Molecular and Cellular Neuroscience Commons^™

Novel Insights Into Oligodendrocyte Biology From Developmental Myelination Studies In Autophagy Deficient Mice And Analysis Of Oligodendrocyte Translatome Response To Contusive Spinal Cord Injury., Michael David Forston

Electronic Theses and Dissertations

Loss of myelin causes severe neurological disorders and functional deficits in white matter injuries (WMI) such as traumatic spinal cord injury (SCI). This dissertation is focused on autophagy in OL development and the OL translatome after SCI. Chapter I describes the history of myelin, OL development, and their involvement in neurodegenerative diseases and SCI. The proteostasis network, in particular autophagy, and its contributions to white matter pathology is discussed. It concludes examining advantages and disadvantages of unbiased omics tools, like RiboTag, to study transcriptional/translational landscapes after SCI. Chapter II focuses on autophagy in OPC/OL differentiation, survival, and proper myelination in …

Connectivity Of Amygdala Somatostatin-Expressing Neurons And Their Role In Taste-Guided Behavior., Jane Jeruto Bartonjo

Electronic Theses and Dissertations

The nucleus of solitary tract (NST) and parabrachial nucleus (PBN) represent the first and second central synapses of ascending gustatory information. Neural processing in these nuclei is influenced by descending input from forebrain regions such as the central nucleus of the amygdala (CeA). In mice, we have shown that somatostatin (Sst) expressing neurons of CeA that project to NST and PBN are largely distinct cell populations and optogenetic inhibition of the CeA/Sst-to-NST subpopulation increases the intake of high concentrations of quinine with no apparent effect on sucrose intake. Synaptic connectivity of these cells is needed to understand the possible mechanisms …

A Comparison Of Pm-Nato3’S Influence On Neural Progenitors And Mature Dopamine Neurons, Mary E. West

Masters Theses

This thesis presents significant findings regarding the role of PM-Nato3 in its interaction with developing neurons in the context of Parkinson's disease (PD) and regenerative medicine. We investigated the effects of PM-Nato3 on dopamine (DA) neurogenesis under different culture conditions, both in vitro and in vivo. In the standard dopaminergic culture condition, PM-Nato3 potentially increased the speed of DA neuron production but did not significantly increase the yield of DA neurons. In a minimal culture condition, there was no notable difference between the control and PM-Nato3 conditions, suggesting minimal impact on DA neurogenesis. In vivo studies using a mouse model …

Inhibition Of Acid Sphingomyelinase Reduces Reactive Astrocyte Secretion Of Mitotoxic Extracellular Vesicles And Improves Alzheimer’S Disease Pathology In The 5xfad Mouse, Simone M. Crivelli, Zainuddin Quadri, Hemendra J. Vekaria, Zhihui Zhu, Priyanka Tripathi, Ahmed Elsherbini, Liping Zhang, Patrick G. Sullivan, Erhard Bieberich

Markey Cancer Center Faculty Publications

In Alzheimer’s disease (AD), reactive astrocytes produce extracellular vesicles (EVs) that affect mitochondria in neurons. Here, we show that Aβ-induced generation of the sphingolipid ceramide by acid sphingomyelinase (A-SMase) triggered proinflammatory cytokine (C1q, TNF-α, IL-1α) release by microglia, which induced the reactive astrocytes phenotype and secretion of EVs enriched with ceramide. These EVs impeded the capacity of neurons to respond to energy demand. Inhibition of A-SMase with Arc39 and Imipramine reduced the secretion of cytokines from microglia, prompting us to test the effect of Imipramine on EV secretion and AD pathology in the 5xFAD mouse model. Brain derived-EVs from 5xFAD …

Utilizing Crispr Cas9 To Visualize Dopamine Receptors In Caenorhabditis Elegans, Lauren Michelle Velasquez

