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- Title
- Protecting Synaptic Function From Acute Oxidative Stress: A Novel Role For Big K+ (BK) Channels And Resveratrol-Like Compounds.
- Creator
- Bollinger, Wesley L., Dawson-Scully, Ken, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
-
Oxidative stress causes neural damage and inhibits essential cellular processes, such as synaptic transmission. Despite this knowledge, currently available pharmaceutical agents cannot effectively protect neural cells from acute oxidative stress elicited by strokes, heart attacks, and traumatic brain injuries in a real life clinical setting. Our lab has developed an electrophysiology protocol to identify novel drugs that protect an essential cellular process (neurotransmission) from acute...
Show moreOxidative stress causes neural damage and inhibits essential cellular processes, such as synaptic transmission. Despite this knowledge, currently available pharmaceutical agents cannot effectively protect neural cells from acute oxidative stress elicited by strokes, heart attacks, and traumatic brain injuries in a real life clinical setting. Our lab has developed an electrophysiology protocol to identify novel drugs that protect an essential cellular process (neurotransmission) from acute oxidative stress-induced damage. Through this doctoral dissertation, we have identified three new drugs, including a Big K+ (BK) K+ channel blocker (iberiotoxin), resveratrol, and a custom made resveratrol-like compound (fly2) that protect synaptic function from oxidative stress-induced insults. Further developing these drugs as neuroprotective agents may prove transformative in protecting the human brain from acute oxidative stress elicited by strokes, heart attacks, and traumatic brain injuries. Inhibiting the protein kinase G (PKG) pathway protects neurotransmission from acute oxidative stress. This dissertation has expanded upon these findings by determining that the PKG pathway and BK K+ channels function through independent biochemical pathways to protect neurotransmission from acute oxidative stress. Taken together, this dissertation has identified two classes of compounds that protect neurotransmission from acute oxidative stress, including resveratrol-like compounds (resveratrol, fly2) and a BK K+ channel inhibitor (iberiotoxin). Further developing these drugs in clinical trials may finally lead to the development of an effective neuroprotective agent.
Show less - Date Issued
- 2018
- PURL
- http://purl.flvc.org/fau/fd/FA00013054
- Subject Headings
- Neural transmission., Oxidative stress., Large-Conductance Calcium-Activated Potassium Channels., Neuroprotective Agents.
- Format
- Document (PDF)
- Title
- Neuroprotection During Acute Oxidative Stress: Role of the PKG Pathway and Identification of Novel Neuromodulatory Agents Using Drosophila Melanogaster.
- Creator
- Caplan, Stacee Lee, Dawson-Scully, Ken, Milton, Sarah L., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
-
Oxidant stress and injury is inherent in many human diseases such as ischemic vascular and respiratory diseases, heart failure, myocardial infarction, stroke, perinatal and placental insufficiencies, diabetes, cancer, and numerous psychiatric and neurodegenerative disorders. Finding novel therapeutics to combat the deleterious effects of oxidative stress is critical to create better therapeutic strategies for many conditions that have few treatment options. This study used the anoxia-tolerant...
Show moreOxidant stress and injury is inherent in many human diseases such as ischemic vascular and respiratory diseases, heart failure, myocardial infarction, stroke, perinatal and placental insufficiencies, diabetes, cancer, and numerous psychiatric and neurodegenerative disorders. Finding novel therapeutics to combat the deleterious effects of oxidative stress is critical to create better therapeutic strategies for many conditions that have few treatment options. This study used the anoxia-tolerant fruit fly, Drosophila melanogaster, to investigate endogenous cellular protection mechanisms and potential interactions to determine their ability to regulate synaptic functional tolerance and cell survival during acute oxidative stress. The Drosophila larval neuromuscular junction (NMJ) was used to analyze synaptic transmission and specific motor axon contributions. Drosophila Schneider 2 (S2) cells were used to assess viability. Acute oxidative stress was induced using p harmacological paradigms that generate physiologically relevant oxidant species: mitochondrial superoxide production induced by sodium azide (NaN3) and hydroxyl radical formation via hydrogen peroxide (H2O2). A combination of genetic and pharmacological approaches were used to explore the hypothesis that endogenous protection mechanisms control cellular responses to stress by manipulating ion channel conductance and neurotransmission. Furthermore, this study analyzed a group of marine natural products, pseudopterosins, to identify compounds capable of modulating synaptic transmission during acute oxidative stress and potential novel neuromodulatory agents.
