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1
Nguyentat, Michael. "Neural Responses to Vibration during Wobble Board Balancing." Scholarship @ Claremont, 2011. http://scholarship.claremont.edu/cmc_theses/196.
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Falling, an epidemic most prevalently seen in the elderly population, accounts for the majority of injury-related cases seen by emergency departments across the United States. Unfortunately, with no large-scale institutionalization of a solution, the problem is only expected to exacerbate as our planet’s population approaches the 7 billion mark. In the wake of the recent surge of falls among the elderly, Japan has implemented a program to include unicycling in the physical education curriculum for elementary schools across the country. The goal for this program is to encourage children to establish strong fundamental balancing skills, which could potentially alleviate the pain—physical, emotional, and financial—incurred from falls in the elderly. This senior thesis study builds off Japan’s unicycling program by investigating ways to improve wobble board balancing, a more practical alternative to unicycling. In previous research, the skill of stick balancing, a motor task that has been shown to behave with the same power laws as wobble board balancing, has been improved with the use of vibrations. Here, we show that learning to wobble board balance is not expedited and wobble board balancing skill is not improved with the employment of vibrations, unlike stick balancing. Nonetheless, those who learned to wobble board balance with background vibrations went on to later outperform those who learned to wobble board balance without vibrations. These results suggest that vibrations (50 Hz, 0.18 mm amplitude) have a beneficial effect on the development of skill for wobble board balancing that is not related to the direct physical effects of the vibration. The observations also suggest that in the presence of vibrations, the nervous system develops more robust strategies for controlling balance.
2
Yin, Terry. "Neuroprotective strategies for traumatic brain injury." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1811.
Full textAbstract:
Traumatic brain injury (TBI) causes life-debilitating conditions. While patient survival after a TBI has improved, the outlook for quality of life after TBI currently remains poor. In order to address this problem, there is a significant unmet need for new therapeutic options to prevent progression of deficits associated with TBI. To this end, we investigated two strategies to combat the deleterious affect of TBI. First, we targeted cerebral acidosis associated with TBI by testing whether disruption of acid sensing ion channel 1a (ASIC1a) in CNS, or buffering acidosis with sodium bicarbonate, could prevent neurological deficits after TBI. We next tested whether treatment with the neovel class of aminopropyl carbozoles, known as the P7C3 series, could also prevent TBI-associated neurological decline.
Using the mouse fluid percussion injury model of TBI, we observed post-injury acidosis in the cortex, consistent with what has been shown in humans following brain injury. Administering HCO3- after fluid percussion injury prevented acidosis and reduced neurodegeneration. Because acidosis activates acid sensing ion channels (ASICs), we also studied AIC1a-/- mice and found reduced neurodegeneration after injury. Both HCO3-3 administration and loss of ASIC1a reduced functional deficits caused by fluid percussion injury. These results suggest that fluid percussion injury induces cerebral acidosis, which activates ASIC channels in the brain and contributes to neurodegeneration. Blocking ASIC1aactivity may thus offer a new therapeutic strategy to attenuate the adverse consequences of TBI.
We next applied the blast injury model of TBI to test whether the P7C3 class of neuroprotective aminopropyl carbazoles would be of therapeutic benefit. In addition to preventing neuronal cell death, P7C3 molecules also preserved axonal integrity before neuronal cell loss in this model. The mechanism of P7C3 neuroprotection may be linked to its ability to activate the enzyme, nicotinamide phosphoribosyltransferase, which catalyzed the rate limiting step of nicotinamide adenine dinucleotide salvage pathway. Administration of the lead compound in the series, P7C3-S243, 1 day after blast-mediated TBI blocked axonal degeneration and preserved normal synaptic activity. P7C3-S243 administration also reduced neuronal functional deficits, including impaired learning, memory, and motor coordination in mice. We additionally reported persistent neurologic deficits and acquisition of anxiety-like phenotype in untreated animals 8-months after blast-mediated TBI. Optimized variants of P7C3 thus offer hope for identifying neuroprotective agents for conditions involving axonal damage, neuronal cell death, or both. Together, the results of this body of work identify novel therapeutic interventions that may attenuate deficits associated with TBI, and thus improve the quality of life in people after TBI.
3
Hall, Alexis, Hannah Oakes, and Brooks B. Pond. "The Long Term Effects of Methylphenidate on the Brain." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/asrf/2018/schedule/119.