Electronic Theses, Projects, and Dissertations

Dopamine (DA) is a neurotransmitter with imperative implications in many functions including movement, reward, and cognition. Studying the pathways of dopaminergic neurons at multiple levels allows us to understand the ways in which these systems can go wrong. We study dopamine in a model system such as the worm Caenorhabditis elegans because of its relatively simple and well-characterized nervous system. DA is involved in regulating chemosensory behaviors in worms. The purpose of this research project is to definitively answer the following question: Are the dopamine receptors DOP-1 and DOP-4 expressed in chemosensory neurons? Previous reporter assays show that neither of …

Complement System In Multiple Sclerosis: Its Role In Disease Course And Potential As A Therapeutic Target, Michael R. Linzey

Dartmouth College Ph.D Dissertations

Multiple sclerosis (MS) is a clinically heterogeneous neurological condition characterized by neuroinflammation and neurodegeneration. Relapsing-remitting MS, defined by inflammatory attacks, is the most common initial form of MS and there are currently 23 FDA-approved treatments for these patients. These therapies work primarily by reducing inflammation in the CNS; they do not work well in progressive disease. Therefore, an unmet medical need exists for effective therapeutic options to treat progressive MS (PMS).

In MS, intrathecal immunoglobulins synthesis (IIgS) correlates with disease progression. My goals for this dissertation were to establish the pathological role of IIgS and identify new potential therapeutic …

Role Of Chronic Stress-Induced Neuroinflammation In Rodent Locus Coeruleus Physiology And Anxiety-Like Behaviors, Arthur Anthony Alfonso Reyes

Graduate School of Biomedical Sciences Theses and Dissertations

The locus coeruleus (LC), the primary site of brain norepinephrine (NE), is a key anatomical brain region implicated in the stress response. Stress is a neuroendocrine physiologic response to a stressor that promotes organism survival through adaptive change and restoration of homeostasis. The central stress response, which drives behavioral and physiological change, is primarily mediated by activating the hypothalamic-pituitary-adrenal (HPA) axis. While advantageous in the short term, chronic stress exposure can lead to HPA axis and LC dysregulation, which are thought to contribute to the etiology of anxiety disorders. Previous studies demonstrate the effects of acute stress in increasing LC …

Investigating Sexual Dimorphism In Lateral Hypothalamic Melanin-Concentrating Hormone Neuron Subpopulations, Mahitha Juttu

Honors Scholar Theses

The lateral hypothalamic area (LHA) is an area crucial for coordinating key behaviors such as sleep, wakefulness, stress, and feeding. Within this area in the brain, Melanin concentrating hormone (MCH) neurons are exclusive to the LHA and also contribute to these key homeostatic behaviors. These neurons can be divided into two different subpopulations: MCH neurons that express cocaine amphetamine-regulated transcript (CART) tachykinin-3 receptor (NK3R) and MCH neurons that do not express CART and NK3R. These neuronal subpopulations have been implicated in coordinating key behaviors but have not been well studied.

In this paper, our project seeks to analyze how the …

The Role Of Complement In Stroke And Traumatic Brain Injury, Christine Couch

MUSC Theses and Dissertations

Brain and neural injury are a non-specific disease category that includes traumatic brain injury (TBI) and stroke. Both TBI and stroke are common, costly, and leading causes of severe disability in adults. Both stroke and TBI are responsible for substantial disability in working age adults, with stroke being the second leading cause of death worldwide [1] and TBI a major cause of disability in people younger than their 40's [2]. The immune response after brain injury is multifactorial and involves both local and systemic events at the cellular and molecular level. The complement system is a component of both the …

Characterizing The Effects Of Light On The Early Onset Photoreceptor Function Loss In Mucolipidosis Type Iv, Rebecca Cistulli