Show less - Date Issued
- 2015
- PURL
- http://purl.flvc.org/fau/fd/FA00004487, http://purl.flvc.org/fau/fd/FA00004487
- Subject Headings
- Drosophila melanogaster -- Life cycles, Oxidative stress -- Ecophysiology, Oxidative stress -- Prevention, Protein kinases, Proteins -- Chemical modification
- Format
- Document (PDF)
- Title
- Neuroprotection during acute hyperthermic stress: Role of the PKG pathway in neurons and glia in the protection of neural function in Drosophila melanogaster.
- Creator
- Krill, Jennifer L., Dawson-Scully, Ken, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
-
The human brain functions within a narrow range of temperatures and variations outside of this range incur cellular damage and death and, ultimately, death of the organism. Other organisms, like the poikilotherm Drosophila melanogaster, have adapted mechanisms to maintain brain function over wide ranges in temperature and, if exposed to high temperatures where brain function is no longer supported, these animals enter a protective coma to promote survival of the organism once the acute...
Show moreThe human brain functions within a narrow range of temperatures and variations outside of this range incur cellular damage and death and, ultimately, death of the organism. Other organisms, like the poikilotherm Drosophila melanogaster, have adapted mechanisms to maintain brain function over wide ranges in temperature and, if exposed to high temperatures where brain function is no longer supported, these animals enter a protective coma to promote survival of the organism once the acute temperature stress is alleviated. This research characterized the role of different neuronal cell types, including glia, in the protection of brain function during acute hyperthermia, specifically looking at two protective pathways: the heat shock protein (HSP) pathway and the cGMP-dependent protein kinase G (PKG) pathway. Whole animal behavioral assays were used in combination with tissue-specific genetic manipulation of protective pathways to determine the specific cell types sufficient to confer protection of neuronal function during acute hyperthermia. Using the neuromuscular junction (NMJ) preparation, calcium imaging techniques were combined with pharmacological and genetic manipulations to test the hypothesis that alterations in ion channel conductance via endogenous mechanisms regulating the cellular response to high temperature stress alter neuronal function. Expression of foraging RNAi to inhibit PKG expression in neurons or glia demonstrated protection of function during acute hyperthermia measured behaviorally through the extension of locomotor function. This extension of function with the tissue-specific inhibition of PKG was also confirmed at the cellular level using the genetically encoded calcium indicator (GECI), GCaMP3, to image calcium dynamics at the NMJ, where preparations expressing foraging RNAi could continue to elicit changes in calcium dynamics in response to stimulation. Over the course of this study, the mechanism underlying a novel glial calcium wave in the peripheral nervous system was characterized in order to elucidate glia’s role in the protection of neuronal function during acute hyperthermia.
Show less - Date Issued
- 2018
- PURL
- http://purl.flvc.org/fau/fd/FA00013026
- Subject Headings
- Cyclic GMP-Dependent Protein Kinases, Neuroprotection, Hyperthermia, Heat shock proteins, Drosophila melanogaster
- Format
- Document (PDF)
- Title
- NEUROPROTECTION AGAINST OXIDATIVE STRESS USING RESVERATROL-INSPIRED ANALOGS.