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Attention Deficit Hyperactivity Disorder, a disorder marked by a pattern of inattention and hyperactivity, is commonly treated with the drug methylphenidate (MPH), which inhibits reuptake of the neurotransmitters norepinephrine and dopamine, thereby increasing the levels of these catecholamines in the synaptic cleft. In addition, MPH is abused by students studying for exams to increase focus and wakefulness. Despite the extensive use of MPH, little is known its long-term effects on the brain. In this study, we examined the impact of 4 weeks of MPH treatment on neurogenesis or the “birth” of new brain cells in the hippocampus of male adolescent mice. Neurogenesis was measured using 5’-ethinyldeoxyuridine (EdU), a thymidine analog that gets incorporated into DNA before cell division, and total neuron numbers were estimated using the neuronal marker, NeuN. Interestingly, low (1 mg/kg) and high (10 mg/kg) doses of MPH delivered twice daily, increased the rate of neurogenesis after 4 weeks. We also examined the survival of the new cells 4 weeks after EdU injection, both with and without continued MPH treatment. Cell counts were performed, and ratios of EdU+/NeuN+ cells were compared. Although both 1 mg/kg and 10 mg/kg MPH increased the ratio of EdU+/NeuN+ cells, the EdU+/NeuN+ ratios were no different from control if MPH was not continued. If low dose of MPH was continued for an extra 4 weeks, survival of newly generated cells was enhanced; this was not the case for the high dose of MPH. To investigate the mechanism for MPH-induced changes in hippocampal neurogenesis, we examined the levels of proteins linked to cell growth and survival in the hippocampus, including brain derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), tropomyosin receptor kinase B (TrkB, the receptor for BDNF) and beta-catenin. Levels of BDNF or GDNF were examined using
enzyme-linked immunosorbent assays (ELISAs), and VEGF, TrkB, and beta-catenin expression was investigated using simple western. Interestingly, 1 mg/kg MPH appears to increase VEGF, TrkB, and beta catenin after 4 weeks. In animals treated with 10 mg/kg MPH, despite the increases in neurogenesis after 4 weeks of treatment, beta catenin levels decreased compared to control at 4 weeks, and VEGF, TrkB and beta catenin levels were decreased at 8 weeks. Thus, long-term exposure to MPH increases neurogenesis rate in the hippocampus, and the effect of low doses of MPH may be related to the increased expression of VEGF, TrkB and beta catenin.
4
Mattinson, Catherine Elizabeth. "DYNAMIC L-GLUTAMATE SIGNALING IN THE PREFRONTAL CORTEX AND THE EFFECTS OF METHYLPHENIDATE TREATMENT." UKnowledge, 2012. http://uknowledge.uky.edu/neurobio_etds/4.
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The prefrontal cortex (PFC) is an area of the brain that is critically important for learning, memory, organization, and integration, and PFC dysfunction has been associated with pathologies including Alzheimer’s disease, schizophrenia, and drug addiction. However, there exists a paucity of information regarding neurochemical signaling in the distinct sub-regions of the PFC, particularly the medial prefrontal cortex (mPFC). The mPFC receives glutamatergic input from a number of brain areas, and functional glutamate signaling is essential for normal cognitive processes. To further understand glutamate neurotransmission, in vivo measurements of glutamate were performed in the cingulate cortex, prelimbic cortex, and infralimbic cortex of anesthetized rats using enzyme-based microelectrode array technology. Measurements of acetylcholine were also performed to examine the relationship between glutamate and other neurotransmitters in the mPFC. The described studies revealed a homogeneity of glutamate and acetylcholine signaling in the mPFC sub-regions, indicating somewhat uniform tonic and phasic levels of these two transmitters. In the infralimbic mPFC of awake freely-moving rats, rapid, phasic glutamate signaling events, termed “transients” were observed and in vivo glutamate signaling was successfully monitored over 24 hour time periods.
The effects of methylphenidate (MPH), a stimulant medication with abuse potential that is used in the treatment of attention-deficit hyperactivity disorder, were measured in mPFC sub-regions of anesthetized rats. Data revealed similar tonic and phasic glutamate levels between chronic MPH-treated rats and controls in all sub-regions. Locomotor data from the chronic treatment period supported the behavioral sensitization effects of multiple MPH treatments. Significant effects were observed in locomotor activity, resting levels of glutamate, and glutamate uptake rates in the infralimbic mPFC of awake, freely-moving animals that received chronic MPH treatment.
Taken together, this body of work characterizes glutamate signaling in the rat mPFC to a degree never before reported, and serves to report for the first time the effects of MPH on glutamate signaling in the mPFC.
5
Bales, Thomas B. "PROLIFERATION, MIGRATION, AND SURVIVAL OF CELLS IN THE TELENCEPHALON OF THE BALL PYTHON, PYTHON REGIUS." DigitalCommons@CalPoly, 2014. https://digitalcommons.calpoly.edu/theses/1271.
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Reptiles exhibit neurogenesis throughout the brain during adulthood. However, very few studies have quantified telencephalon-wide neurogenesis in adulthood, and no studies have performed these investigations in snakes. Quantifying neurogenesis in the adult snake is essential to understanding class-wide adult neurogenesis and providing insight into the evolution of this trait. The thymidine analog 5-bromo-2’-deoxyuridine (BrdU) was used to quantify cell proliferation, migration, and survival in the ball python (Python regius). First, to determine the proper dose of BrdU for injection we subcutaneously injected 50mg/kg, 100mg/kg, and 250mg/kg into 15 adult male P. regius. We found the 250mg/kg dose marked significantly more cells than the 50mg/kg dose, but not the 100mg/kg dose. Then we subcutaneously injected 100mg/kg BrdU into 15 juvenile male P. regius at 3 different time points (2 days, 2 weeks, 2 months) prior to sacrifice to quantify proliferation, migration, and survival of cells in several telencephalic subregions. After sectioning and immunohistochemical staining, we found proliferation to be highest in the accessory olfactory bulb (AoB), retrobulbar regions (AD, AV), dorsal ventricular ridge (DVR), and dorsolateral amygdala/lateral amygdala (DLA/LA). Of the proliferating cells, the proportions of cells that migrated after 2 weeks were highest in the ventral lateral region (VL), anterior medial and lateral cortices (aMC, aLC), and anterior NS (aNS). After 2 months, the highest proportional survival was in the AoB, aLC, aMC, aNS, DVR, and ventral medial regions (VM). Regions involved in long-term functions like spatial memory may require less proliferation and longer survival, while regions involved in short-term functions undergo more proliferation with higher relative attrition.
