Molecular and Cellular Neuroscience Commons^™

Oligodendrocyte 2phatal Reveals Dynamics Of Myelin Degeneration And Repair, Timothy W. Chapman

Dartmouth College Ph.D Dissertations

Oligodendrocytes are responsible for producing myelin in the central nervous system. This lipid-rich coating along axons helps to increase action potential velocity, provide metabolic support to axons, and facilitate fine-tuning of neuronal circuitry. Demyelination and/or myelin dysfunction is widespread in neurodegenerative diseases and aging. Despite this, we know very little about how individual oligodendrocytes, or the myelin sheaths they produce, degenerate. Myelin repair, carried out by resident oligodendrocyte precursor cells (OPCs), is known to occur following myelin damage in certain contexts. We sought to investigate the cellular dynamics of oligodendrocyte degeneration and repair by developing a non-inflammatory demyelination model, combining …

Unraveling The Consequence Of Adult Onset Sulfatide Depletion: Its Implications In Myelin And Axonal Heath In The Context Of Neurodegenerative Disease, Elizabeth Dustin

Theses and Dissertations

Multiple Sclerosis is an immune mediated disease of the CNS. MS is diagnosed through detection of demyelinated regions. However, recent studies demonstrate that Normal Appearing White Matter (NAWM) contains substantial pathology. One such pathology observed in the NAWM is the reduction of sulfatide. The proper stoichiometry of lipids in myelin acts to maintain rapid conduction velocity, provide trophic support to the neuron, and protect the axon from degeneration. We previously characterized a mouse lacking sulfatide’s synthesizing enzyme, CST through constitutive gene disruption and demonstrate that sulfide is required for proper stability of the myelin sheath. However, since MS is typically …

Clinical And Biological Factors Determine Spinal Cord Injury Outcomes: Liquor To Lipids, Ethan Glaser

Theses and Dissertations--Physiology

Spinal cord injuries (SCI) are debilitating and life altering events that can lead to permanent motor and sensory loss. SCI outcomes are impacted by both clinical factors such as blood alcohol content (BAC) at the time of injury as well as biological factors like the lipid-rich myelin debris that accumulates in the injury site. Both clinical and biological factors contribute to SCI recovery, impacting neuroinflammation, locomotor recovery, and histopathology. The purpose of the studies described here is to investigate the role of acute alcohol intoxication and intracellular lipid processing pathways on SCI outcomes in a rodent model.

An elevated BAC …

Effects Of Hiv-1 Tat And Opiates On Gene Regulation Of Oligodendrocyte Lineage Cells: Identification Of Myrf As A Novel Target, Kelly M. Flounlacker

Theses and Dissertations

HIV-associated neurocognitive disorders remain pervasive even with increased efficacy/use of antiretroviral therapies. Opioid use/abuse among HIV+ individuals is documented to exacerbate deficits. White matter (WM) alterations (myelin pallor, volume/structural) detected by diffusion tensor imaging, are common observations in HIV+ individuals. Using transgenic mice expressing HIV-1 Tat, we examined effects of 2-6 weeks of Tat/morphine exposure on WM using genomic/biochemical methods. RNA sequencing of striatal tissue after 2-weeks revealed robust changes in mRNAs associated with oligodendrocyte populations/myelin integrity, including Transferrin, Ndrg1, and myelin regulatory factor (Myrf/Mrf), an oligodendrocyte-specific transcription factor involved in differentiation/maturation. Immunoblots conducted after 6-weeks exposure in …

Med12 Is A Critical Regulator Of Neural Crest Lineage And Nervous System Myelination, Fatma Betul Aksoy Yasar

Dissertations & Theses (Open Access)

The Mediator complex (MED) is a multi-subunit protein complex integral to the eukaryotic transcription machinery. MED12 is a Cdk8- regulatory kinase module subunit directly implicated in human disease and is genetically altered in neurological disease and cancer. Numerous attempts at generating an in vivo system to study the role of Med12 failed due to embryonic lethality associated with germline or developmental disruption of Med12 gene. To understand the cellular and molecular processes associated with its role in disease, we generated multiple mouse models with targeted depletion of MED12 in distinct cellular lineages. Our genetically engineered models with induced and conditional …

