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Undergraduate Research Opportunities Program

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Now showing 1 - 10 of 304

Production of ryanodine receptor calcium release channel ATP-binding site mutants

(Georgia Institute of Technology, 2023-01-18) Cutter, Catarina Santos

Ryanodine receptors (RyRs) are a class of mammalian ion channels which are the primary efflux pathways for the release of Ca2+ from the sarcoplasmic reticulum. They play a critical role in muscle excitation-contraction coupling (ECC). Because it is the largest known ion channel, the mechanisms for its activation are not fully understood. ATP is a well characterized channel activator. However, its mechanism of activation has not been determined and the importance of ATP regulation of RyRs in vivo is not clear. In 2016, des George, et al. published a structure of RyR1 with ATP bound. The adenosine group of ATP is contained within a hydrophobic cleft while the triphosphate tail is extended and interacts with positively charged residues. The goal of this study was to identify residues important for ATP binding to the channel. Site-directed mutagenesis of the receptor was used to substitute specific residues in order to change their size and or charge. After transfection with recombinant DNA, HEK293 cells were harvested for isolation of microsomal membranes. Two of the largest hydrophobic residues of the cleft were replaced with alanine with the goal of drastically reducing or abolishing ATP binding to RyR1. The selected mutations F4960A and L4985A were expected to impair channel activation by both ATP and adenosine. After initial verification of wild type channel expression in HEK293 cells, later transfections with wild type and mutant RyR1 DNA failed to produce detectable amounts of protein. Low DNA transfection efficiency combined with the low yield of microsomal membrane likely contributed to the inability to detect channels in these preparations. Optimizing DNA transfections and scaling up the cell culture may increase the likelihood of successful protein production.
Identifying the potential effect of zolmitriptan on the 1b pathway of Golgi tendon organs in regulating intermuscular inhibition in the extremities to find a link in the mechanism of spasticity

(Georgia Institute of Technology, 2023-01-18) Davis, Adam Eugene

The deep dorsal horn (DDH) of the spinal cord is a major integration center for receiving a variety of neural projections from the brainstem as well as a variety of afferent inputs from muscle spindles and Golgi tendon organs (GTOs) in the muscles. Following spinal cord injury (SCI) to the DDH, an overall loss of serotonergic input from the brainstem is observed, for which there is evidence to suggest that this may play a role in inhibiting the activity of bursting interneurons in the DDH, possibly leading to uncontrolled motoneuron activity, hyperreflexia. GTOs primarily supply the force feedback network (FBB), which also receives supraspinal input through the DDH, likely also affected by its loss in SCI. The purpose of this current study is to investigate if FBB function changes, with or without SCI, after the administration of a specific serotonin reuptake inhibitor (SSRI), zolmitriptan, which inhibits the activity of the bursting interneurons. FBB function was determined primarily as inhibitory signals from the flexor hallucis longus (FHL) onto the gastrocnemius (GAS), the muscle tensions compared after being stretched individually and pairwise, with some data from rectus femoris (RF) onto GAS. The autogenic stretch reflex was analyzed only in GAS. Animals with an intact spinal cord (n=1) and with a lateral hemisection (n=2) were used to compare the changes in reflexes following zolmitriptan administration. Data was variable across the subjects with no clear effect on the autogenic stretch reflex in GAS. The more stable lateral hemisection subject revealed that zolmitriptan largely and consistently increased inhibition from FHL onto GAS from a miniscule baseline, suggesting connectivity between the GTO circuit and the bursting interneurons of the DDH. Notably in the intact spinal cord animal, there was an immediate and complete correction of oscillations in the baseline tension of all muscles after drug administration, treating a symptom of hyperreflexia. These results suggest a connection between the two systems or a more significant role of this particular serotonin receptor on GTO circuit and the DDH. More studies may provide a deeper understanding of this network and these findings.
Emotional wellbeing in those with chronic illness due to a genetic mutation in valosin-containing protein

(Georgia Institute of Technology, 2023-01-18) Jones, Mallory

Valosin-containing protein (VCP) is a ubiquitous protein and a member of the ATPases Associated with a variety of cellular Activities (AAA proteins) superfamily. VCP has many functions in the cell including protein quality control, membrane fusion, and maintenance of the cell cycle and apoptosis. Mutations of the gene encoding VCP lead to a rare but devastating disorder with several pathologies including inclusion body myopathy, Paget’s disease of bone, ALS, and frontotemporal dementia. People who develop VCP Disease often feel disenfranchised with their diagnosis, being unable to access appropriate treatments or support systems. Another complication of its rare nature is that this disease is frequently misdiagnosed, due in large part to lack of awareness. Advocacy programs like Cure VCP Disease, Inc. seek to educate caregivers, patients, and medical professionals about the disease and advocate for increased research and resources devoted to its cure. These groups are an integral facet of the rare disease community, and it is imperative that the scientific community bolster and encourage the work of these groups. This review will examine existing literature concerning VCP Disease and will present what is currently known of this multisystem proteinopathy through the lens of patient advocacy. Unpublished and deidentified testimonials of several patients and caregivers will be presented to emphasize the importance of patient advocacy work. Additionally, grip strength data obtained using a dynamometer is analyzed in an effort to identify factors for prediction of symptom progression.
Using Infrared Technology to Examine Arousal in Brown Tufted Capuchin Monkeys (Sapajus [Cebus] apella)