6
Mondo, Erica. "Investigating Microglia-Vascular Interactions in the Developing and Adult Central Nervous System." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1105.
Full textAbstract:
Microglia, the resident macrophages of the central nervous system (CNS), are dynamic cells, constantly extending and retracting their processes as they contact and functionally regulate neurons and other glial cells. There is far less known about how microglia interact with the CNS vasculature, particularly under healthy steady-state conditions. Here, I provide the first extensive characterization of juxtavascular microglia in the healthy, postnatal brain and identify a molecular mechanism regulating the timing of these interactions during development. Using the mouse cerebral cortex, I show that microglia are intimately associated with the vasculature in the CNS, directly contacting the basal lamina in vascular sites that are devoid of astrocyte endfeet. I demonstrate a high percentage of microglia are associated with the vasculature during the first week of postnatal development, which is concomitant with a peak in microglial colonization of the cortex and recruitment to synapses. I find that as microglia colonize the cortex, juxtavascular microglia are highly motile along vessels and become largely stationary as the brain matures. 2-photon live imaging in adult mice reveals that these vascular-associated microglia in the mature brain are stable and stationary for several weeks. Further, a decrease in microglia motility along the vasculature is tightly correlated with the expansion of astrocyte endfeet along the vasculature. Finally, I provide evidence that the timing of these microglia-vascular interactions during development is regulated by the microglial fractalkine receptor (CX3CR1). Together, these data support a model by which microglia use the vasculature as a scaffold to migrate and colonize the developing brain and the timing of these associations is modulated by CX3CR1. This migration along the vasculature becomes restricted as astrocyte vascular endfoot territory expands and, upon maturation, vascular-associated microglia become largely stationary.
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Younkin, Jason W. "Allosteric Effects of G-Protein Coupled Receptor Heteromerization: Relevance to Psychosis." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4457.
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G-protein coupled receptors (GPCRs) implicated in disease are the predominant pharmaceutical targets. Growing evidence suggests that GPCRs form homo- and heteromeric complexes, resulting in allosteric functional changes. Ligands targeting one receptor can alter the function of the other receptor or receptors. Knowledge of these functional changes will provide unique opportunities to treat diseases. We examined two GPCR heteromers implicated in psychosis: mGlu2R-5HT2AR and D2R-5HT2AR. Using whole-cell patch clamp, we studied HEK-293 cells stably transfected with mGlu2R and 5HT2AR. Maximal heteromer formation allows inverse agonists to increase the G-protein activity of the opposite receptor, while sub-maximal heteromer formation does not. However, similar results are obtained in sub-maximal heteromer cells by applying a combination of a mGlu2R synthetic agonist with a 5HT2AR anti-psychotic drug. These results confirm our oocyte results, now in a mammalian cell line. Using two-electrode voltage clamp, we also investigated the allosteric changes upon heteromerization of D2R-5HT2AR in oocytes injected with appropriate cRNAs. Heteromer formation in the presence of dopamine or serotonin results in an increase in G-protein activity of each receptor while the simultaneous presence of both neurotransmitters further increases the G-protein activity. The addition of synthetic agonists or anti-psychotics decreases the G-protein activity of the opposite receptor while agonizing or antagonizing its target receptor, respectively. Maximal allosteric effects upon D2R-5HT2AR formation only occur at a specific cRNA injection ratio, but partial effects exist at other ratios. Our data suggest that allosteric functional changes upon heteromerization are physiologically relevant and are mostly different when comparing mGlu2R-5HT2AR to D2R-5HT2AR.
8
Lai, Daniel. "Quantifying Pathophysiology in Visual Snow: A Comparison of the N170 and P300 Components." Scholarship @ Claremont, 2018. http://scholarship.claremont.edu/cmc_theses/1741.
