Neurosciences Commons^™

Proteome Analysis Of Bronchoalveolar Lavage From Calves Infected With Bovine Respiratory Syncytial Virus-Insights In Pathogenesis And Perspectives For New Treatments., Sara Hägglund, Krister Blodörn, Katarina Näslund, Karin Vargmar, Sara Bergström Lind, Jia Mi, Mariluz Araínga, Sabine Riffault, Geraldine Taylor, John Pringle, Jean François Valarcher

Journal Articles: Pharmacology & Experimental Neuroscience

Human and bovine respiratory syncytial viruses (HRSV/BRSV) are major causes of severe lower respiratory tract infections in children and calves, respectively. Shared epidemiological, clinical, pathological and genetic characteristics of these viruses make comparative research highly relevant. To characterise the host response against BRSV infection, bronchoalveolar lavage supernatant (BAL) from i) non-vaccinated, BRSV-infected ii) vaccinated, BRSV-infected and iii) non-infected calves was analysed by tandem mass spectrometry. Proteins were semi-quantified and protein expression was validated by immunoblotting. Correlations between selected proteins and pathology, clinical signs and virus shedding were investigated. Calves with BRSV-induced disease had increased total protein concentrations and a decreased …

Pathogenic Determinants And Mechanisms Of Als/Ftd Linked To Hexanucleotide Repeat Expansions In The C9orf72 Gene., Xinmei Wen, Thomas Westergard, Piera Pasinelli, Davide Trotti

Department of Neuroscience Faculty Papers

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two apparently distinct neurodegenerative diseases, the former characterized by selective loss of motor neurons in the brain and spinal cord and the latter characterized by selective atrophy of frontal and temporal lobes. Over the years, however, growing evidence from clinical, pathological and genetic findings has suggested that ALS and FTD belong to the same clinic-pathological spectrum disorder. This concept has been further supported by the identification of the most common genetic cause for both diseases, an aberrantly expanded hexanucleotide repeat GGGGCC/ CCCCGG sequence located in a non-coding region of the gene …

Brief Cognitive Screening Tools For Primary Care Practice, K Rhoads, Nancy B. Isenberg, L Korte

Articles, Abstracts, and Reports

Early detection and diagnosis of Alzheimer’s disease and other cognitive impairment presents as a critical issue facing primary and specialty care providers in Washington State. In order to address the gaps and challenges faced by providers, the Dementia Action Collaborative offers the current paper to provide information and guidance around early detection and diagnosis of memory loss and dementia, including Alzheimer’s disease. At the conclusion of this paper, providers should be able to identify indications and opportunities for detection, appropriate tools, and care pathways for individuals and families affected by cognitive impairment and dementia.

Brain Connectivity After Concussion, Armin Iraji

Wayne State University Dissertations

Mild traumatic brain injury (mTBI) accounts for over one million emergency visits in the United States each year. While most mTBI patients have normal findings in clinical neuroimaging, alterations in brain structure and functional connectivity have frequently been reported. In this study, we investigated the large-scale brain structural and functional connectivity using diffusion MRI and resting-state fMRI data. Data from 40 mTBI patients was acquired at the acute stage (within 24 hrs after injury). 35 patients returned for data acquisition at a follow-up (4-6 weeks after injury). Data was also collected from a cohort of 58 healthy subjects, 36 of …

Examining The Effects Of Adolescent Binge Alcohol Exposure On The Negative Feedback Of The Hpa Axis And Adult Responses To Psychological Stress, Audrey Rose Torcaso

Dissertations

Binge drinking during adolescence is a common occurrence which is associated with increased risk of developing alcohol dependence and other mental health disorders. Hypothalamo-pituitary-adrenal (HPA) axis dysfunction is one characteristic commonly observed in many affective disorders, including anxiety and depression. Our laboratory has previously demonstrated that adolescent binge-pattern alcohol exposure results in long-term dysfunction of the HPA axis in a Wistar rat model, characterized by deficient glucocorticoid feedback inhibition. The current study aimed to characterize the behavioral phenotype of these rats in response to psychological stress during adulthood, and furthermore sought to understand the molecular mechanisms by which adolescent binge …

Alzheimer’S Disease And Other Dementias Workgroup: Alzheimer’S Disease And Other Dementias Report And Recommendations, V Weir (Ed), K Rhoads (Chair), Nancy B. Isenberg, See All Group Members In Comments

