal C-terminus-associated protein that modulates CB1R signaling via G proteins, and CB1R down-regulation but not desensitization (Blume et al. [2015] Cell Signal., 27, 716-726; Smith et al. [2015] Mol. Pharmacol., 87, 747-765). In this study, we determined the involvement of CRIP1a in CB1R plasma membrane trafficking. To follow the effects of agonists and antagonists on cell surface CB(1)Rs, we utilized the genetically homogeneous cloned neuronal cell line N18TG2, which endogenously expresses both CB1R and CRIP1a, and exhibits a well-characterized endocannabinoid signaling system. We developed stable CRIP1a-over-expressing and CRIP1a-siRNA-silenced knockdown …

The Effect Of Caffeine On Migraine Headaches, Deborah Shimshoni

Honors Undergraduate Theses

As the most widely consumed drug around the globe, there is a vast array of contradicting research available on caffeine. One of the most debated and researched topics on caffeine is its effect on the brain. Meanwhile, the data on the neurological condition of migraine has information scattered throughout countless research articles and experiments.

Although neither migraine or caffeine are completely understood by the medical world, this analysis attempts to give a more coherent understanding of the relationship between the two. This is done by first understanding the known and theorized mechanisms of caffeine as well as the pathologies of …

Targeting Methylglyoxal And Ppar Gamma To Alleviate Neuropathic Pain Associated With Type 2 Diabetes, Ryan B. Griggs

Theses and Dissertations--Physiology

Neuropathic pain affects up to 50% of the 29 million diabetic patients in the United States. Neuropathic pain in diabetes manifests as a disease of the peripheral and central nervous systems. The prevalence of type 2 diabetes is far greater than type 1 (90%), yet the overwhelming focus on type 1 models this has left the mechanisms of pain in type 2 diabetes largely unknown. Therefore I aimed to improve the current mechanistic understanding of pain associated with type 2 diabetes using two preclinical rodent models: Zucker Diabetic Fatty rats and db/db mice. In addition, I highlight the translational importance …

Enhanced Cgmp-Dependent Signaling In Astrocytes: Novel Therapeutic Target In Alzheimer's Disease, Nyema M. Woart

PCOM Biomedical Studies Student Scholarship

Over five million Americans suffer from Alzheimer’s Disease (AD), with an expected 34% increase in the incidence in this disease over the next decade. Unfortunately, there is no cure for AD. Recent studies have indicated that drugs which increase the levels of cyclic guanosine-3’5’-monophosphate (cGMP) may help preserve learning and memory in AD and enhance cognition in the aging brain; however, the mechanism(s) of how cGMP exerts this beneficial effect is unknown. The present findings now suggest that elevation of cGMP in astrocytes depresses inhibitory potassium currents in these cells to stimulate their protective influence on neuronal activity. Cellular currents …

Gene Expression And Alzheimer's Disease: Evaluation Of Gene Expression Patterns In Brain And Blood For An Alzheimer's Disease Mouse Model, Amanda Hazy

Senior Honors Theses

Previous studies have established a causative role for altered gene expression in development of Alzheimer’s disease (AD). These changes can be affected by methylation and miRNA regulation. In this study, expression of miRNA known to change methylation status in AD was assessed by qPCR. Genome-wide expression changes were determined by RNA-sequencing of mRNA from hippocampus and blood of control and AD mice. The qPCR data showed significantly increased expression of Mir 17 in AD, and sequencing data revealed 230 genes in hippocampus, 58 genes in blood, and 8 overlapping genes showing significant differential expression (p value ≤ 0.05). Expression data …

Analysis Of Differential Mrna And Mirna Expression In An Alzheimer’S Disease Mouse Model, Amanda Hazy, Matthew Dalton

Other Undergraduate Scholarship

Research has shown that changes in gene expression play a critical role in the development of Alzheimer’s Disease (AD). Our project will evaluate genome-wide RNA expression patterns from brain and blood in an AD mouse model. This analysis will provide insight regarding the mechanisms of AD pathology as well as determine a possible diagnostic tool utilizing RNA expression patterns found in the blood as biomarkers for AD.