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Visual snow syndrome is a persistent visual disturbance characterized by rapid flickering dots in the entire visual field. Hypothesized to arise from reduced inhibition of sensory cortex, visual snow has recently been linked to potentiation (enhancement) of the P100, an event-related potential (ERP) component associated with early visual processing. Here, we investigate whether this potentiation in visual snow is specific to visual responses, by comparing ERPs linked to early, bottom-up perceptual versus late, top-down cognitive processes. Specifically, we examined two components, the N170 and P300, associated respectively with rapid face categorization and attentional orienting towards targets. We predicted that if visual snow predominantly reflects diminished inhibition of perceptual areas, there should be stronger potentiation for the earlier perceptual N170 component. ERPs associated with the N170 (Face > House) and P300 (Target > Nontarget) were recorded in a 22 year-old male with a 2-year history of visual snow symptoms and a set of age- and gender-matched controls. Although N170 and P300 responses in all participants showed appropriate face- and target-selectivity, respectively, the visual snow patient demonstrated consistent potentiation relative to controls, particularly for the early N170 response. Bootstrapped estimates of mean amplitude computed within participants similarly revealed larger and more variable ERP amplitudes in the visual snow patient, especially for the N170 component. These results support an early perceptual locus of ERP potentiation in visual snow, further supporting the idea that this condition arises from diminished inhibition of sensory cortices.
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Keeney, Jeriel T. "DOXORUBICIN-INDUCED, TNF-α-MEDIATED BRAIN OXIDATIVE STRESS, NEUROCHEMICAL ALTERATIONS, AND COGNITIVE DECLINE: INSIGHTS INTO MECHANISMS OF CHEMOTHERAPY INDUCED COGNITIVE IMPAIRMENT AND ITS PREVENTION". UKnowledge, 2013. http://uknowledge.uky.edu/chemistry_etds/27.
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The works presented in this dissertation provide insights into the mechanisms of chemotherapy-induced cognitive impairment (CICI or “ChemoBrain”) and take steps toward outlining a preventive strategy. CICI is now widely recognized as a complication of cancer chemotherapy experienced by a large percentage of cancer survivors. Approximately fifty percent of existing FDA-approved anti-cancer drugs generate reactive oxygen species (ROS). Doxorubicin (Dox), a prototypical ROS-generating chemotherapeutic agent, produces the reactive superoxide radical anion (O2-•) in vivo. Dox treatment results in oxidation of plasma proteins, including ApoA-I, leading to TNF-α-mediated oxidative stress in plasma and brain. TNF-α elevation in brain leads to further central nervous system toxicity including mitochondrial dysfunction, neuronal death, and cognitive impairment. Co-administration of the antioxidant drug, 2-mercaptoethane sulfonate sodium (MESNA), prevents Dox-induced protein oxidation and subsequent TNF-α elevation in plasma without interfering with the cancer-killing ability of Dox.
In studies presented in this dissertation, we measured oxidative stress in both brain and plasma of Dox-treated mice both with and without MESNA. MESNA ameliorated Dox-induced oxidative protein damage in plasma, confirming our prior studies, and in a new finding led to decreased oxidative stress in brain. Using novel object recognition (NOR), we demonstrated the Dox administration resulted in memory deficits. Using hydrogen magnetic resonance imaging spectroscopy (H1-MRS) techniques, we demonstrated that Dox administration led to a dramatic decrease in choline(phosphocholine)/creatine (Cho/Cr) ratios in mouse hippocampus. The activities of both phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D(PLD) were severely diminished following Dox administration. The activity of PC-PLC was preserved when MESNA was co-administered with Dox. In the absence of TNF-α, MRS-indexed Cho/Cr ratio, PLD activity, and mitochondrial oxygen consumption are preserved in brain, and markers of oxidative stress are reduced.
Together with results from our previous studies, these results provide strong evidence that TNF-α is strongly associated, if not responsible for CICI. We also tested the notion that O2-• is responsible for Dox-induced plasma protein oxidation and TNF-α release. O2-• resulted in increased oxidative damage to proteins when added to plasma and increased levels of TNF-α in macrophage culture, providing strong evidence that O2-• is responsible for these Dox-induced toxicities.
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Moxley-Paquette, Elizabeth Ann. "Testing a Structural Equation Model of Language-based Cognitive Fitness." ScholarWorks, 2014. https://scholarworks.waldenu.edu/dissertations/1545.
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The normative development of language is often taken for granted, yet problems with language development can result in stress for the individual and family. A challenge with these language development problems lies within the contemporary education system, which assumes that children have appropriate skills when they begin school. The purpose of the study was to test a theoretical model of language readiness known as language-based cognitive fitness, which includes measures associated with structural concepts of language involving receptive language, expressive language, spontaneous narrative speech, and writing fluency. The sample included children from a private school who received an extensive battery of tests at admission and annually thereafter. Scores from a variety of cognitive measures were used in a structural equation modeling framework to test the model. Results demonstrated language-based cognitive fitness to be an interplay of verbal reasoning abilities, visual synthesis, and active analysis broadly representing receptive language, expressive language, spontaneous narrative expression, and writing fluency. Verbal reasoning, visual synthesis, and active analysis explained 91% of the variance in achievement. Implications for positive social change include an improved understanding for those who work with children's language development, specifically of the language structures responsible for language deficits and how these relate to overall cognitive fitness; interventions can be provided to help children more quickly make up language deficits.
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Wyatt, Laura, and Ephron Rosenzweig. "Possible T Cell Immune Response to AAV Treatment in non-Human Primates with Spinal Cord Injury." Scholarship @ Claremont, 2013. http://scholarship.claremont.edu/scripps_theses/163.