(Georgia Institute of Technology, 2023-01-18) Andrews, Charles James

From a well-being standpoint, having a reliable measure of emotion is important for species in captivity for the purpose of determining animal welfare. This holds especially true as habitat destruction is increasing, and there are more animals being held in captivity as a result. From a research standpoint, having a reliable measure of arousal can be particularly useful when performing certain experiments that require subjective experiences and quantifiable behaviors. Infrared Thermography (IRT) is a technology that could possibly aid scientists interested in studying emotions and arousal in animals mainly due to its advantage of non-invasiveness, and there is a growing amount of evidence supporting its validity. Although multiple monkey taxa have been studied using IRT technology, there has been little to no research on brown tufted capuchins, Sapajus [Cebus] apella, thus far. Examining capuchin monkeys with IRT could help to further demonstrate the technology’s validity among all non-human primate (NHP) species. For Sapajus [Cebus] apella research specifically, having a reliable means of quantifying emotional states non-invasively could be valuable for future studies. Many experiments performed in this field currently depend on subjective behavioral cues to measure emotion and well-being. Having a valid and possibly automated tool like IRT to measure emotion could eliminate these potential errors and biases. In addition, IRT may be a useful tool when examining Sapajus [Cebus] apella welfare in captivity, and demonstrating this technology’s validity would allow for an improved measure of well-being for this species. In this study, a procedure was created and performed in order to investigate the relationship between arousal and nasal temperature in capuchin monkeys.
Can Equating Perception Also Equate Working Memory Performance in Young Adults? A Stage Report for an Attempt to Resolve Individual Differences in Working Memory

(Georgia Institute of Technology, 2023-01-18) Wang, Minzhi

Working memory performances are not the same among different individuals, here we examined the role initial perceptual processing plays in working memory functioning. We sought to examine whether equating subjects on the initial perceptual processing could also equate their working memory performances. We did this by using a standard 2-back test using slanted bars as stimuli. Perception was equated by obtaining subjects’ 79% threshold for discrimination of two slanted bars with different orientation using a 3-down-1-up staircase. At this stage, we found some evidence that subjects equated on perception performance performed similarly in working memory tasks. A large scale experiment is needed to generalize the findings.
The effects of 40 Hz gamma flicker stimulation on spatial memory, perceptual discrimination, and recall

(Georgia Institute of Technology, 2022-08) Salen, Ashley

The rising prevalence of Alzheimer's Disease (AD), which leads to progressively deteriorating memory and thinking skills is alarming. A preliminary data analysis was performed to predict potential behavioral changes that may occur in cognitively healthy older adults between conditions as a result of using the flicker for 8 weeks. Although the preliminary data analysis has not yet yielded any statistically significant effects induced by the 40 Hz gamma flicker on the memory of the flicker group compared to the control group, it may provide insight into what the results could look like further down the line. Based on graph analysis, it could be predicted that the flicker group may have fewer spatial memory deficits.
Cyclic mechanical stretch upregulates Akt, MAPK, and NF-kappaB signaling pathways in BV2 microglia

(Georgia Institute of Technology, 2022-05-24) Udeshi, Kareena Jaydeep

Mild traumatic brain injury (mTBI) is prevalent in contact sports. Post injury, microglia in the central nervous system are known to produce an inflammatory response. Moreover, with repeated injuries, chronic inflammation may be sustained, which is detrimental to the host. This study focuses on the signaling pathways that are activated with brain injury-induced injury. We hypothesize that mechanical stretch activates inflammatory signaling pathways in microglia. This experiment utilized impulse, cyclic, and sham-stretch conditions in the presence or absence of the mechanosensitive channel inhibitor GSMTx4. Afterwards, the cell lysate was collected, and the samples were analyzed by a Luminex multiplexed ELISA to determine if there was a change in protein phosphorylation across 27 phosphoproteins in three main signaling pathways: Akt, MAPK, and NFkB. My data showed that GSMTx4 had little impact on phosphorylation, but it did increase the expression of the Akt pathway proteins. Nonetheless, the minimal role GSMTx4 played in the measured phospho-protein signaling pathways at acute timepoints could imply that Piezo1 does not play a direct role in acute pathway activation. Of note, however, a control 20% cyclic stretch resulted in an upregulation in phosphorylation in all signaling pathways. As such, future studies will include GSMTx4-treated BV2 microglia that undergo cyclic stretch at varying degrees. Clinically, this data is useful in understanding how sustained injury can force the progression of neurodegenerative diseases.
Measuring Cerebral Blood Flow in a Mouse Model of Alzheimer's Disease

