Molecular and Cellular Neuroscience Commons^™

Jun Upregulation Drives Aberrant Transposable Element Mobilization, Associated Innate Immune Response, And Impaired Neurogenesis In Alzheimer’S Disease, Chiara Scopa, Samantha Barnada, Maria Cicardi, Mo Singer, Davide Trotti, Marco Trizzino

Farber Institute for Neuroscience Faculty Papers

Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer's disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death …

Telomerase Reverse Transcriptase Marks A Novel Population Of Adult Stem Cells In The Mouse Brain That Respond To Metabolic Interventions By Modulating Adult Brain Plasticity, Gabriel S. Jensen

Electronic Theses and Dissertations

Telomerase reverse transcriptase (TERT) is expressed by quiescent adult stem cells (qASC) in numerous adult murine and human tissues but has never been explored in the adult brain. Here, these data demonstrate that TERT+ cells in the adult mouse brain represent a novel population of multipotent qASCs. TERT+ cells were localized to numerous classical neuro/gliogenic niches including the ventricular-subventricular zone, hypothalamus and olfactory bulb, as well as newly discovered regions of adult tissue plasticity such as the meninges and choroid plexus. TERT+ cells expressed neural stem cell markers such as Nestin and Sox2, but not markers of activated stem/progenitor cells, …

Neural Stem Cells: Age-Dependent Outcomes During Viral Infections In The Central Nervous System, Manisha N. Chandwani

Electronic Theses and Dissertations

Viral infections in the central nervous system (CNS) are associated with neurodevelopmental and neurobehavioral deficits. The outcomes of viral infections can be driven by damage and death of neurons. Neural stem cells (NSCs) play key roles in neurodevelopment, repair, and physiological brain function. During a viral infection, NSC activity can disturbed by direct infection of NSCs by the virus or by anti-viral immune response. Here, we aimed to assess whether the anti-viral immune response can impact NSC activity during an immunocompetent response in the adult brain. We utilized a transgenic mouse model of Measles virus infection where only the CNS …

Translational Fidelity And Its Role In Neuronal Homeostasis, Markus Terrey

Electronic Theses and Dissertations

The process of translation, which refers to decoding genetic information from mRNA to protein, is vital for all cellular function. Translational fidelity starts at the level of aminoacylation of transfer RNAs (tRNA). This reaction is catalyzed by aminoacyl tRNA synthetases where each amino acid is transferred to its corresponding cognate tRNA. Because tRNAs harbor the anticodon sequence to decodes a particular mRNA codon, the specific aminoacylation of the tRNA with a cognate amino acid establishes the rules of decoding genetic code into proteins. Aminoacylated tRNAs are then delivered to ribosomes, where ribosomes in a highly organized manner need to accurately …

Effect Of Reduced Neurogenesis On Microglial Activation, Amelia Smith

Honors Scholars Collaborative Projects

The geriatric population of America has grown exponentially in the past century. Health degradations and expensive medical care are characteristic of this population with many of these costs due to age-related cognitive decline. It is essential to completely understand the mechanisms of normal and abnormal aging in the search for treatments for cognitive decline. A reduction of neurogenesis is a common factor in aging, but this reduction is even more drastic in individuals experiencing cognitive decline. It is unclear what effect reduced neurogenesis has on the extracellular environment, including glial cells. In particular, changes in microglial activation could be related …

Interhemispheric Communication And Lateralization In The Mouse Hippocampus, Jake Jordan

Dissertations, Theses, and Capstone Projects

The hippocampus is essential for memory and spatial navigation. Many theories have been proposed to explain how the hippocampus contributes to cognition; however, none has fully explained relevant neurophysiological and behavioral data. Hemispheric lateralization of hippocampal function has been reported in humans and in rodents, and lateralization of hippocampal neural circuitry has been reported in rodents. Most theories of hippocampal function fail to consider the hippocampus as a bilateral structure with hemispheric differences. Further, proposed theories of hippocampal lateralization have their own limitations in explaining empirical data concerning left/right function. Little is known about communication between the hippocampi across hemispheres. …

Investigating Neurogenesis As A Veritable Epigenetic Endophenotype For Alzheimer's Disease, Layne Wells

Scripps Senior Theses

Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by progressive amyloid plaque aggregation, neurofibrillary tangles, and cortical tissue death. As the prevalence of AD is projected to climb in coming years, there is a vested interest in identifying endophenotypes by which to improve diagnostics and direct clinical interventions. The risk for complex disorders, such as AD, is influenced by multiple genetic, environmental, and lifestyle factors. Significant strides have been made in identifying genetic variants linked to AD through the genome-wide association study (GWAS). It has been estimated in more recent years, however, that GWAS-identified variants account for limited …