- Creator
- Simonson, Alec Jordan, Dawson-Scully, Ken, Florida Atlantic University, Department of Biological Sciences, Charles E. Schmidt College of Science
- Abstract/Description
-
Synaptic transmission is a mechanism that makes life possible for many organisms. Damaging this crucial process, such as with a buildup of Reactive Oxygen Species (ROS), is extremely detrimental for the entire organism. Previously, the Dawson-Scully lab has determined that exposure of the Drosophila melanogaster neuromuscular junction (NMJ) to ROS accumulation can result in synaptic failure at a faster rate than saline controls (Caplan et al., 2013). To combat such effects, novel three...
Show moreSynaptic transmission is a mechanism that makes life possible for many organisms. Damaging this crucial process, such as with a buildup of Reactive Oxygen Species (ROS), is extremely detrimental for the entire organism. Previously, the Dawson-Scully lab has determined that exposure of the Drosophila melanogaster neuromuscular junction (NMJ) to ROS accumulation can result in synaptic failure at a faster rate than saline controls (Caplan et al., 2013). To combat such effects, novel three-dimensional Resveramorph compounds were created to act as a neuroprotective agent against the harmful effects of acute oxidative stress (Bollinger et al., 2019; Sial et al., 2019). With the initial Resveramorph compounds demonstrating neuroprotective effects, additional analysis of other Resveramorph compounds were of interest to better understand their role in neuroprotection. Further testing of these compounds allows for the investigation of how chemical structure affects a compound’s neuroprotective activity.
Show less - Date Issued
- 2021
- PURL
- http://purl.flvc.org/fau/fd/FA00013687
- Subject Headings
- Resveratrol, Neuroprotective agents
- Format
- Document (PDF)
- Title
- HISTAMINERGIC AND NOCICEPTIVE GROOMING IN DROSOPHILA MELANOGASTER: AN ANALYSIS OF THE MOLECULAR MECHANISMS AND A BEHAVIORAL RESPONSE TO NOXIOUS CHEMICAL STIMULI.
- Creator
- John, Ciny, Dawson-Scully, Ken, Murphey, Rodney, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
-
Insect grooming has various functions, including defense against parasites and pathogens, cleaning of dust particles, and maintenance of sensory receptors. The hierarchy of grooming behavior suggests that cleaning one body part is more crucial than the other, the priority order more specifically being eyes, antennae, abdomen, then wings, followed by the thorax. Histamine is an extensively studied neurotransmitter found in the central nervous system of many animals. In Drosophila, histamine is...
Show moreInsect grooming has various functions, including defense against parasites and pathogens, cleaning of dust particles, and maintenance of sensory receptors. The hierarchy of grooming behavior suggests that cleaning one body part is more crucial than the other, the priority order more specifically being eyes, antennae, abdomen, then wings, followed by the thorax. Histamine is an extensively studied neurotransmitter found in the central nervous system of many animals. In Drosophila, histamine is found in both the peripheral and central nervous systems and is necessary for visual and mechanosensory behaviors. Histamine-gated chloride channel 1 (HisCl1) and Ora transientless (Ort) are two characterized histamine receptors, both of which are vital for visual signaling in the fly.
Show less - Date Issued
- 2019
- PURL
- http://purl.flvc.org/fau/fd/FA00013321
- Subject Headings
- Drosophila melanogaster, Grooming behavior in animals, Nociception, Histaminergic mechanisms
- Format
- Document (PDF)
- Title
- Functional Stress Resistance: The Role of Protein Kinase G in Modulating Neuronal Excitability in Caenorhabditis Elegans and Drosophila Melanogaster.
- Creator
- Kelly, Stephanie Suzanne, Dawson-Scully, Ken, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
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Diseases such as epilepsy, pain, and neurodegenerative disorders are associated with changes in neuronal dysfunction due to an imbalance of excitation and inhibition. This work details a novel electroconvulsive seizure assay for C. elegans using the well characterized cholinergic and GABAergic excitation and inhibition of the body wall muscles and the resulting locomotion patterns to better understand neuronal excitability. The time to recover normal locomotion from an electroconvulsive...