(Georgia Institute of Technology, 2022-05) Daniel, Christy

Mild traumatic brain injuries (mTBIs), which are defined by an absence of overt structural damage in the brain have been associated with an increased risk of Alzheimer's Disease when sustained multiple times over an interval. Within mTBI, indirect evidence suggests that persistent post-concussive symptoms may be linked to reduced cerebral blood flow (CBF), of which deficits have been observed in cases of Alzheimer's Disease. Diffuse correlation spectroscopy (DCS) is a non-invasive optical method that uses near-infrared light to measure fluctuations in intensity that are caused by moving red blood cells that can be used to measure cerebral blood flow (CBF) in C57bl/6 mice. This dissertation will adapt this novel protocol to a mouse model of Alzheimer’s Disease (3xTg). This strain will be utilized due to its accelerated AD pathology and the presence of literature that have observed impairments in CVR, CBF, among other biomarkers of Alzheimer’s Disease and traumatic brain injury. Given the smaller size of the 3xTg mice compared to C57bl/6, the DCS optical sensor must be modified. Herein, the design of a smaller sensor is detailed, along with a series of validation tests, which include measurements on a liquid phantom with known flow properties and on a pilot cohort of four 6–7-month-old 3xTg mice (2 males, 2 females). This data provides the foundational work to characterize the feasibility of DCS as a technique to monitor CBF and CVR in 3xTg mice for future experiments.
The Effects of Nerve Injury and Synaptic Preservation on Motoneuron Activity

(Georgia Institute of Technology, 2022-05) Garcia, Violet

Peripheral nerve injury currently has a poor prognosis that often results in motor deficits such as discoordination and co-contraction of muscle antagonists (Brushart, 2011; Horstman et al., 2019). Because of this, studying the effects of peripheral nerve injury on the morphology and functional connectivity of the central nervous system (CNS) is of utmost importance. Our study centers around the anatomical changes that occur after peripheral nerve injury in the rat spinal cord, namely the degradation of Ia input defined by the expression of the vesicular glutamate transporter 1 (VGLUT1). This study is based on the proposed microglia-dependent mechanism of permanent synaptic loss from the Rotterman et al. (2019) paper. We ask if 1) we can suppress microglia accumulation with minocycline, a tetracycline antibiotic, and 2) if using minocycline can help preserve the Ia sensory afferent synapses after nerve injury. We first retrogradely labeled the medial gastrocnemius motor pool in 15 adult Wistar rats. One week later, we transected the medial gastrocnemius nerve in the left hindlimb. Rats were either treated with vehicle or minocycline for 14 days following injury. Control animals were also produced. At 14 days post injury, animals were perfused, spinal cords were collected and subsequently sectioned. Using immunohistochemistry (IHC), we labeled VGLUT1 synapses on these injured motor neurons and imaged them with confocal microscopy for subsequent reconstruction and analysis. We found four main results: 1) treatment with minocycline for 14 days after nerve injury does not seem to prevent microglia proliferation, 2) the chromalytic reaction (somatic expansion) that commonly occurs after axotomy did not seem to occur in the minocycline- treated animals, 3) there was partial preservation of somatic VGLUT1 synapses in the minocycline-treatment animals, and 4) there was complete dendritic VGLUT1 synapse preservation in the minocycline-treated animals. Although there were limitations to the study with regards to the methods of counting microglia, the study produced robust conclusions that will aid in the development of further research. Future studies should be conducted on the efficacy of minocycline preserving the synapses, the molecular mechanisms underlying minocycline’s effects, and the potential recovery of nerve function.
Improving Online Instructional Design using Memory, Attention, and Engagement

(Georgia Institute of Technology, 2022-05) Chanda, Ritika

Neuroscience research supports a relationship between the psychological constructions of attention and engagement. The level of selective attention and engagement present during the learning process correlates with increased memory and recall. With the recent rise in online learning, new questions regarding the improvement of educational design, teaching techniques, and learning have created a new avenue of investigation within the field of Neuroeducation. The objective of this study is to identify whether attentional brain networks related to Gagné’s Nine Events of Instruction and engagement can predict learning in an online setting by using fMRI and behavioral techniques. Overall, we found fMRI evidence of engagement, verified engagement’s role in memory and retrieval, and identified three Gagné events (Events 5, 6 and 7) that increase learning among students. This investigation allows for further advancements in online educational design as it will provide instructors with guidance on how to properly build their curriculum and modify the content structure of online classes to highlight techniques that promote successful learning.