Articles, Abstracts, and Reports

Rates of Alzheimer’s disease and other dementias are expected to increase greatly over the next decades. Many practices lack guidelines on how to increase quality of diagnosing, treating, and supporting people with dementia and their family members and other caregivers. This workgroup met from January to November 2017, aligned with and built off the Alzheimer’s State Plan, and organized recommendations with the following focus areas:

• Early detection and appropriate diagnosis
• Ongoing care and support or management including for family members and caregivers
• Advance care planning and palliative care
• Assessment and planning for need for increased support and/or higher levels …

Somatosensory Deficits In Post-Acl Reconstruction Patients: A Case-Control Study, Johanna M. Hoch, William O. Perkins, Jonathan R. Hartman, Matthew C. Hoch

Rehabilitation Sciences Faculty Publications

Introduction: Diminished cutaneous detection thresholds have been identified in patients with multiple orthopedic conditions, and these phenomena may occur in postanterior cruciate ligament reconstructed (ACLR) patients. The purpose of this study was to determine if differences in lower extremity cutaneous detection thresholds exist in post-ACLR patients when compared with healthy controls. Methods: Fifteen individuals who were post-ACLR and 15 individuals who had no history of knee injury participated. Light touch cutaneous detection thresholds were assessed at 4 locations on the foot and ankle (first metatarsal, fifth metatarsal, medial malleolus, and lateral malleolus). Nonparametric statistics examined group differences between the …

Synaptotagmin C2b Ca2+-Binding Loops Impose Distinct Exocytosis Phenotypes, Michael W. Schmidtke

Wayne State University Theses

Regulated exocytosis from chromaffin cells in the adrenal medulla plays a critical role in maintaining organismal homeostasis. In the absence of stress, these cells release physiologically relevant substances into the blood stream only in limited quantities, whereas stressful conditions result in a rapid deluge of signaling molecules used, for example, to increase heart rate and pain tolerance. Although the cellular mechanisms governing the switch from low-level to stress-induced secretion are not well understood, recent evidence has implicated the exocytotic Ca2+-sensing protein Synaptotagmin (Syt) in this role.

Two isoforms of Syt are expressed in chromaffin cells (Syt-1 and Syt-7), and each …

The Severity Of Intracranial Hemorrhages Measured By Free Hemoglobin In The Brain Depends On The Anticoagulant Class: Experimental Data., Kyle M Ware, Douglas L Feinstein, Israel Rubinstein, Prudhvi Battula, Jose Otero, Lee Hebert, Tzu-Fei Wang, Alexandra Ivanova, Shweta Chaudhary, Jessica Hemminger, Sergey V Brodsky

Neuroscience Articles

Background and Purpose. Anticoagulant therapy is broadly used to prevent thromboembolic events. Intracranial hemorrhages are serious complications of anticoagulation, especially with warfarin. Direct oral anticoagulants reduce but do not eliminate the risk of intracranial hemorrhages. The aim of this study is to determine the degree of intracranial hemorrhage after application of anticoagulants without additional triggers. Methods. Rats were treated with different anticoagulant classes (vitamin K antagonists, heparin, direct thrombin inhibitor, and factor Xa inhibitor). Brain hemorrhages were assessed by the free hemoglobin concentration in the brain parenchyma. Results. Vitamin K antagonists (warfarin and brodifacoum) significantly increased free hemoglobin in the …

Assessment Of Treatment Patterns Associated With Injectable Disease-Modifying Therapy Among Relapsing-Remitting Multiple Sclerosis Patients., J Nicholas, J J Ko, Y Park, P Navaratnam, H S Friedman, F R Ernst, V Herrera

Neuroscience Articles

BACKGROUND: Availability of oral disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS) may affect injectable DMT (iDMT) treatment patterns.

OBJECTIVE: The objective of this paper is to evaluate iDMT persistency, reasons for persistency lapses, and outcomes among newly diagnosed RRMS patients.

