Life Sciences Commons^™

Exercise As A Treatment For Cognitive Decline In Older Adults: The Role Of Growth Factors And Inflammatory Cytokines, Joshua A. Titus

Electronic Thesis and Dissertation Repository

The purpose of this thesis was to investigate the effects that exercise modalities have on neurotrophic and inflammatory blood markers and cognitive outcomes in older adults. A systematic review and meta-analysis were completed. The included studies illustrated that most of the literature evaluated the effect of aerobic exercise interventions on systemic concentrations of the blood marker brain-derived neurotrophic factor (BDNF). The review found that aerobic exercise increases BDNF and resistance training increases insulin-like growth factor 1 (IGF-1). Interventions with sex-specific cohorts presented advantages in males for blood marker and cognitive outcomes compared to females. One of three included interventions decreased …

Regional Lipid Expression Abnormalities Identified Using Maldi Ims Correspond To Mri-Defined White Matter Hyperintensities Within Post-Mortem Human Brain Tissue., William J. Pinsky

Electronic Thesis and Dissertation Repository

Periventricular white matter hyperintensities (pvWMHs) are a neurological feature detected with magnetic resonance imaging (MRI) and are clinically associated with an increased risk of stroke and dementia. pvWMHs are characterized by white matter lesions with myelin and axon rarefaction, and as such likely involve changes in lipid composition, however these alterations remain unknown. Lipids are critical in determining cell function and survival, although their detection within tissue, until recently has been challenging. Perturbations in lipid expression have previously been associated with neurological disorders. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is an emerging technique for untargeted, high-throughput investigation of …

The Functional And Structural Consequences Of Aberrant Microglial Activity In Major Depressive Disorder, Jasmine D. Cakmak

Electronic Thesis and Dissertation Repository

Major depressive disorder (MDD) is a highly debilitating neuropsychiatric illness which has been linked with increases in both peripheral and central inflammation, as well as with changes in connectivity. Although countless studies have investigated these two topics, the relationship between neuroinflammation and functional/structural connectivity has not been explored. Using [¹⁸F]FEPPA PET imaging, we measured translocator protein-related (TSPO) microglial activity in the subgenual anterior cingulate cortex (sgACC) and insula and confirmed significantly increased [¹⁸F]FEPPA uptake in depressed patients (N=12) compared to healthy controls (N=23). Using a seed-based ROI analysis of fMRI data, we found that patients show …

Examining The Role Of Chloride Homeostasis And Pge2 Signaling In The Neuroendocrine Stress Response To Inflammation, Samuel A. Mestern

Electronic Thesis and Dissertation Repository

The brain senses inflammatory signals and drives the release of glucocorticoids (GCs) — potent immunosuppressants — via the activation of the hypothalamic-pituitary-adrenal (HPA) axis. This inflammation-induced HPA axis activation is largely mediated by prostaglandin E2 (PGE2), acting on two subtypes of the PGE2 receptor, EP1 and EP3. Recently, our group revealed EP3 signaling mechanisms that excite HPA axis regulatory neurons. This thesis sought to tease out the remaining EP1 signaling mechanisms. Considering that the excitability of HPA axis regulatory neurons is constrained by GABA_A receptor-mediated synaptic inhibition that relies on low-level intracellular Cl^-. We hypothesized that PGE2-EP1 …

Investigating The Effects Of Maternal Immune Activation On Sensory Processing: Timing, Immune Mechanisms, And Gene-Environment Interactions, Faraj Haddad

Electronic Thesis and Dissertation Repository

Maternal infection during the first or second trimester of pregnancy poses a risk factor for the child to have neurodevelopmental disorders like autism spectrum disorder (ASD) and schizophrenia. Various clinical and preclinical studies have shown that the maternal immune response to infection, also known as maternal immune activation (MIA), can disrupt fetal brain development.