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Neurons in the spinal cord do not spontaneously regenerate, which often leads to debilitating injuries. One method proposed to promote axonal regeneration is the injection of viruses carrying genes for growth factors into the injured spinal cord. One such virus, the adeno-associated virus (AAV), has shown promise in gene therapy medical research. However, injecting AAV into rhesus macaques with C7 spinal cord hemisection lesions actually leads to motor neuron loss in the gray matter of the spinal cord, rather than contributing to the preservation or regeneration of axons. This unexpected result highlights the necessity of further testing with therapeutic approaches for axon regeneration in nonhuman primate models before moving into clinical trials. It is possible that an immune-related T cell response to the AAV-transfected cells causes this motor neuron loss. T cells are white blood cells that play a role in attacking cells infected with viruses. It is unknown whether such a response of the immune system to respond with an up-regulation of T cells may be taking place over a relatively short period (weeks) or over many months. This question was tested here: T cells were stained in spinal cord sections caudal (below) the lesion in the spinal cord and near AAV injection sites to determine whether there was a greater quantity of T cells in these areas compared to the subject’s baseline levels. Subjects that had AAV therapeutic injections and that were examined 6 months after the injection were found to have greater quantities of T cells than those who did not have injections containing AAV. It was also found that the AAV-injected subjects examined only 6 weeks post injection did not have greater quantities of T cells than control subjects. These results suggest that there may be a delayed immune response to the AAV injections in nonhuman primates with spinal cord injury, which occurs over a period of months. Pinpointing the mechanism that causes this cell death would allow researchers to create a safer therapeutic that could promote axonal growth in people with spinal cord injuries.
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Armstrong, Michael G. "Effect of zymosan-induced peritonitis on the expression of substance P in primary sensory neurons and spinal nerve processes." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/honors/328.
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Macrophages and other cells of the innate immune system recognize foreign particles that could be potentially dangerous and respond by initiating an inflammatory response. The biologically active chemical mediators of this response called pro-inflammatory cytokines are produced in various myeloid derived immune cells and can affect other cells of the body. Interleukin-1β, a pro-inflammatory cytokine, has been shown to have direct effects on dorsal root ganglion (DRG) cell bodies including the upregulation and direct release of a nociceptive neurotransmitter called substance P (SP). Using a zymosan-induced model of systemic inflammation, we hypothesized that murine DRG neurons and the nerve processes associated with them in the dorsal horn of the spinal cord (SC) at the L1 level will show an upregulation of SP expression in response to inflammation in the peritoneum. Experimental mice were treated with a zymosan suspension (500mg/kg, intraperitoneal injection), and control mice received sterile filtered solution (intraperitoneal injection). Both DRG and SC specimens were collected after in situ fixation and subjected to immunofluorescence staining to label SP. Using confocal microscopy, fluorescence microscopy, and image analysis software this expression of SP was quantified and compared. In both tissue specimen groups, an increase in SP expression was discovered in zymosan treated mice. The exact cause of this increase was not specifically determined in this experiment. This experiment provided valuable insight about how a systemic inflammatory response can affect sensory nerve function. Successful methods for further experimentation were identified and information about the zymosan model of inflammation was obtained
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Showemimo, Opeyemi F. "Vitamin B12 Deficiency Does Not Stimulate Amyloid-beta Toxicity in a Ceanorhabditis elegans Model of Alzheimer’s Disease." Digital Commons @ East Tennessee State University, 2021. https://dc.etsu.edu/etd/3869.
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Alzheimer’s disease (AD) is symptomized by amyloid-beta plaques in the brain and accounts for more than 65 percent of dementia cases. Vitamin B12 (cobalamin) deficiency can result in similar cognitive impairment and roughly 15% of the elderly are vitamin B12 deficient. Vitamin B12 deficiency results in the accumulation of toxic methylmalonic acid and homocysteine. Hyperhomocysteinemia is a strong risk factor for AD. To test if vitamin B12 deficiency stimulates amyloid-beta toxicity, Caenorhabditis elegans expressing amyloid-beta in muscle were fed either vitamin B12-deficient OP50-1 or vitamin B12-rich HT115(DE3) E. coli bacteria. Increased amyloid-beta toxicity was found in worms fed the 0P50-1 diet. Supplementation of the OP50-1 diet with vitamin B12 did not rescue the increased C. elegans toxicity. Knockdown of either of the only two C. elegans vitamin B12-dependent enzymes metr-1 or mmmc-1 protected against toxicity. Therefore, vitamin B12 deficiency does not stimulate Alzheimer’s amyloid-beta-mediated toxicity in C. elegans.
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Majeed, Zana R. "MODULATORY ACTIONS OF SEROTONERGIC SYSTEM IN CARDIAC FUNCTION, BEHAVIOR, AND SENSORIMOTOR CIRCUIT ACTIVITY IN DROSOPHILA MELANOGASTER." UKnowledge, 2016. http://uknowledge.uky.edu/biology_etds/32.