METHODS: Medical records of 300 RRMS patients initiated on iDMT between 2008 and 2013 were abstracted from 18 US-based neurology clinics. Eligible patients had ≥3 visits: pre-iDMT initiation, iDMT initiation (index), and ≥1 visit within 24 months post-index. MS-related symptoms, relapses, iDMT treatment patterns (i.e. persistency, discontinuation, switching, and restart), and reasons for non-persistency were tracked for 24 months. …

Localization Of Fam171b Mrna Expression In Mouse Brain Using In-Situ Hybridization, Ashani Kumudika Sudasinghe

All Graduate Theses, Dissertations, and Other Capstone Projects

Proteins containing polyglutamine (polyQ) tracts within their primary amino acid sequence are particularly interesting because expansion mutation within them has been shown to underlie a growing list of severe neurodegenerative disorders including Huntington's Disease and several types of Spinocerebellar Ataxias. FAM171B is a novel polyQ protein that was originally identified via large scale sequencing efforts. However, to date, very little is known regarding its normal cellular function and expression pattern. In this study, in situ hybridization was utilized to assess whether FAM171B is expressed in developing (postnatal days 7, 21, 42) and adult mouse brains. The results of the experiments …

The Effects Of Exercise Preconditioning On Focal Ischemic Stroke, Gillian Grohs

Theses and Dissertations--Medical Sciences

Cleaved fragments of the extracellular matrix protein perlecan have been shown to promote neuroprotection and repair after ischemic stroke. The cysteine proteases cathepsin B and L as well as the metalloprotease bone morphogenic protein 1 (BMP-1) are capable of releasing the biologically active C-terminal laminin-like globular domain (LG3) of perlecan. Exercise, a known method of reducing stroke risk and severity, has been shown to increase the expression of some proteases associated with perlecan processing. Using a transient distal middle cerebral artery occlusion (MCAo) model for focal ischemic stroke we show that while 7 days of running only slightly decreased infarct …

Insulin Actions On Hippocampal Neurons, Shaniya Maimaiti

Theses and Dissertations--Pharmacology and Nutritional Sciences

Aging is the main risk factor for cognitive decline. The hippocampus, a brain region critical for learning and memory formation, is especially vulnerable to normal and pathological age-related cognitive decline. Dysregulation of both insulin and intracellular Ca2+ signaling appear to coexist and their compromised actions may synergistically contribute to neuronal dysfunction with aging. This dissertation focused on the interaction between insulin, Ca2+ dysregulation, and cognition in hippocampal neurons by examining the contributions of insulin to Ca2+ signaling events that influence memory formation. I tested the hypothesis that insulin would increase cognition in aged animals by altering Ca2+-dependent physiological mechanisms involved …

Neuroinflammation In Alzheimer's Disease And Vascular Cognitive Impairment, Erica M. Weekman

Theses and Dissertations--Physiology

It was once believed that the brain was immunologically privileged with no resident or infiltrating immune cells; however, now it is understood that the cells of the brain are capable of a wide range of inflammatory processes and phenotypes. Inflammation in the brain has been implicated in several disease processes such as Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID); however, the role of inflammation in these two dementias is poorly understood.

When we stimulated a pro-inflammatory phenotype with an adeno-associated viral vector in a transgenic mouse model of AD that develops Aβ plaques, we saw a pro-inflammatory …

Steroidogenesis In The Green Anole Lizard Brain And Gonad, Christine Peek

All Graduate Theses, Dissertations, and Other Capstone Projects

Seasonally breeding animals reproduce during certain times of the year and, subsequently, behaviors, steroid hormone levels, and brain morphology change. The green anole lizard (Anolis carolinensis) is an excellent model to study the regulation of steroid hormone production because they have distinct hormonal and behavioral differences between sexes and seasons. As in other vertebrates, steroidogenesis in anoles is under the control of the hypothalamus-pituitary-gonadal (HPG) axis. We tested the hypothesis that natural variations in steroid hormone levels between sexes and seasons are mediated within the brain and gonad by examining four genes involved in steroidogenesis: StAR, Cyp17α1, HSD17β3, and Cyp19α1. …

Pantothenate Kinase-Associated Neurodegeneration, Khalid Hundallah, Afnan Al Hakeem

Neurosciences

No abstract provided.

Cyclic Ac253, A Novel Amylin Receptor Antagonist, Improves Cognitive Deficits In A Mouse Model Of Alzheimer’S Disease, Rania Soudy, Aarti Patel, Wen Fu, Kamaljit Kaur, David Mactavish, David Westaway, Rachel Davey, Jeffrey Zajac, Jack Jhamandas

Pharmacy Faculty Articles and Research

Introduction: Amylin receptor serves as a portal for the expression of deleterious effects of amyloid b-protein (Ab), a key pathologic hallmark of Alzheimer’s disease. Previously, we showed that AC253, an amylin receptor antagonist, is neuroprotective against Ab toxicity in vitro and abrogates Ab-induced impairment of hippocampal long-term potentiation.