Show moreDiseases such as epilepsy, pain, and neurodegenerative disorders are associated with changes in neuronal dysfunction due to an imbalance of excitation and inhibition. This work details a novel electroconvulsive seizure assay for C. elegans using the well characterized cholinergic and GABAergic excitation and inhibition of the body wall muscles and the resulting locomotion patterns to better understand neuronal excitability. The time to recover normal locomotion from an electroconvulsive seizure could be modulated by increasing and decreasing inhibition. GABAergic deficits and a chemical proconvulsant resulted in an increased recovery time while anti-epileptic drugs decreased seizure duration. Successful modulation of excitation and inhibition in the new assay led to the investigation of a cGMP-dependent protein kinase (PKG) which modulates potassium (K+) channels, affecting neuronal excitability, and determined that increasing PKG activity decreases the time to recovery from an electroconvulsive seizure. The new assay was used as a forward genetic screening tool using C. elegans and several potential genes that affect seizure susceptibility were found to take longer to recover from a seizure. A naturally occurring polymorphism for PKG in D. melanogaster confirmed that both genetic and pharmacological manipulation of PKG influences seizure duration. PKG has been implicated in stress tolerance, which can be affected by changes in neuronal excitability associated with aging, so stress tolerance and locomotor behavior in senescent flies was investigated. For the first time, PKG has been implicated in aging phenotypes with high levels of PKG resulting in reduced locomotion and lifespan in senescent flies. The results suggest a potential new role for PKG in seizure susceptibility and aging.
Show less - Date Issued
- 2019
- PURL
- http://purl.flvc.org/fau/fd/FA00013225
- Subject Headings
- Caenorhabditis elegans, Drosophila melanogaster, Cyclic GMP-Dependent Protein Kinases, Seizures
- Format
- Document (PDF)
- Title
- Characterizing electroconvulsive seizure recovery time in the invertebrate model systems Caenorhabditis elegans and Drosophila melanogaster.
- Creator
- Risley, Monica G., Dawson-Scully, Ken, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
-
Seizures are a symptom of epilepsy, characterized by spontaneous firing due to an imbalance of excitatory and inhibitory features. While mammalian seizure models receive the most attention, the simplicity and tractability of invertebrate model systems, specifically C. elegans and D. melanogaster, have many advantages in understanding the molecular and cellular mechanisms of seizure behavior. This research explores C. elegans and D. melanogaster as electroconvulsive seizure models to...
Show moreSeizures are a symptom of epilepsy, characterized by spontaneous firing due to an imbalance of excitatory and inhibitory features. While mammalian seizure models receive the most attention, the simplicity and tractability of invertebrate model systems, specifically C. elegans and D. melanogaster, have many advantages in understanding the molecular and cellular mechanisms of seizure behavior. This research explores C. elegans and D. melanogaster as electroconvulsive seizure models to investigate methods to both modulate and better understand seizure susceptibility. A common underlying feature of seizures in mammals, worms, and flies involves regulating excitation and inhibition. The C. elegans locomotor circuit is regulated via well characterized GABAergic and cholingeric motoneurons that innervate two rows of dorsal and ventral body wall muscles. In this research, we developed an electroconvulsive seizure assay which utilizes the locomotor circuit as a behavioral read out of neuronal function. When inhibition is decreased in the circuit, for example by decreasing GABAergic input, we find a general increase in the time to recovery from a seizure. After establishing the contribution of excitation and inhibition to seizure recovery, we explored a ubiquitin ligase, associated with comorbidity of an X-linked Intellectual Disorder and epilepsy in humans, and established that the worm homolog, eel-1, contributes to seizure susceptibility similarly to the human gene. Next, we investigated a cGMP-dependent protein kinase (PKG) that functions in the nervous system of both worms and flies and determined that increasing PKG activity, decreases the time to recovery from an electroconvulsive seizure. These experiments suggest a potential novel role for a major protein, PKG, in seizure susceptibility and that the C. elegans and D. melanogaster electroconvulsive seizure assays can be used to investigate possible genes involved in seizure susceptibility and future therapeutic to treat epilepsy.