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In this dissertation, I have focused on the role of serotonin (5-HT) as a modulator in heart rate, feeding and locomotion behaviors as well as sensorimotor circuit activity in Drosophila melanogaster. A general overview in the actions of the serotonergic (5-HTergic) system on the larval heart and nervous system in larvae and adults is reviewed in Chapter One. I sought to further study the actions of serotonergic system to provide additional insights into cellular and molecular underpinnings in the actions of 5-HT.In Chapter two, I present studies on mechanisms of action by 5-HT in larvae cardiac system. For this purpose, genetic and pharmacological approaches were used. The transgenic flies used expressed hM4Di receptors (designer receptors exclusively activated by designer drugs (DREADDs)) which were employed to manipulate the activity of Gαi heterotrimeric protein through activation of engineered G-protein coupled receptors hM4Di DREADD. The activation of hM4Di DREADD receptors by clozapine-N-oxide (CNO) arrested the heart beat; however, pharmacological manipulation of adenylyl cyclase activity and cAMP levels had no significant effect on heart rate. In Chapter Three the role of various 5-HT receptor subtypes that mediate 5-HT action in larval cardiac tissue is addressed. In this study, various 5-HT agonists and antagonists were employed. The pharmacological results demonstrate that a 5-HT2 agonist significantly increases the heart rate. Furthermore, 5-HT2 antagonist, markedly reduces the effect of 5-HT. In addition, I employed genetic approaches to corroborate the pharmacological results.
In addition, I investigated the role of the 5-HTergic system in locomotion and feeding behaviors as well as in modulation of sensorimotor circuits. This study is delineated in Chapter Four. The 5-HT biosynthesis was dysregulated by feeding Drosophila larvae various pharmacological agents. 5-HT receptor subtypes were manipulated using RNA interference mediated knockdown and 5-HT receptor insertional mutations. Moreover, synaptic transmission at 5-HT neurons was blocked or induced in both larvae and adult flies. The results demonstrate that disruption of components within the 5-HT system significantly impairs locomotor activity and feeding behavior in larvae. In addition, acute activation of 5-HT neurons disrupts normal locomotor activity in adult flies. In Chapter Five, I addressed direct actions of fluoxetine on synaptic transmission at neuromuscular junctions (NMJs), neural properties, and cardiac function unrelated to fluoxetine’s action as a selective 5-HT reuptake inhibitor using Drosophila, crayfish and primary neurons in mouse model system. Fluoxetine application blocked action potentials in crayfish axons, enhanced occurrences of spontaneous synaptic vesicle fusion events at NMJs of both Drosophila and crayfish. In rodent primary neurons, fluoxetine application resulted in increase of cytoplasmic Ca2+.
I also developed teaching modules, which are presented in Chapter Seven, to guide students how to exploit a vast array of genetic tools, such as optogenetics in Drosophila to manipulate various neural circuits and to observe their effects on behavior and sensorimotor circuit activity. I also developed a module to teach college level students a hands-on experiment regarding proprioception and tension receptors in crab limb, which is detailed in Chapter Eight.
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Ivy, Devon. "DEFINING THE RADIORESPONSE OF MOSSY CELLS." CSUSB ScholarWorks, 2018. https://scholarworks.lib.csusb.edu/etd/633.
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Clinical radiotherapy is used to treat a variety of brain tumors within the central nervous system. While effective, it can result in progressive and debilitating cognitive impairment that can diminish quality of life. These impairments have been linked to hippocampal dysfunction and corresponding deficits in spatial learning and memory. Mossy cells are a major population of excitatory neurons located within the dentate hilus and highly involved in hippocampal circuitry. They play critical roles in spatial navigation, neurogenesis, memory, and are particularly vulnerable to a variety of neurotoxic insults. However, their sensitivity to ionizing radiation has yet to be investigated in detail. I hypothesize that mossy cells are critical targets for ionizing radiation, whereby damage to these targets contributes to the mechanisms associated with radiation-induced hippocampal dysfunction.
To test this idea, wild-type mice were exposed to clinically relevant doses of cranial x-ray irradiation and their hippocampi were examined 1 month and 3 months post treatment. A significant decline in both the number of mossy cells and their activity were observed. In addition, dentate granular cells demonstrated reduced levels of activity, as well as reduced proliferation within the subgranular zone. A second cohort of mice was introduced to a novel environment in order to induce the expression of immediate early genes. Analysis of c-Fos mRNA yielded a significant increase in control but not irradiated animals, suggesting that radiotherapy impaired immediate early gene expression and resultant functional behavioral outcomes. These findings support the proposition that radiation-induced damage to mossy cells contributes to hippocampal deficiencies which result in cognitive dysfunction.
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Gaetano, Thomas M. "Ontogenetic and Adult Shape Variation in the Endocast of Tapirus: Implications for T. polkensis from the Gray Fossil Site." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/etd/3765.