Masters Theses, 2020-current

Retinal degenerative diseases (RDD’s) are a diverse group of retinal disorders that cause visual impairment. While RDD prevalence is high, little is known about the molecular mechanisms underlying the pathogenesis within some of these disorders. Here we are trying to elucidate the molecular mechanisms that drive early onset photoreceptor function loss in the RDD, Mucolipidosis type IV (MLIV). MLIV is a lysosomal storage disorder that results from loss of function mutations in the MCOLN1 gene and leads to a disruption of autophagy. The MCOLN1 gene encodes a lysosomal cation channel called Trpml1. Based on previous data from our lab, we …

All The Rage: Assessing The Age/Rage Signaling Pathway’S Effects On Healthspan And The Physiological Processes Of Aging, Brandon Ashmore

Honors Theses

Advanced glycation end products (AGEs) are protein, lipid, or nucleotide molecules that have been combined with sugars through nonenzymatic, irreversible glycation and oxidation reactions. Their accumulation in the body has been associated with the natural aging process and a wide range of pathologies, including chronic inflammation, sustained oxidative stress, diabetes, neurodegenerative diseases, atherosclerosis, and cancer. Their interaction with the receptor for advanced glycation end products (RAGE) has been linked to several proinflammatory signaling pathways associated with neurotoxicity and vascular lesions. While some research has been done on the possible health benefits of RAGE inhibition to extend lifespan, our study hopes …

Microglia Refine Early Multisensory Circuits In The Lateral Cortex Of The Inferior Colliculus In A Complement-Dependent Manner, Shaida Hamidi

Masters Theses, 2020-current

Microglia cells (MGCs), the resident macrophage of the brain, play a pivotal role in synaptic pruning of newly established circuits during early critical periods. Classical complement cascade signaling enables MGCs to identify unnecessary or underutilized contacts and specifically target them for removal and subsequent degradation. Such recognition and engulfment behaviors require receptor-ligand interactions, whereby “eat me” tags (complement component 3, C3) bind their cognate receptor (complement receptor 3, CR3) expressed on MGCs. Compromised complement signaling in certain systems results in under-pruning or unrefined map configurations, and is thought perhaps to underlie certain autism-related behavioral phenotypes (e.g. sensory hypersensitivities, decreased social …

Synaptic Transmission At The Photoreceptor Ribbon Synapse, Chris Mesnard

Theses & Dissertations

Synaptic transmission relies on the Ca²⁺-dependent release of neurotransmitters packaged into synaptic vesicles. Ribbon synapses have the capability to release multiple vesicles at a time in a highly coordinated and synchronized manner. Glutamate release from rod and cone photoreceptor cells involves presynaptic ribbons composed largely of the protein RIBEYE. To examine roles of ribbons in rods and cones, we studied mice in which GCamP3 replaced the B-domain of RIBEYE. We discovered that ribbons were absent from rods and cones of both knock-in mice possessing GCamP3 and conditional RIBEYE knockout mice. Mice lacking ribbons showed reduced temporal resolution and …

Evaluating Sex Differences In The Neuroimmune Response Following Neuroinflammation And Relief Due To Nanotheranostic Treatment, Brooke Deal

Electronic Theses and Dissertations

Until recently, the majority of preclinical neuroinflammatory studies were performed on males. Because of this, less is known about the female neuroinflammatory response to injury, formation of pain, or response to pain-relieving therapies. The neuroinflammatory response is multifaceted with neuronal, glial, and immune cells all contributing to the induction and resolution of neuroinflammation. During this response, macrophages typically undergo an upregulation of cyclooxygenase-2 (COX-2) leading to the production of prostaglandin E2 (PGE2), which is linked to neuronal sensitization and pain. Non-steroidal anti-inflammatory drugs (NSAIDs) attenuate PGE2 by the inhibition of COX-2. A limitation with NSAIDs is that due to the …

Swallowing Disrupts Tongue-Jaw Coordination During Chewing In A Rat Model Of Parkinson's Disease, Meejan Palhang, N. Charles, Francois Gould

