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- All Subjects: Genetics
- All Subjects: Neuroscience
- Creators: School of Life Sciences
Description
The mammalian target of rapamycin (mTOR) is integral in regulating cell growth as it maintains a homeostatic balance of proteins by modulating their synthesis and degradation. In the brain, mTOR regulates protein-driven neuroplastic changes that modulate learning and memory. Nevertheless, upregulation of mTOR can cause detrimental effect in spatial memory and synaptic plasticity. The proline-rich Akt-substrate 40 kDa (PRAS40) is a key negative regulator of mTOR, as it binds mTOR and directly reduces its activity. To investigate the role of PRAS40 on learning and memory, we generated a transgenic mouse model in which we used the tetracycline-off system to regulate the expression of PRAS40 specifically in neurons of the hippocampus. After induction, we found that mice overexpressing PRAS40 performed better than control mice in the Morris Water Maze behavioral test. We further show that the improvement in memory was associated with a decrease in mTOR signaling, an increase in dendritic spines in hippocampal pyramidal neurons, and an increase in the levels of brain-derived neurotrophic factor (BDNF), a neurotrophin necessary for learning and memory. This is the first evidence that shows that increasing PRAS40 in the mouse brain enhances learning and memory deficits.
ContributorsSarette, Patrick William (Author) / Oddo, Salvatore (Thesis director) / Caccamo, Antonella (Committee member) / Kelleher, Raymond (Committee member) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Lactase persistence is the ability of adults to digest lactose in milk (Segurel & Bon, 2017). Mammals are generally distinguished by their mammary glands which gives females the ability to produce milk and feed their newborn children. The new born therefore requires the ability to breakdown the lactose in the milk to ensure its proper digestion (Segurel & Bon, 2017). Generally, humans lose the expression of lactase after weaning, which prevents them being able to breakdown lactose from dairy (Flatz, 1987).
My research is focused on the people of Turkana, a human pastoral population inhabiting Northwest Kenya. The people of Turkana are Nilotic people that are native to the Turkana district. There are currently no conclusive studies done on evidence for genetic lactase persistence in Turkana. Therefore, my research will be on the evolution of lactase persistence in the people of Turkana. The goal of this project is to investigate the evolutionary history of two genes with known involvement in lactase persistence, LCT and MCM6, in the Turkana. Variants in these genes have previously been identified to result in the ability to digest lactose post-weaning age. Furthermore, an additional study found that a closely related population to the Turkana, the Massai, showed stronger signals of recent selection for lactase persistence than Europeans in these genes. My goal is to characterize known variants associated with lactase persistence by calculating their allele frequencies in the Turkana and conduct selection scans to determine if LCT/MCM6 show signatures of positive selection. In doing this, we conducted a pilot study consisting of 10 female Turkana individuals and 10 females from four different populations from the 1000 genomes project namely: the Yoruba in Ibadan, Nigeria (YRI); Luhya in Webuye, Kenya; Utah Residents with Northern and Western European Ancestry (CEU); and the Southern Han Chinese. The allele frequency calculation suggested that the CEU (Utah Residents with Northern and Western European Ancestry) population had a higher lactase persistence associated allele frequency than all the other populations analyzed here, including the Turkana population. Our Tajima’s D calculations and analysis suggested that both the Turkana population and the four haplotype map populations shows signatures of positive selection in the same region. The iHS selection scans we conducted to detect signatures of positive selection on all five populations showed that the Southern Han Chinese (CHS), the LWK (Luhya in Webuye, Kenya) and the YRI (Yoruba in Ibadan, Nigeria) populations had stronger signatures of positive selection than the Turkana population. The LWK (Luhya in Webuye, Kenya) and the YRI (Yoruba in Ibadan, Nigeria) populations showed the strongest signatures of positive selection in this region. This project serves as a first step in the investigation of lactase persistence in the Turkana population and its evolution over time.