Show less - Date Issued
- 2018
- PURL
- http://purl.flvc.org/fau/fd/FA00005954
- Subject Headings
- Seizures, Epilepsy, Drosophila melanogaster, Caenorhabditis elegans
- Format
- Document (PDF)
- Title
- CHARACTERIZATION OF PROCONVULSANT MECHANISMS ON GABAERGIC NEUROTRANSMISSION IN CAENORHABDITIS ELEGANS.
- Creator
- Suthakaran, Nirthieca, Dawson-Scully, Ken, Florida Atlantic University, Department of Biological Sciences, Charles E. Schmidt College of Science
- Abstract/Description
-
Epilepsy is a prevalent brain disorder that affects more than 1 in 26 people in the United States. The recurring increased neuronal excitability during seizures results in sleep disturbances and muscle convulsions that reduce the quality of life and increase the healthcare costs for these patients. An epilepsy diagnosis is made when patients have had two or more seizures. There are many types of seizures and an individual can have more than one type. Seizures are classified into two groups, 1...
Show moreEpilepsy is a prevalent brain disorder that affects more than 1 in 26 people in the United States. The recurring increased neuronal excitability during seizures results in sleep disturbances and muscle convulsions that reduce the quality of life and increase the healthcare costs for these patients. An epilepsy diagnosis is made when patients have had two or more seizures. There are many types of seizures and an individual can have more than one type. Seizures are classified into two groups, 1) generalized seizures that affect both sides of the brain and 2) focal seizures that are located in just one area of the brain. The causes of epilepsy vary by the age of the person, some with no clear cause may have a genetic form of epilepsy. Due to the various causes and types of seizures, many treatments including invasive surgeries and antiepileptic drugs (AEDs) do not work for all epileptic/seizure patients and are merely used to ease symptoms. The physiological complexity of the disorder and limited knowledge on its specific molecular mechanisms may contribute to the lack of effective treatment. In recent years, there has been an estimated average cost in billions of dollars to bring new medicine to the market; due to the lack of novel antiseizure targets and mechanism-based therapies on seizure phenotypes. In response to this, we utilized the electroconvulsive seizure behavioral assay to characterize one generalized seizure phenotype, tonic-clonic/grand mal seizures.
Show less - Date Issued
- 2023
- PURL
- http://purl.flvc.org/fau/fd/FA00014198
- Subject Headings
- Epilepsy, Epilepsy--physiopathology, Seizures, Caenorhabditis elegans
- Format
- Document (PDF)
- Title
- Characterization of Group B Sox genes in the development of Drosophila nervous system.
- Creator
- Singh, Shweta, Dawson-Scully, Ken, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
-
Sox proteins all contain a single ~70 amino acid High Mobility Group (HMG) DNA-binding domain with strong homology to that of Sry, the mammalian testisdetermining factor. In Drosophila melanogaster, there are four closely related members of the B group, Dichaete (D), Sox Neuro (Sox N), Sox 21a, and Sox 21b that each exhibit ~90% sequence identity within the HMG domain.The previous study has shown that Dichaete plays a major role in embryonic nervous system development and is expressed in...
Show moreSox proteins all contain a single ~70 amino acid High Mobility Group (HMG) DNA-binding domain with strong homology to that of Sry, the mammalian testisdetermining factor. In Drosophila melanogaster, there are four closely related members of the B group, Dichaete (D), Sox Neuro (Sox N), Sox 21a, and Sox 21b that each exhibit ~90% sequence identity within the HMG domain.The previous study has shown that Dichaete plays a major role in embryonic nervous system development and is expressed in several clusters of neurons in the brain, including intermingled olfactory LNs and central-complex neurons strongly expressed in local interneuron of the olfactory system. However, little is known about the possible expression and functions of the related group B Sox genes in the larval and adult brain. In particular, it is unclear if Sox N may function along with Dichaete in controlling the development or physiology of the adult olfactory system. Our data suggests Sox N potential role in the elaboration of the olfactory circuit formation.