Role Of Nuclear Lamins In Oligodendrocyte Lineage Cells, Camila Yattah

Dissertations, Theses, and Capstone Projects

Differentiation of oligodendrocytes from progenitor cells is a highly regulated process characterized by a series of molecular changes, resulting in nuclear and morphological features unique to the mature oligodendrocyte state. Heterochromatin formation starting at the nuclear periphery, as well as increased nuclear rigidity are characteristically observed. The nuclear periphery is characterized by the presence of the nuclear lamina and it has been implicated in higher-order genome organization in cells. Lamins are the protein components of the nuclear lamina, and their expression is dependent upon the cell differentiation stage of the cells. While Lamin B1 (LMNB1) expression is high in progenitors …

Third Harmonic Generation: A Method For Visualizing Myelin In The Murine Cerebral Cortex, Michael Redlich

Dissertations, Theses, and Capstone Projects

Here we present the use of Third Harmonic Generation (THG) for the label-free imaging of myelinated axons in the murine cerebral cortex. Myelin plays an important role in the processes of learning and disease. However, much of the myelin biology research thus far has focused on white matter tracts where myelin is more visible. Much is still unknown, particularly with regard to myelin in gray matter. First, we engage in THG microscopy using an optical parametric oscillator pumped by a titanium-sapphire laser to demonstrate the utility of the technique for imaging myelin in vivo. Second, we investigate the use of …

Qki-Mediated Cholesterol Biosynthesis In Eye Lens And Myelin Of The Central Nervous System, Seula Shin, Seula Shin

Dissertations & Theses (Open Access)

Cells obtain cholesterol in two ways, de novo biosynthesis and uptake from circulation. While most tissues utilize both sources, eye lens and brain depend extensively on cholesterol biosynthesis due to the limited supply from circulation. Lens cell membrane consists of highest portion of cholesterol. Brain is the most cholesterol-rich organ, which accounts for 23% of total cholesterol. Genetic mutations of cholesterol biosynthesis enzymes in humans and animal models present cataracts and hypomyelinating disorders linked to neurological impairment. Yet, it remains unclear how gene expression of cholesterol biosynthesis is regulated in lens and brain. Therefore, studying cholesterol biosynthesis in both tissues …

Qki-Mediated Cholesterol Biosynthesis In Eye Lens And Myelin Of The Central Nervous System, Seula Shin, Seula Shin

Dissertations & Theses (Open Access)

Cells obtain cholesterol in two ways, de novo biosynthesis and uptake from circulation. While most tissues utilize both sources, eye lens and brain depend extensively on cholesterol biosynthesis due to the limited supply from circulation. Lens cell membrane consists of highest portion of cholesterol. Brain is the most cholesterol-rich organ, which accounts for 23% of total cholesterol. Genetic mutations of cholesterol biosynthesis enzymes in humans and animal models present cataracts and hypomyelinating disorders linked to neurological impairment. Yet, it remains unclear how gene expression of cholesterol biosynthesis is regulated in lens and brain. Therefore, studying cholesterol biosynthesis in both tissues …

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 …}

Axon Initial Segment Loss Is Not Observed In The Hippocampus Of A Experimental Autoimmune Encephalomyelitis Mouse Model, Praveen Mohanraju

Undergraduate Research Posters

The axon initial segment (AIS) is fundamental for neuronal communication and action potential initiation, a characteristic which has been shown to be disrupted in inflammatory diseases such as Multiple Sclerosis (MS). Previous work from our lab has shown AIS breakdown in layer 5 of the cortex in a mouse model of MS known as experimental autoimmune encephalomyelitis (EAE). Moreover, it was shown that AIS breakdown was independent of demyelination but temporally correlated with microglial inflammatory reactivity. In order to determine if this pathology is specific to the cortex or affects other regions of the brain, we exploited these EAE induced …

Characterization Of The Transporter Protein Sodium-Potassium Adenosine Triphosphatase In The Myelin Membrane, Dara E C Schaefer

Theses and Dissertations (Comprehensive)

Sodium-potassium adenosine triphosphatase (Na⁺/K⁺-ATPase) is an integral membrane protein with known involvement in the maintenance of resting membrane potentials, nutrient uptake, cellular signal transduction, and cell-cell adhesion. The functional enzyme contains a catalytic alpha subunit and a glycosylated beta subunit, of which three isoforms of each are known to exist in the central nervous system (CNS). Altered expression and/or activity of Na⁺/K⁺-ATPase subunit isoforms has been previously implicated in the pathophysiology of several neurological disorders. This study characterized Na⁺/K⁺-ATPase expression and distribution in the myelin membrane, identified its …