My research is focused on the people of Turkana, a human pastoral population inhabiting Northwest Kenya. The people of Turkana are Nilotic people that are native to the Turkana district. There are currently no conclusive studies done on evidence for genetic lactase persistence in Turkana. Therefore, my research will be on the evolution of lactase persistence in the people of Turkana. The goal of this project is to investigate the evolutionary history of two genes with known involvement in lactase persistence, LCT and MCM6, in the Turkana. Variants in these genes have previously been identified to result in the ability to digest lactose post-weaning age. Furthermore, an additional study found that a closely related population to the Turkana, the Massai, showed stronger signals of recent selection for lactase persistence than Europeans in these genes. My goal is to characterize known variants associated with lactase persistence by calculating their allele frequencies in the Turkana and conduct selection scans to determine if LCT/MCM6 show signatures of positive selection. In doing this, we conducted a pilot study consisting of 10 female Turkana individuals and 10 females from four different populations from the 1000 genomes project namely: the Yoruba in Ibadan, Nigeria (YRI); Luhya in Webuye, Kenya; Utah Residents with Northern and Western European Ancestry (CEU); and the Southern Han Chinese. The allele frequency calculation suggested that the CEU (Utah Residents with Northern and Western European Ancestry) population had a higher lactase persistence associated allele frequency than all the other populations analyzed here, including the Turkana population. Our Tajima’s D calculations and analysis suggested that both the Turkana population and the four haplotype map populations shows signatures of positive selection in the same region. The iHS selection scans we conducted to detect signatures of positive selection on all five populations showed that the Southern Han Chinese (CHS), the LWK (Luhya in Webuye, Kenya) and the YRI (Yoruba in Ibadan, Nigeria) populations had stronger signatures of positive selection than the Turkana population. The LWK (Luhya in Webuye, Kenya) and the YRI (Yoruba in Ibadan, Nigeria) populations showed the strongest signatures of positive selection in this region. This project serves as a first step in the investigation of lactase persistence in the Turkana population and its evolution over time.
ContributorsJobe, Ndey Bassin (Author) / Wilson Sayres, Melissa (Thesis director) / Paaijmans, Krijn (Committee member) / Taravella, Angela (Committee member) / School of Earth and Space Exploration (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Chronic restraint stress leads to apical dendritic retraction in CA3 pyramidal neurons and often no quantifiable changes in CA1 dendritic complexity. When chronic stress ends, a post-stress recovery period results in an enhancement in CA3 dendritic complexity. We investigated the relationship between CA3 and CA1 pyramidal neurons to determine whether dendritic restructuring in CA3 neurons leads to region-specific changes in the dendritic complexity of CA1 neurons. Adult male Sprague-Dawley rats were restrained (wire mesh, 6h/d/21d) and brains were removed soon after restraint ended (Str-Imm) or after a 21d post-stress recovery period (Str-Rec). In addition, BDNF downregulation targeting the CA3 region prevents enhancement in dendritic complexity following recovery in chronically stressed rats, providing robust conditions to investigate the CA3-CA1 relationship. Consequently, rats were infused into the CA3 area with either an AAV vector with a coding sequence against BDNF (shRNA) or a sequence with no known mRNA complements (Scr). Apical and basal dendritic complexity of CA3 and CA1 was quantified by counting total dendritic bifurcations and dendritic intersections using the Sholl analysis (20 µm distances from soma). Please note that the quantification of the CA3 dendritic arbors was not part of this thesis project. The outcome of that investigation revealed that apical CA3 dendritic retraction was found in Str-Imm-Scr and Str-Rec-shRNA. For the CA1 apical area, gross dendritic bifurcation differences were not detected, but the Sholl quantification revealed regionally-enhanced dendritic complexity that varied by distance from the soma at the distal apical dendrites (Str-Imm-Scr) and proximal basal dendrites (Str-Rec-shRNA). For the latter, significant increases in basal branch points were detected with total branch point quantification method. Moreover, a correlation using all groups revealed a significant inverse relationship between CA3 apical dendritic complexity and CA1 basal dendritic complexity. The results demonstrate that chronic stress-induced CA3 apical dendritic retraction may relate to region-specific changes in CA1 dendritic complexity. The inability of past studies to detect changes in CA1 dendritic complexity may be due to the shortcoming of gross dendritic arbor measures in accounting for subtle region-specific alterations. To address this, the current study included a cohort with BDNF downregulated in the CA3 region. Overall, this suggests that decreased levels of BDNF in the hippocampus provide robust conditions in which changes to CA1 dendritic complexity can be detected.