Rowan-Virtua Research Day

The primary motor symptoms of Parkinson’s disease, including bradykinesia, rigidity, and tremor, are associated with difficulties regulating transitions between motor behaviors due to basal ganglia dysfunction. Chewing and swallowing, which are disordered in most patients with Parkinson’s disease, are two complex motor behaviors which overlap in time and share some neuromuscular components. The objective of this study is to identify how Parkinson’s disease affects the coordination of chewing and swallowing. We hypothesize that as a result of impaired regulation of shift between motor patterns, chewing cycles that occur with a swallow will be more affected that chewing cycles occurring in …

Perineuronal Nets Are Not Required To Close The Critical Period For Ocular Dominance Plasticity., Emily Crouse

Electronic Theses and Dissertations

In the developing visual system, a transient critical period demarcates when neural circuits are most sensitive to visual experience. In the mouse, the critical period occurs between approximately postnatal day(P) 19 to 32. Closing one eye (monocular deprivation, MD) within the critical period shifts ocular dominance (OD) to be more responsive to the open eye. Nogo-66 Receptor 1 (NGR1) limits OD plasticity to the critical period yet it remains unknown how OD plasticity propagates through primary visual cortex or by which mechanisms NGR1 utilizes to confine said plasticity. In primary studies, NGR1 was selectively deleted in different cortical layers to …

Transcriptional Regulation Of Stem Cell Function In The Drosophila Central Nervous System, Amalia S. Parra

Biology ETDs

Development of multicellular organisms depends on coordination of various molecular mechanisms to ensure proper tissue size and structure. This is accomplished through intrinsic and extrinsic cues that regulate cell growth and proliferation both spatially and temporally. These well-coordinated signals are present from early developmental stages and remain active throughout development to ensure tissue structure is appropriate for function. This is particularly important in early cell types that form specialized lineages such as stem cells or those found throughout the body such as epithelia. While much progress has been made in understanding growth regulatory mechanisms, several fundamental aspects remain unknown. This …

Validating A New In Vivo Model To Study Als, Izabela J. Cimachowska

Student Theses and Dissertations

Buildup of oxidative stress and mitochondrial dysfunction are well known characteristics of both sporadic and hereditary amyotrophic lateral sclerosis (ALS). While both forms of the disease seem to arise from common cellular dysfunction, the genetic disease is studied to a much greater extent. Engineering novel animal models of the sporadic form of the disease is crucial for development of druggable targets to treat ALS and understand the underlying mechanisms. Interestingly, accumulation of oxidative stress by exacerbated emission of reactive oxygen species (ROS) from presynaptic mitochondria is a hallmark of both hereditary and sporadic ALS. Previous work by our laboratory showed …

Synaptic Properties Of Parabigeminal Circuits., Kyle Whyland

Electronic Theses and Dissertations

Subcortical structures of the visual system have been the subject of intense study in recent years, but there remain some important unanswered questions regarding the synaptic relationships linking the nuclei that comprise this important sensory network within the brain. In these studies, we use several modern and traditional approaches, including viral tract tracing, in vitro slice physiology, immunohistochemistry, optogenetics, and electron microscopy to characterize the circuits linking the superior colliculus (SC), parabigeminal nucleus (PBG), and lateral geniculate nucleus (LGN), with particular focus on GABAergic and cholinergic cell types. We found that the SC, an important visuomotor structure with connections to …

An Investigation Into Structural Plasticity In Peripheral Taste Neurons Associated With Taste Cell Turnover., Zachary Whiddon

Electronic Theses and Dissertations

The continual replacement of taste cells creates interesting questions regarding how the innervating neurons are impacted during this process. Here we ask how innervation within taste buds is affected when taste cell entry is inhibited and reestablished. Inhibition of sonic hedgehog signaling (Shh) is thought to inhibit taste cell turnover. Consistently, fewer new cells were added to individual taste buds after treatment with a Shh-inhibitor compared to vehicle treatment, and taste bud volume decreased after 16 days of treatment. We next examined how taste nerve fiber extension into the gustatory epithelium is affected by preventing taste cell turnover. Ten days …