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Endocranial morphology provides evidence of sensory ecology and sociality of extinct vertebrates. The Earliest Pliocene Gray Fossil Site (GFS) of NE Tennessee features a conspicuous dominance of skeletal elements belonging to the dwarf tapir, Tapirus polkensis. Numerous individuals in one fossil locality often suggests gregarious behavior, but sociality in T. polkensis contradicts behavior documented for extant Tapirus species. I test T. polkensis for variation in sensory and social ecology using computed tomography and 3D digital endocasts from an ontogenetic sequence. I compare the T. polkensis endocasts with extant Tapirus species using Encephalization Quotients (EQs) and 3D geometric morphometrics. Results show conserved endocast morphology for Tapirus, and thus, conserved sensory and social ecology. Tapirus behavior is likely consistent for ~5 Ma, and extant Tapirus behavior can be inferred for T. polkensis. The large number of individuals from the GFS is likely the result of a preservation bias unrelated to gregariousness.
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Baer, Matthew L. "Elucidating the Role of Endogenous Electric Fields in Regulating the Astrocytic Response to Injury in the Mammalian Central Nervous System." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/4007.
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Endogenous bioelectric fields guide morphogenesis during embryonic development and regeneration by directly regulating the cellular functions responsible for these phenomena. Although this role has been extensively explored in many peripheral tissues, the ability of electric fields to regulate wound repair and stimulate regeneration in the mammalian central nervous system (CNS) has not been convincingly established. This dissertation explores the role of electric fields in regulating the injury response and controlling the regenerative potential of the mammalian CNS. We place particular emphasis on their influence on astrocytes, as specific differences in their injury-induced behaviors have been associated with differences in the regenerative potential demonstrated between mammalian and non-mammalian vertebrates. For example, astrocytes in both mammalian and non- mammalian vertebrates begin migrating towards the lesion within hours and begin to proliferate after an initial delay of two days; subsequently, astrocytes in non-mammalian vertebrates support neurogenesis and assume a bipolar radial glia-like morphology that guides regenerating axons, whereas astrocytes in mammals do not demonstrate robust neurogenesis and undergo a hypertrophic response that inhibits axon sprouting. To test whether injury-induced electric fields drive the astrocytic response to injury, we exposed separate populations of purified astrocytes from the rat cortex and cerebellum to electric field intensities associated with intact and injured mammalian tissues, as well as to those electric field intensities measured in regenerating non-mammalian vertebrate tissues. Upon exposure to electric field intensities associated with uninjured tissue, astrocytes showed little change in their cellular behavior. However, cortical astrocytes responded to electric field intensities associated with injured mammalian tissues by demonstrating dramatic increases in migration and proliferation, behaviors that are associated with their formation of a glial scar in vivo; in contrast, cerebellar astrocytes, which do not organize into a demarcated glial scar, did not respond to these electric fields. At electric field intensities associated with regenerating tissues, both cerebellar and cortical astrocytes demonstrated robust and sustained responses that included morphological changes consistent with a regenerative phenotype. These results support the hypothesis that physiologic electric fields drive the astrocytic response to injury, and that elevated electric fields may induce a more regenerative response among mammalian astrocytes.
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Rahrig, Hadley. "The Role of Mindfulness in Self-view Investment: Neural and Subjective Indicators." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5944.
Full textAbstract:
Self-concept is strongly influenced by beliefs about one’s personal psychological attributes, and these beliefs are held with varying degrees of confidence and consequence. Hence, it is investment in self-views of those attributes that helps to regulate and maintain stable self-concept. Self-view investment is relevant to numerous self-related functions, but high self-view investment can also contribute to maladaptive self-views. Theory suggests that mindfulness cultivates a less personal, more objective perception of one’s thoughts, emotions and behaviors, and training in mindfulness has been shown to alter self-referential processing. The current pilot study (N=21) investigates the possible role of dispositional mindfulness in two forms of self-view investment, epistemic certainty and emotive importance, as indicated by self-reported and neural (functional magnetic resonance imaging-based) indicators of investment. Results indicated that dispositional mindfulness was positively associated with self-reported epistemic certainty but not emotive importance. Trait mindfulness was associated with activity in the amygdala and parahippocampal gyrus during judgements of both epistemic certainty and emotive importance. Caudate activity was positively associated with trait mindfulness specifically for judgements of emotive importance.
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Avery, Michelle A. "Axon Death Prevented: Wlds and Other Neuroprotective Molecules: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/520.
Full textAbstract:
A common feature of many neuropathies is axon degeneration. While the reasons for degeneration differ greatly, the process of degeneration itself is similar in most cases. Axon degeneration after axotomy is termed ‘Wallerian degeneration,’ whereby injured axons rapidly fragment and disappear after a short period of latency (Waller, 1850). Wallerian degeneration was thought to be a passive process until the discovery of the Wallerian degeneration slow (Wlds) mouse mutant. In these mice, axons survive and function for weeks after nerve transection. Furthermore, when the full-length protein is inserted into mouse models of disease with an axon degeneration phenotype (such as progressive motor neuronopathy), Wlds is able to delay disease onset (for a review, see Coleman, 2005). Wlds has been cloned and was found to be a fusion event of two neighboring genes: Ube4b, which encodes an ubiquitinating enzyme, and NMNAT-1 (nicotinamide mononucleotide adenylyltransferase-1), which encodes a key factor in NAD (nicotinamide adenine dinucleotide) biosynthesis, joined by a 54 nucleotide linker span (Mack et al., 2001).