The Role Of Endoplasmic Reticulum Stress In Ethanol-Induced Neurodegeneration, Yongchao Wang

Theses and Dissertations--Pharmacology and Nutritional Sciences

Heavy ethanol use causes neurodegeneration manifested by neuronal loss and dysfunction. It is becoming imperative to delineate the underlying mechanism to promote the treatment of ethanol-induced neurodegeneration. Endoplasmic reticulum (ER) stress is a hallmark and an underlying mechanism of many neurodegenerative diseases. This study aims to investigate the role of ER stress in ethanol-induced neurodegeneration. In experimental design, adult mice were exposed to binge ethanol drinking by daily gavage for 1, 5, or 10 days and the response of ER stress was examined. We found the induction of ER stress appeared at 5 days and remained at 10 days. Moreover, …

Investigating Autophagy Dysfunction Induced By A Parkinson's Disease-Causing Mutation In Vps35, Abir Ashfakur Rahman

Boise State University Theses and Dissertations

Parkinson’s Disease (PD) is an idiopathic disorder with no known cure. With number of cases steadily rising around the world, it is imperative to turn to the underlying cellular and molecular mechanisms of the disease manifestation and neurodegeneration to craft novel modes of therapy. VPS35 is one of the few genes that have identified and definitively linked to familial PD. The particular mutation that has been associated is known to cause dysfunction of a key cellular process known as autophagy. This process is primarily responsible for clearance of unwanted, damaged or misfolded proteins, among other things. Our study reveals an …

Tributyltin Inhibits Neural Induction Of Human Induced Pluripotent Stem Cells, Shigeru Yamada, Yusuke Kubo, Daiju Yamazaki, Yuko Sekino, Yoko Nomura, Sachiko Yoshida, Yusunari Kanda

Publications and Research

Tributyltin (TBT), one of the organotin compounds, is a well-known environmental pollutant. In our recent study, we reported that TBT induces mitochondrial dysfunction, in human-induced pluripotent stem cells (iPSCs) through the degradation of mitofusin1 (Mfn1), which is a mitochondrial fusion factor. However, the effect of TBT toxicity on the developmental process of iPSCs was not clear. The present study examined the effect of TBT on the differentiation of iPSCs into the ectodermal, mesodermal, and endodermal germ layers. We found that exposure to nanomolar concentration of TBT (50 nM) selectively inhibited the induction of iPSCs into the ectoderm, which is the …

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 …

An Analysis Of Neurogenesis In A Mouse Model Of Chemotherapy Related Cognitive Impairment, Maxwell A. Hennings

Electronic Theses and Dissertations

Cancer patients treated with adjuvant chemotherapy often experience cognitive decline following treatment. This phenomenon, often dubbed “chemo brain” or “chemo fog” is usually temporary, but for a subset of survivors, these cognitive impairments can be long-lasting (>10 years) and negatively affect patients’ quality of life, career performance, and social fulfillment. While it is unclear what neurobiological mechanisms underlie chemotherapy related cognitive impairment, the majority of the animal literature has focused on adult neurogenesis. One process important for neurogenesis is the proliferation of new neurons within the dentate gyrus of the hippocampus. It is evident that many chemotherapy agents can …

The Role Of Forebrain Cholinergic Signalling In Regulating Hippocampal Function And Neuropathology, Mohammed Al-Onaizi

Electronic Thesis and Dissertation Repository

Cholinergic dysfunction has been associated with cognitive abnormalities in a variety of neurodegenerative and neuropsychiatric disorders, including Alzheimer’s Disease (AD). Cumulative use of drugs with anticholinergic activity is associated with increased risk for dementia and AD. Also, cholinergic function has been implicated in predicting the development of key neuropathological hallmarks seen in AD. However, the relationship between cholinergic dysfunction and conservation of cognitive ability as well as neuronal cell maintenance is not fully understood. Here, we tested how information processing and distinct molecular mechanisms associated with AD are regulated by cholinergic tone in genetically-modified mice in which cholinergic transmission was …

Probing The Functional Relevance Of Reactive Hippocampal Neurogenesis In A Model Of An Alcohol Use Disorder, Chelsea Rhea Geil Nickell

Theses and Dissertations--Pharmacy

Alcoholism, or alcohol use disorders (AUDs), represent a major public health concern both locally and globally. Critically, excessive alcohol consumption results in neurodegeneration in brain regions such as the hippocampus which is known for its role in learning and memory. Recovery of hippocampal volume loss has been observed after prolonged abstinence, but the mechanisms underlying this process are not well understood. Adult neurogenesis is thought to contribute to this recovery since after alcohol exposure a reactive increase in adult neurogenesis is observed. This reactive neurogenesis (the process by which brain insult results in a compensatory increase in neurogenesis) may represent …