Fty720 (Fingolimod) Provides Insight Into The Molecular Mechanisms Of Multiple Sclerosis, Madelyn Elizabeth Crawford

Pursuit - The Journal of Undergraduate Research at The University of Tennessee

Multiple sclerosis (MS) is a neurodegenerative disorder caused by a prolonged immune- mediated inflammatory response that targets myelin. Nearly all of the drugs approved for the treatment of MS are general immunosuppressants or only function in symptom management. The oral medication fingolimod, however, is reported to have direct therapeutic effects on cells of the central nervous system in addition to immunomodulatory functions. Fingolimod is known to interact with sphingosine-1-phosphate (S1P) receptors, and the most widely- accepted theory for its mechanism of action is functional antagonism of the receptor. This review examines significant neuromodulatory effects achieved by functional antagonism of the …

Fatty Acids Increase Neuronal Hypertrophy Of Pten Knockdown Neurons, Catherine J. Fricano, Tyrone Despenza, Paul W. Frazel, Meijie Li, A. James O'Malley, Gary Westbrook, Bryan Luikart

Dartmouth Scholarship

Phosphatase and tensin homolog (Pten) catalyzes the reverse reaction of PI3K by dephosphorylating PIP3 to PIP2. This negatively regulates downstream Akt/mTOR/S6 signaling resulting in decreased cellular growth and proliferation. Co-injection of a lentivirus knocking Pten down with a control lentivirus allows us to compare the effects of Pten knockdown between individual neurons within the same animal. We find that knockdown of Pten results in neuronal hypertrophy by 21 days post-injection. This neuronal hypertrophy is correlated with increased p-S6 and p-mTOR in individual neurons. We used this system to test whether an environmental factor that has been implicated in cellular hypertrophy …

Aβ Alters The Dna Methylation Status Of Cell-Fate Genes In An Alzheimer’S Disease Model, Gary D. Isaacs, Noor Taher, Courtney Mckenzie, Rebecca Garrett, Matthew Baker, Nena Fox

Faculty Publications and Presentations

Alzheimer’s disease (AD) is characterized by neurofibrillary tangles and extracellular amyloid-β plaques (Aβ). Despite ongoing research, some ambiguity remains surrounding the role of Aβ in the pathogenesis of this neurodegenerative disease. While several studies have focused on the mutations associated with AD, our understanding of the epigenetic contributions to the disease remains less clear. To that end, we determined the changes in DNA methylation in differentiated human neurons with and without Aβ treatment. We isolated the DNA from neurons treated with Aβ or vehicle, and digested the two samples with either a methylation-sensitive (HpaII) or a methylation-insensitive (MspI) restriction endonuclease. …

Parkinson’S Disease: Molecular Mechanisms And Treatments, Delia Vahey

Senior Honors Theses

Parkinson’s disease is a motor system disorder that is caused primarily by the loss of dopamine-producing brain cells. The most affected brain structure is the pars compacta of the substantia nigra. This area of the brain is essential to the control of voluntary movement, and so its impairment leads to symptoms such as tremors, rigidity, and impaired balance. The neuronal protein alpha-synuclein has been shown to be heavily involved in the pathogenesis of the disease at the cellular level. The currently available treatments for PD mainly target dopamine regulation, and there been no cure developed for the disease at present. …

The Role Of The Androgen Receptor Cofactor P44/Wdr77 In Astrocyte Activation, Bryce H. Vincent

Dissertations and Theses (Open Access)

Astrogliosis is induced by neuronal damage and is also a pathological feature of the major aging-related neurodegenerative disorders. The mechanisms that control the cascade of astrogliosis have not been well established. In a previous study, we identified a novel androgen receptor (AR)-interacting protein (p44/WDR77) and found that it plays a critical role in the control of proliferation and differentiation of prostate epithelial cells. In the present study, we found that deletion of the p44 gene in the mouse brain caused accelerated aging with dramatic astrogliosis. The p44/WDR77 is expressed in astrocytes and loss of p44/WDR77 expression in astrocytes leads to …