ContributorsDaas, Eshaan Jatin (Author) / Conrad, Cheryl (Thesis director) / Orchinik, Miles (Committee member) / Ortiz, J. Bryce (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Previous research has shown that a loud acoustic stimulus can trigger an individual's prepared movement plan. This movement response is referred to as a startle-evoked movement (SEM). SEM has been observed in the stroke survivor population where results have shown that SEM enhances single joint movements that are usually performed with difficulty. While the presence of SEM in the stroke survivor population advances scientific understanding of movement capabilities following a stroke, published studies using the SEM phenomenon only examined one joint. The ability of SEM to generate multi-jointed movements is understudied and consequently limits SEM as a potential therapy tool. In order to apply SEM as a therapy tool however, the biomechanics of the arm in multi-jointed movement planning and execution must be better understood. Thus, the objective of our study was to evaluate if SEM could elicit multi-joint reaching movements that were accurate in an unrestrained, two-dimensional workspace. Data was collected from ten subjects with no previous neck, arm, or brain injury. Each subject performed a reaching task to five Targets that were equally spaced in a semi-circle to create a two-dimensional workspace. The subject reached to each Target following a sequence of two non-startling acoustic stimuli cues: "Get Ready" and "Go". A loud acoustic stimuli was randomly substituted for the "Go" cue. We hypothesized that SEM is accessible and accurate for unrestricted multi-jointed reaching tasks in a functional workspace and is therefore independent of movement direction. Our results found that SEM is possible in all five Target directions. The probability of evoking SEM and the movement kinematics (i.e. total movement time, linear deviation, average velocity) to each Target are not statistically different. Thus, we conclude that SEM is possible in a functional workspace and is not dependent on where arm stability is maximized. Moreover, coordinated preparation and storage of a multi-jointed movement is indeed possible.
ContributorsOssanna, Meilin Ryan (Author) / Honeycutt, Claire (Thesis director) / Schaefer, Sydney (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Genetic engineering has become an increasingly prevalent topic in the media today. It has raised bioethical concerns nationwide as philosophers and scientists alike realize the challenges behind where to draw the line in certain modifications. As an introduction to the topic, this paper discusses the history behind eugenics and its importance in modern society. There is a discussion on what gene alterations are and the many processes of its scientific background. This is followed by how certain procedures and the ethical issues they raise are not cut and dry. The basis of the arguments in this paper focus on two ethical approaches: Kantian and Utilitarian. These approaches exemplify the difficulty on the decision making process behind what sort of therapeutic or enhancement therapies should be legalized or denied. These approaches can be applied to the two types of gene alterations: somatic cell therapy and germline therapy. The concluding decisions made in regards to what should or should not be accepted could have an effect on future generations, altering our species subsequently, and leading to an advancement in medicine and science.
ContributorsZangana, Shadan (Author) / McGregor, Joan (Thesis director) / Woien, Sandra (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
ContributorsSavarese, Erica (Author) / Robert, Jason (Thesis director) / Hurlbut, Ben (Committee member) / Verrelli, Brian (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2013-05
Description
Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disease characterized by progressive muscle loss and weakness. This disease arises from a mutation that occurs on a gene that encodes for dystrophin, which results in observable muscle death and inflammation; however, the genetic changes that result from dystrophin's dysfunctionality remain unknown. Current DMD research uses mdx mice as a model, and while very useful, does not allow the study of cell-autonomous transcriptome changes during the progression of DMD due to the strong inflammatory response, perhaps hiding important therapeutic targets. C. elegans, which has a very weak inflammatory response compared to mdx mice and humans, has been used in the past to study DMD with some success. The worm ortholog of the dystrophin gene has been identified as dys-1 since its mutation phenocopies the progression of the disease and a portion of the human dystrophin gene alleviates symptoms. Importantly, the extracted RNA transcriptome from dys-1 worms showed significant change in gene expression, which needs to be further investigated with the development of a more robust model. Our lab previously published a method to isolate high-quality muscle-specific RNA from worms, which could be used to study such changes at higher resolution. We crossed the dys-1 worms with our muscle-specific strain and demonstrated that the chimeric strain exhibits similar behavioral symptoms as DMD patients as characterized by a shortened lifespan, difficulty in movement, and a decrease in speed. The presence of dys-1 and other members of the dystrophin complex in the body muscle were supported by the development of a resulting phenotype due to RNAi knockdown of each component in the body muscle; however, further experimentation is needed to reinforce this conclusion. Thus, the constructed chimeric C. elegans strain possesses unique characteristics that will allow the study of genetic changes, such as transcriptome rearrangements and dysregulation of miRNA, and how they affect the progression of DMD.