Exercise-Induced Adult Neruogenesis And The Seizure Threshold: The Role Of Cox-2, Gina Kim

Honors Capstone Projects - All

Neurogenesis, the generation of new neurons, is most prevalent when the brain is being formed during pre-natal development. However, this process continues in select areas in the brain during adult life as well. One such area in the brain is the dentate gyrus (DG) of the hippocampus, an area known to be associated with learning and memory. In this region, neurogenesis is believed to contribute to neuroplasticity as well as improving its functions in learning and memory. Interestingly, this synthesis of neurons is increased by physical activity—predominantly running—and by seizures originating in the limbic system. The increased excitatory neuronal activity …

Astroglial Boundary Formation And Epha4 Signaling In Neuroblast Migration, Nicholas B. Gallo

University Scholar Projects

Adult neurogenesis, the process of generating new neurons from neural precursors, is a highly complex process that is limited to two specific areas of the brain, the dentate gyrus of the hippocampus and the subventricular zone (SVZ). Despite continued research investigating neurogenesis in these two regions, we still lack a fundamental understanding of the molecular mechanisms of neural cell division, migration, differentiation, and integration in the postnatal brain. In particular, the rostral migratory stream (RMS), which is a cellular migratory route for newly generated neuronal precursors that travel from the SVZ to the olfactory bulb, will provide a useful model …

Astroglial Boundary Formation And Epha4 Signaling In Neuroblast Migration, Nicholas B. Gallo

Honors Scholar Theses

Adult neurogenesis, the process of generating new neurons from neural precursors, is a highly complex process that is limited to two specific areas of the brain, the dentate gyrus of the hippocampus and the subventricular zone (SVZ). Despite continued research investigating neurogenesis in these two regions, we still lack a fundamental understanding of the molecular mechanisms of neural cell division, migration, differentiation, and integration in the postnatal brain. In particular, the rostral migratory stream (RMS), which is a cellular migratory route for newly generated neuronal precursors that travel from the SVZ to the olfactory bulb, will provide a useful model …

Investigation Of Sox9 Ablation On Neural Stem Cell Behaviour After Spinal Cord Injury, Stephen Mcdonald

Electronic Thesis and Dissertation Repository

After spinal cord injury neural stem cells are activated to proliferate and differentiate primarily into astrocytes, but are unable to replace lost neurons or aid in neurological recovery. Recent research shows that the transcription factor Sox9 promotes gliogenesis while inhibiting neurogenesis, and that Sox9 ablation causes improved recovery after spinal cord injury. The purpose of this study was to determine how Sox9 ablation alters neural stem cell behaviour after spinal cord injury and whether it leads to neurological improvements. We used BrdU and YFP to label and track neural stem cells and a neural stem cell-specific Sox9 knockout mouse model …

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. …

Interspecies Comparison Of Αii-Spectrin Abundance Between Chinook Salmon And Steelhead, Brielle D. Kemis, Ann L. Miracle, Katie A. Wagner, Christa M. Woodley

STAR Program Research Presentations

Salmonids, such as Chinook salmon (Oncorhynchus tshawytscha) and steelhead (O. mykiss), are a staple economic, recreational, tribal, and environmental resource, yet many populations are unsustainable. This study was part of a broad scale effort to monitor the impact of downstream migration obstacles on juvenile salmonid health and survival, which is an essential step towards increasing Smolt-to-Adult Return ratios (SARs). The objective of this study was to determine if juvenile Chinook salmon and steelhead exhibit differing quantities of alphaII-Spectrin Breakdown Products (SBDPs) over two consecutive spring migration periods, indicative of neurogenesis rate and/or biological response to head …

Dopaminergic Innervation Of The Subventricular Zone In The Murine Brain, Linda Beth Drozdowicz

Honors Scholar Theses

The subventricular zone (SVZ) is one of two areas in the brain that, in a healthy mouse, continually generate neurons throughout adulthood. While it was previously thought that only the A9 neurons of the substantia nigra sent dopaminergic afferents to the SVZ, recent studies suggest that the A10 neurons of the ventral tegmental area may innervate this area. This project has aimed to discover which, if either, model is correct.

Examination of the Aphakia (AK) mouse was used to determine the role of distinct midbrain regions in SVZ regulation. Additionally, intraperitoneal injections of the chemical MPTP were used to deduce …