Show less - Date Issued
- 2017
- PURL
- http://purl.flvc.org/fau/fd/FA00004907, http://purl.flvc.org/fau/fd/FA00004907
- Subject Headings
- Drosophila melanogaster--Physiology., Transcription factors., Gene expression., Genetic transcription., Cell cycle., Neural stem cells.
- Format
- Document (PDF)
- Title
- cGMP/PKG-regulated mechanisms of protection from low oxygen and oxidative stress.
- Creator
- Mahneva, Olena, Milton, Sarah L., Dawson-Scully, Ken, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
-
Stroke is one of the leading causes of human death in the United States. The debilitating effects of an ischemic stroke are due to the fact that mammalian neurons are highly susceptible to hypoxia and subsequent oxygen reperfusion. From studies in Drosophila melanogaster, cGMP-dependent Protein Kinase (PKG) enzyme is thought to affect anoxia tolerance by modifying the electrical current through potassium ion channels. In this research, two animal models were employed: Drosophila melanogaster...
Show moreStroke is one of the leading causes of human death in the United States. The debilitating effects of an ischemic stroke are due to the fact that mammalian neurons are highly susceptible to hypoxia and subsequent oxygen reperfusion. From studies in Drosophila melanogaster, cGMP-dependent Protein Kinase (PKG) enzyme is thought to affect anoxia tolerance by modifying the electrical current through potassium ion channels. In this research, two animal models were employed: Drosophila melanogaster and mammalian neurons exposed to stroke-like conditions. First, in vivo studies using Drosophila were performed to further our knowledge about the differences between the naturally occurring variants of the Drosophila foraging gene, which shows different protein levels of PKG. Mitochondrial density and metabolic activity between two fly genotypes exposed to anoxia and reoxygenation were compared. It was found that flies with less enzyme potentially showed mitochondrial biogenesis and higher metabolic rates upon reoxygenation. Next, in vivo studies where PKG enzyme was activated pharmacologically were performed; it was found that the activation of the cGMP/PKG pathway led to neuroprotection upon anoxia and reoxygenation. Furthermore, this model was translated into the in vitro model using Drosophila cells. Instead of anoxia and reoxygenation, hypoxia mimetics and hydrogen peroxide were used to induce cellular injury. After showing the cGMP/PKG pathway activation-induced cell protection, the potential downstream targets of the molecular signaling as well as underlying biochemical changes were assessed. It was found that mitochondrial potassium ion channels were involved in the protective signaling and the signaling modulated metabolic function. Furthermore, it was found that acidosis protected Drosophila cells from cell death, metabolic disruption, and oxidative stress. Finally, this research was translated to a mammalian in vitro model of neuronal damage upon stroke-like conditions; there, it was demonstrated that the cGMP/PKG pathway activation in rat primary cortical neurons and human cortical neurons was protective from low oxygen and acute oxidative stress. The results of this study lead to a better understanding of molecular mechanisms taking place during low oxygen and oxidative stresses. Consequently, this knowledge may be used to identify potential therapeutic targets and treatments that may prevent detrimental neurological effects of an ischemic stroke in humans.
Show less - Date Issued
- 2018
- PURL
- http://purl.flvc.org/fau/fd/FA00013013
- Subject Headings
- Stroke, Cyclic GMP-Dependent Protein Kinases, Oxidative Stress
- Format
- Document (PDF)
- Title
- CAENORHABDITIS ELEGANS MMP STRAINS AND THEIR POTENTIAL DRIVING FORCE IN ANTIEPILEPTIC DRUG RESEARCH.