ContributorsNguyen, Thuy-Duyen Cao (Author) / Mangone, Marco (Thesis director) / Newbern, Jason (Committee member) / Duchaine, Thomas (Committee member) / School of Social Transformation (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
As the incidence of dementia continues to rise, the need for an effective and non-invasive method of intervention has become increasingly imperative. Music therapy has exhibited these qualities in addition to relatively low implementation costs, therefore establishing itself as a promising means of therapeutic intervention. In this review, current research was investigated in order to determine its effectiveness and uncover the neurochemical mechanisms that lead to positive manifestations such as improved memory recall, increased social affiliation, increased motivation, and decreased anxiety. Music therapy has been found to improve several aspects of memory recall. One proposed mechanism involves temporal entrainment, during which the melodic structures present in music provide a framework for chunking information. Although entrainment's role in the treatment of motor defects has been thoroughly studied, its role in treating cognitive disorders is still relatively new. Musicians have also been shown to demonstrate extensive plastic changes; therefore, it is hypothesized that non-musicians may also glean some benefits from engaging in music. Social affiliation has been found to increase due to increases in endogenous oxytocin. Oxytocin has also been shown to strengthen hippocampal spike transmission, a promising outcome for Alzheimer's patients. An increase in motivation has also been found to occur due to music's ability to tap into the reward center of the brain. Dopaminergic transmission between the VTA, NAc and higher functioning regions such as the OFC and hypothalamus has been revealed. Additionally, relaxing music decreases stress levels and modifies associated autonomic processes, i.e. heart rate, blood pressure, and respiratory rate. On the contrary, stimulating music has been found to initiate sympathetic nervous system activity. This is thought to occur by either a reflexive brainstem response or stimulus interpretation by the amygdala.
ContributorsFlores, Catalina Nicole (Author) / Redding, Kevin (Thesis director) / Hoffer, Julie (Committee member) / Neisewander, Janet (Committee member) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and has been shown to have genetic factors that contribute to cancer susceptibility. These genetic factors can be studied using Genome-Wide association studies (GWAS), which allow for the assessment of associations between specific biologic markers. Through GWAS, associations can be analyzed to identify genetic components that contribute to the onset of HCC. This study uses an extended version of Pathways of Distinction analysis (PoDA) to identify the subset of SNPs within the Antigen Presentation and Processing Pathway that distinguish cases from controls. Further analysis was performed to explore SNP-SNP association differences between HCC cases and controls using R-squared values and p-values. Three SNPs show significant inter-SNP associations in both HCC cases and controls. Additionally, 4 SNPs showed significant SNP-SNP associations exclusively in the control data set, possibly suggesting that control pathways have a greater degree of genetic regulation and robustness that is lost in carcinogenesis. This result suggests that these SNP associations may contribute to HCC susceptibility.
ContributorsAghili, Ardesher Joshua (Author) / Buetow, Kenneth (Thesis director) / Wilson Sayres, Melissa (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Neurological manifestations may be more prominent and have a larger role in ankylosing spondylitis than previously thought. Ankylosing Spondylitis is a rheumatic disease primarily identified by its autoinflammatory characteristics and is highly associated with the HLA-B27 gene. While it’s cause is not yet fully understood and it’s symptoms widely vary, neurological impairment is not uncommon. The neurological manifestations of Ankylosing Spondylitis include but are not limited to pain sensitization, altered brain phenotype, and disrupted cardiac conduction. Central and peripheral nervous system involvement may be more significant than previously thought and have the potential to cause demyelinating diseases, spinal cord, and nerve root injuries. Altered connectivity throughout various regions within the brain further exemplify the need for a better understanding of the disease and better treatment development. Higher instances of depression and dementia were also reported and coincide with not only a less active lifestyle, but altered brain activity. Studies on cardiac conduction and arrhythmias in AS patients revealed parasympathetic and sympathetic nervous system dysregulation. These studies have explored the possibility of new targets for treatment involving cardiac mechanisms. Treatments for diseases of a similar suspected pathology, new prospective targets for therapy, and a more thorough understanding of current treatments for the disease may be the key in providing more substantial relief. By further investigation in the role of the nervous system in Ankylosing Spondylitis, the disease may become more manageable for patients and greatly increase quality of life in the future.
ContributorsHill, Jordan (Author) / Newbern, Jason (Thesis director) / Anderson, Karen (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05