Methods: Amyloid precursor protein–overexpressing TgCRND8 mice received intracerebroventricularly AC253 for 5 months. New cyclized peptide cAC253 was synthesized and administered intraperitoneally three times a week for 10 weeks in the same mouse model. Cognitive functions were monitored, and pathologic changes were quantified biochemically and immunohistochemically.

Results: AC253, when administered …

The Effects Of Perinatal Oxycodone Exposure On The Stress Axis And Neurobehavior, Thitinart Sithisarn

Theses and Dissertations--Physiology

Opiate addiction is now a major public health problem. Pregnant women continue to use opiates during gestation; up to 5.4% of pregnant women report using illicit drugs during pregnancy. Previous studies have shown that perinatal insults and exposure to opiates such as morphine in utero can affect the development of the hypothalamic-pituitary-adrenal (HPA)-axis of the offspring and are associated with higher risk of developing neurobehavioral problems. Oxycodone, a semisynthetic putative kappa opioid receptor and partial mu opioid receptor agonist is now one of the most frequently abused pain killers during pregnancy, however limited data are available regarding whether and how …

Implication Of Alpha-Synuclein Transcriptional Regulation And Mutagenesis In The Pathogenesis Of Sporadic Parkinson's Disease, Sambuddha Basu

Electronic Theses and Dissertations

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by selective loss of dopaminergic neurons (DA neurons) from the substantia nigra (SN) of the mid-brain. PD is classically associated with cytoplasmic inclusion of aggregated proteins called Lewy bodies. alpha-synuclein (α-SYN) coded by the gene SNCA, is one of the major components of Lewy body and neurite along with several other proteins like ubiquitin, neurofilament to name a few. PD is broadly categorized into two groups based on their incidence of occurrence. First is the familial form that occurs due to known genetic aberrations like mutation, gene duplication/triplication in important PD …

Understanding The Mechanism Of Oxidative Stress Generation By Oxidized Dopamine Metabolites: Implications In Parkinson's Disease, Nihar Mehta

Wayne State University Dissertations

Oxidation of dopamine to toxic metabolites is considered to be one of the prime factors involved in the death of dopaminergic neurons in Parkinson’s disease. Some dopamine oxidation products have the capability to redox cycle in the presence of molecular oxygen, further contributing to oxidative stress. Therefore, our aim here was to study the redox cycling of dopamine oxidized metabolites and elucidate the underlying mechanism by which they cause oxidative stress.

Redox reactions involve transfer of one or more electrons between two compounds

resulting in either oxidation or reduction. In redox cycling, a compound undergoes

alternate oxidation and reduction, transferring …

Analysis Of The Secondary Neurodegenerative Consequences Of Primary Oligodendrocyte Stress Through The Use Of The Novel Obiden Mouse Model, Daniel Zdzislaw Radecki

Wayne State University Dissertations

The work of this project was to develop, test and characterize a potential novel mouse model of the neurodegenerative disease Multiple Sclerosis (MS). Historically, MS has been identified as a primary autoimmune disease of the central nervous system (CNS). However, treatments based on this view have met with limited success, and in most cases, fail to prevent progression of MS from mild to moderate and severe forms. Original observations regarding axonal and neuronal pathology in the white and gray matter of the CNS were rediscovered in the 1990s. These observations indicated that even in the absence of the immune system, …

Estimating The Variables Of The Nonlinear Dynamical Theory Of Acute Cell Injury, Fika Tri Anggraini

Wayne State University Dissertations

This Dissertation is the first to estimate the variables D and S of the nonlinear theory of acute cell injury in hippocampal regions CA1 and CA3 using a rat model of global brain ischemia and reperfusion (I/R). D was estimated by quantifying protein aggregates using ubiquitin Western blotting. S was estimated by quantifying changes in polysomal mRNAs as measured by microarray chips. D and S time courses were sampled at 0.5, 8, 16, 24, 48, and 72 hrs of reperfusion after 10 min brain ischemia. CA1 dies and CA3 survives. The theory predicts D will be larger in CA1 and …

Epigenetic Editing To Validate Findings From Methylome-Wide Association Studies Of Neuropsychiatric Disorders, Robin F. Chan

Theses and Dissertations

DNA methylation is necessary for learning, memory consolidation and has been implicated in a number of neuropsychiatric disorders. Obtaining high quality and comprehensive data for the three common forms of methylation in brain is challenging for methylome-wide association studies (MWAS). To address this we optimized a panel of enrichment methods for screening the brain methylome. Results show that these enrichment techniques approach the coverage and fidelity of the current gold standard bisulfite based techniques. Our MBD-based method can also be used with low amounts of genomic material from limited human biomaterials. Psychiatric disorders have high prevalence and are often chronic …