Orbitofrontal Cortex Provides Cross-Modal Valuation Of Self-Generated Stimuli, William A. Cunningham, Ingrid J. Haas, Ashley S. Waggoner

Department of Political Science: Faculty Publications

Prior research has shown that the orbitofrontal cortex (OFC) plays an important role in the representation of the evaluation of stimuli, regardless of stimulus modality. Based on these findings, researchers have proposed that the OFC serves a common currency function, allowing for the direct comparison of different types of perceptual stimuli (e.g. food, drink, money). The present study was designed to extend this research and investigate whether these same regions of OFC that have been identified in previous research are involved in evaluating imagined stimuli. Specifically, we asked participants to draw on prior attitudinal knowledge to generate internal representations of …

Prolonged Cyclooxygenase-2 Induction In Neurons And Glia Following Traumatic Brain Injury In The Rat, Kenneth I. Strauss, Mary F. Barbe, Renee Marshall Demarest, Ramesh Raghupathi, Samir Mehta, Raj K. Narayan

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Cyclooxygenase-2 (COX2) is a primary inflammatory mediator that converts arachidonic acid into precursors of vasoactive prostaglandins, producing reactive oxygen species in the process. Under normal conditions COX2 is not detectable, except at low abundance in the brain. This study demonstrates a distinctive pattern of COX2 increases in the brain over time following traumatic brain injury (TBI). Quantitative lysate ribonuclease protection assays indicate acute and sustained increases in COX2 mRNA in two rat models of TBI. In the lateral fluid percussion model, COX2 mRNA is significantly elevated (>twofold, p < 0.05, Dunnett) at 1 day postinjury in the injured cortex and bilaterally in the hippocampus, compared to sham-injured controls. In the lateral cortical impact model (LCI), COX2 mRNA peaks around 6 h postinjury in the ipsilateral cerebral cortex (fivefold induction, p < 0.05, Dunnett) and in the ipsilateral and contralateral hippocampus (two- and six-fold induction, respectively, p < 0.05, Dunnett). Increases are sustained out to 3 days postinjury in the injured cortex in both models. Further analyses use the LCI model to evaluate COX2 induction. Immunoblot analyses confirm increased levels of COX2 protein in the cortex and hippocampus. Profound increases in COX2 protein are observed in the cortex at 1-3 days, that return to sham levels by 7 days postinjury (p < 0.05, Dunnett). The cellular pattern of COX2 induction following TBI has been characterized using immunohistochemistry. COX2-immunoreactivity (-ir) rises acutely (cell numbers and intensity) and remains elevated for several days following TBI. Increases in COX2-ir colocalize with neurons (MAP2-ir) and glia (GFAP-ir). Increases in COX2-ir are observed in cerebral cortex and hippocampus, ipsilateral and contralateral to injury as early as 2 h postinjury. Neurons in the ipsilateral parietal, perirhinal and piriform cortex become intensely COX2-ir from 2 h to at least 3 days postinjury. In agreement with the mRNA and immunoblot results, COX2-ir appears greatest in the contralateral hippocampus. Hippocampal COX2-ir progresses from the pyramidal cell layer of the CA1 and CA2 region at 2 h, to the CA3 pyramidal cells and dentate polymorphic and granule cell layers by 24 h postinjury. These increases are distinct from those observed following inflammatory challenge, and correspond to brain areas previously identified with the neurological and cognitive deficits associated with TBI. While COX2 induction following TBI may result in selective beneficial responses, chronic COX2 production may contribute to free radical mediated cellular damage, vascular dysfunction, and alterations in cellular metabolism. These may cause secondary injuries to the brain that promote neuropathology and worsen behavioral outcome.