Over the past two decades, MIA has been studied in rodents using the Polyinosinic Polycytidylic acid (Poly I:C) rodent model. Poly I:C has a molecular pattern resembling viruses that can induce a robust immune response. Following exposure to Poly I:C MIA, rodent offspring exhibit many brain …

Investigation Of The Hsp90 Co-Chaperone, Sti1, In Cellular Resilience And Neurodegenerative Diseases, Rachel E. Lackie

Electronic Thesis and Dissertation Repository

In neurodegenerative diseases, certain proteins misfold and form toxic aggregates that cause brain matter atrophy, leading to decline in motor and/or cognitive functions. To maintain cellular proteostasis and survival, molecular chaperones regulate protein maturation and help to prevent aberrant protein aggregation. The molecular chaperone Hsp90 regulates hundreds of proteins and interestingly, several of those are misfolded in neurodegenerative diseases. Stress inducible-phosphoprotein-1 (STI1, STIP1), an Hsp90 co-chaperone, orchestrates client protein transfer between chaperones Hsp70 and Hsp90 through physical interactions with both chaperones. Notably, previous work in yeast, worms, and mouse neurons all showed that STI1 protects organisms against stressors and amyloid-like …

The Role Of Neuronal Nitric Oxide Synthase In Regulating Cerebellar Network Formation Across Murine Development, Vasiliki Tellios

Electronic Thesis and Dissertation Repository

The cerebellum is a region of the central nervous system widely known for its role in motor learning and coordination. In the past, mutant mice have been critical in discerning key pathways associated with cerebellar dysfunction and motor deficits. Although a variety of mouse models exist that model the symptoms and pathogenesis of cerebellar ataxia, some have yet to be characterized at the molecular level. Nitric oxide (NO), specifically derived from neuronal nitric oxide synthase (nNOS), is a well-established regulator of synaptic transmission in Purkinje neurons (PNs), governing fundamental processes such as motor learning and coordination. Previous morphological analyses showed …

Blocking Pirb Function Increases Dendritic Spine Density In The Prefrontal Cortex Of Adult Rats, Hannah J. Macneil

Electronic Thesis and Dissertation Repository

Schizophrenia is a psychotic disorder consisting of positive, negative, and cognitive symptoms. While patients currently have access to treatments for the positive and negative symptoms, no satisfactory treatment exists to alleviate the cognitive deficits, which cause severe impairments to the quality of life of patients and their families. Although the mechanisms underlying the cognitive deficits of schizophrenia are not clear, a decreased dendritic spine density on layer 3 pyramidal neurons in the dorsolateral prefrontal cortex has been strongly implicated. Generally, the adult brain is not permissive to the formation of new dendritic spines. Recently, an immune receptor called paired immunoglobulin-like …

Expression And Subcellular Localization Of Circrnas Dysregulated Als That Are Encoded In Cytoskeletal Protein Genes, Asieh Alikhah

Electronic Thesis and Dissertation Repository

Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disorder that causes the death of motor neurons. While alterations in the metabolism of RNA, including RNA-binding proteins have been linked to the pathogenesis of ALS, our understanding of the role of non-coding RNAs including circRNAs is less well developed. In this study, using a combination of fluorescence in situ hybridization (FISH) and immunofluorescence (IF) with markers of RNP granules, I investigated the effect of osmotic stress on the localization and expression of a selection of circRNAs whose expression is dysregulated in ALS. Alteration in the number of granules for …

Modulation Of Gabaa Receptor By Neurosteroids And Protein Kinases In Health And Disease, Jaymin Jeong

Electronic Thesis and Dissertation Repository

γ-aminobutyric acid type A receptors (GABA_A receptors) underlie the majority of inhibitory synaptic transmission in the brain. Modulation of GABAergic activity occurs in development and normal physiological functioning of the brain, and changes to GABAergic function has been implicated in numerous neurological disorders including epilepsy. Neurosteroids, metabolites of steroid hormones, and kinases are known to modulate GABA_A receptor mediated currents in health and disease. This thesis aims to investigate the effects of kinases and neurosteroids on modulating GABA_A receptor-mediated currents in cortical pyramidal cells and their effects on the piriform cortex (PCtx) circuit in naïve rats and …

Protein Misfolding Toxicity And Inclusion Formation In Cellular Models Of Neurodegeneration, Sonja E. Di Gregorio

Electronic Thesis and Dissertation Repository

Protein misfolding characterizes most neurodegenerative diseases. Protein misfolding is the conversion of specific proteins from their normal, often soluble, and native three-dimensional conformation into an aberrant, often insoluble, non-functional conformation. Protein inclusions and aggregates are among the major pathological hallmarks of protein misfolding associated with many neurodegenerative diseases. Yet, the role of aggregates and inclusions is not clearly defined and heavily debated. This study utilizes powerful genetic approaches in yeast and verification in mammalian neuronal cell lines to address the misfolding and toxicity of three proteins, the Rho Guanine Nucleotide Exchange Factor (RGNEF), Matrin3, which are involved in amyotrophic lateral …