Long Days Enhance Recognition Memory And Increase Insulin-Like Growth Factor 2 In The Hippocampus, Adriano Dellapolla, Ian Kloehn, Harshida Pancholi, Ben L. Callif, David Wertz, Kayla Rohr, Matthew M. Hurley, Kimberly Baker, Samer Hattar, Marieke R. Gilmartin, Jennifer A. Evans

Biomedical Sciences Faculty Research and Publications

Light improves cognitive function in humans; however, the neurobiological mechanisms underlying positive effects of light remain unclear. One obstacle is that most rodent models have employed lighting conditions that cause cognitive deficits rather than improvements. Here we have developed a mouse model where light improves cognitive function, which provides insight into mechanisms underlying positive effects of light. To increase light exposure without eliminating daily rhythms, we exposed mice to either a standard photoperiod or a long day photoperiod. Long days enhanced long-term recognition memory, and this effect was abolished by loss of the photopigment melanopsin. Further, long days markedly altered …

Elevated Hydrostatic Pressure Selectively Enhances Matricellular Gene Expression In Human Trabecular Meshwork Cells, Jonathan Lautz

Dissertations

Primary open-angle glaucoma (POAG) is a progressive optic neuropathy

characterized by loss of peripheral vision secondarily associated with elevated intraocular pressure (IOP). Transforming growth factor (TGF)-β2 is markedly elevated in the aqueous humor (AH) of patients with POAG. It has been previously shown that TGF-β2 increases IOP, in part, by inducing expression and release of endothelin-1 (ET-1) and connective tissue growth factor (CTGF) within the trabecular meshwork (TM). ET-1 and CTGF may ultimately lead to increases in IOP by enhancing TM cell contractility and extracellular matrix (ECM) deposition. Here we confirm that TGF-β2 enhances mRNA content of ET-1, CTGF, and …

The Unconventional Secretion Of Alpha-Synuclein By Autophagic Mechanisms And The Novel Characterization Of Pathological Alpha-Synuclein Associated Extracellular Vesicles, Kevin Burbidge

Master's Theses

Synucleinopathies are a group of neurodegenerative diseases associated with the intracellular accumulation of aggregated α-synuclein, a neurotoxic process resulting in cell death. Research indicates that pathology results from α-synuclein misfolding and self-propagation, as well as, cell-to-cell transmission. Furthermore, pathological α-synuclein transmission may occur through unconventional secretion.

In this thesis, we investigated how autophagy influences unconventional secretion of our novel α-synuclein dual-split protein model that we first verified by reproducing documented results from treatment of known autophagic regulators. Afterwards, we investigated how knocking out autophagic proteins ATG7 and Beclin-1 influenced α-synuclein secretion.

Additionally, we developed a methodology for analyzing extracellular vesicles …

Harnessing The Power Of Cell Transplantation To Target Respiratory Dysfunction Following Spinal Cord Injury., Brittany A. Charsar, Mark W. Urban, Angelo C. Lepore

Department of Neuroscience Faculty Papers

The therapeutic benefit of cell transplantation has been assessed in a host of central nervous system (CNS) diseases, including disorders of the spinal cord such as traumatic spinal cord injury (SCI). The promise of cell transplantation to preserve and/or restore normal function can be aimed at a variety of therapeutic mechanisms, including replacement of lost or damaged CNS cell types, promotion of axonal regeneration or sprouting, neuroprotection, immune response modulation, and delivery of gene products such as neurotrophic factors, amongst other possibilities. Despite significant work in the field of transplantation in models of SCI, limited attention has been directed at …

Intravenous Formulation Of Het0016 Decreased Human Glioblastoma Growth And Iimplicated Survival Benefit In Rat Xenograft Models, M Jain, N Gamage, M Alsulami, A Shankar, B Achyut, Austin Guo, A Arbab, A Arbab

NYMC Faculty Publications

Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 is a selective CYP450 inhibitor, which has been shown to inhibit angiogenesis and tumor growth. Therefore, to explore novel treatments, we have generated an improved intravenous (IV) formulation of HET0016 with HPssCD and tested in animal models of human and syngeneic GBM. Administration of a single IV dose resulted in 7-fold higher levels of HET0016 in plasma and 3.6-fold higher levels in tumor at 60 min than that in IP route. IV treatment with HPssCD-HET0016 decreased tumor growth, and altered vascular kinetics in early and late treatment groups …