- Creator
- Sanchez, Christina Laura, Dawson-Scully, Ken, Florida Atlantic University, Department of Biological Sciences, Charles E. Schmidt College of Science
- Abstract/Description
-
Over 70 million people worldwide suffer from epilepsy, with 90% of those cases taking place in developing countries (Singh & Trevick, 2016). Epilepsy can be defined as at least two unprovoked seizures occurring more than 24 hours apart, one unprovoked seizure with at least 60% chance of another seizure occurring within the next 10 years, or a diagnosis of epilepsy syndrome (Fisher et al., 2005). Varying physiological, molecular, genetic, and environmental factors can contribute to epileptic...
Show moreOver 70 million people worldwide suffer from epilepsy, with 90% of those cases taking place in developing countries (Singh & Trevick, 2016). Epilepsy can be defined as at least two unprovoked seizures occurring more than 24 hours apart, one unprovoked seizure with at least 60% chance of another seizure occurring within the next 10 years, or a diagnosis of epilepsy syndrome (Fisher et al., 2005). Varying physiological, molecular, genetic, and environmental factors can contribute to epileptic episodes. Although antiepileptic drugs (AEDs) exist, the complexity and lack of understanding behind the molecular mechanisms of the syndrome leaves the few drugs available to be insufficient for many patients (Rho & White, 2018). Therefore, the discovery of genetic pathways involved in epilepsy is imperative for the innovation of antiepileptic drugs. This thesis explores a novel method to add to mutant C.elegans libraries and improve antiepileptic drug discovery in a cost-effective and efficient manner by uncovering candidate molecular pathways through the candidate genes involved with antiepileptic strains.
Show less - Date Issued
- 2022
- PURL
- http://purl.flvc.org/fau/fd/FA00014049
- Subject Headings
- Caenorhabditis elegans, Epilepsy, Drug development
- Format
- Document (PDF)
- Title
- A DISINHIBITORY MICROCIRCUIT FOR GATED CEREBELLAR LEARNING.
- Creator
- Zhang, Ke, Christie, Jason, Dawson-Scully, Ken, Florida Atlantic University, Department of Biological Sciences, Charles E. Schmidt College of Science
- Abstract/Description
-
Performance motor errors trigger animals’ adaptive learning behaviors to improve the accuracy and efficiency of the movement. The cerebellum is one of the key brain centers for encoding motor performance and motor learning. Climbing fibers relay information related to motor errors to the cerebellar cortex, evoking elevation of intracellular Ca2+ signals at Purkinje cell dendrites and inducing plasticity at coactive parallel fiber synapses, ultimately recalibrating sensorimotor associations to...
Show morePerformance motor errors trigger animals’ adaptive learning behaviors to improve the accuracy and efficiency of the movement. The cerebellum is one of the key brain centers for encoding motor performance and motor learning. Climbing fibers relay information related to motor errors to the cerebellar cortex, evoking elevation of intracellular Ca2+ signals at Purkinje cell dendrites and inducing plasticity at coactive parallel fiber synapses, ultimately recalibrating sensorimotor associations to alter behavior. Molecular layer interneurons (MLIs) inhibit Purkinje cells to modulate dendritic excitability and action potential output. How MLIs contribute to the regulation and encoding of climbing fiber-evoked adaptive movements remains poorly understood. In this dissertation, I used genetic tools to manipulate the activity of MLIs while monitoring Purkinje cell dendritic activity during a cerebellum-dependent motor learning task with different contexts to evaluate how MLIs are involved in this process. The results show that by suppressing dendritic Ca2+ signals in Purkinje cells, MLI activity coincident with climbing fiber-mediated excitation prevents the occurrence of learning when adaptation is not necessary. On the other hand, with error signals present, disinhibition onto Purkinje cells, mediated by MLI-MLI microcircuit, unlocked the ability of climbing fibers to induce plasticity and motor learning.
Show less - Date Issued
- 2020
- PURL
- http://purl.flvc.org/fau/fd/FA00013526
- Subject Headings
- Cerebellum, Interneurons, Purkinje cells, Dendrites, Sensorimotor integration, Neuroplasticity
- Format
- Document (PDF)