To address the role of Wlds domains in axon protection and to characterize the subcellular localization of Wlds in neurons, our lab developed a novel method to study Wallerian degeneration in Drosophila in vivo (MacDonald et al., 2006). Using this method, we have discovered that mouse Wlds can also protect Drosophila axons for weeks after acute injury, indicating that the molecular mechanisms of Wallerian degeneration are well conserved between mouse and Drosophila. This observation allows us to use an easily manipulated genetic model to move the Wlds field forward; we can readily identify what Wlds domains give the greatest protection after injury and where in the neuron protection occurs. In chapter two of this thesis, I identify the minimal domains of Wlds that are needed for protection of severed Drosophila axons: the first 16 amino acids of Ube4b fused to Nmnat1. Although Nmnat1 and Wlds are nuclear proteins, we find evidence of a non-nuclear role in axonal protection in that a mitochondrial protein, Nmnat3, protects axons as well as Wlds.
In chapter 3, I further explore a role for mitochondria in Wlds-mediated severed axon protection and find the first cell biological changes seen in a Wlds-expressing neuron. The mitochondria of Wlds- and Nmnat3-expressing neurons are more motile before injury. We find this motility is necessary for protection as suppressing the motility with miro heterozygous alleles suppresses Wldsmediated axon protection. We also find that Wlds- and Nmnat3- expressing neurons show a decrease in calcium fluorescent reporter, gCaMP3, signal after axotomy. We propose a model whereby Wlds, through production of NAD in the mitochondria, leads to an increase in calcium buffering capacity, which would decrease the amount of calcium in the cytosol, allowing for more motile mitochondria. In the case of injury, the high calcium signal is buffered more quickly and so cannot signal for the axon to die.
Finally, in chapter 4 of my thesis, I identify a gene in an EMS-based forward genetic screen which can suppress Wallerian degeneration. This mutant is a loss of function, which, for the first time, definitively demonstrates that Wallerian degeneration is an active process. The mammalian homologue of the gene encodes a mitochondrial protein, which in light of the rest of the work in this thesis, highlights the importance of mitochondria in neuronal health and disease.
In conclusion, the work presented in this thesis highlights a role for mitochondria in both Wlds-mediated axon protection and Wallerian degeneration itself. I identified the first cell biological changes seen in Wlds-expressing neurons and show that at least one of these is necessary for its protection of severed axons. I also helped find the first Wallerian degeneration loss-of-function mutant, showing Wallerian degeneration is an active process, mediated by a molecularly distinct axonal degeneration pathway. The future of the axon degeneration field should focus on the mitochondria as a potential therapeutic target.
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Narayanaswami, Vidya. "DIET-INDUCED OBESITY: DOPAMINERGIC AND BEHAVIORAL MECHANISMS AS OUTCOMES AND PREDICTORS." UKnowledge, 2013. http://uknowledge.uky.edu/pharmacy_etds/12.
Full textAbstract:
Obesity and drug abuse share common neural circuitries including the mesocoticolimbic and striatal dopamine reward system. In the current study, a rat model of diet-induced obesity (DIO) was used to determine striatal dopamine function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. For the outcome study, rats were randomly assigned a high-fat (HF) or a low-fat (LF) diet for 8 wk. Following the 8-wk HF-diet exposure, rats were segregated into obesity-prone and obesity-resistant groups based on maximum and minimum body weight gain, respectively, and neurobehavioral outcomes were evaluated. For the predictor study, neurobehavioral antecedents were evaluated prior to an 8-wk high-fat diet exposure and were correlated with subsequent body weight gain. Striatal D2 receptor density was determined by in vitro kinetic analysis of [3H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [3H]dopamine uptake, methamphetamine-evoked [3H]dopamine overflow and no net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and Western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule for food-reinforcers, respectively. Relative to obesity-resistant, obesity-prone rats exhibited 18% greater body weight, 42% lower striatal D2 receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine concentration, and 2-fold greater methamphetamine-evoked [3H]dopamine overflow. Obesity-prone rats exhibited higher motivation for food, but were less impulsive relative to obesity-resistant rats. Neurobehavioral antecedents of DIO included greater motivation for high-fat reinforcers in rats subsequently shown to be obesity-prone relative to obesity-resistant. Impulsivity, DAT function and extracellular dopamine concentration did not predict the DIO-phenotype. Thus, motivation for food is linked to both initiation and maintenance of obesity. Importantly, obesity results in decreased striatal DAT function, which may underlie the maintenance of compulsive food intake in obesity.
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Alterman, Julia F. "A CNS-Active siRNA Chemical Scaffold for the Treatment of Neurodegenerative Diseases." eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1027.
Full textAbstract:
Small interfering RNAs (siRNAs) are a promising class of drugs for treating genetically-defined diseases. Therapeutic siRNAs enable specific modulation of gene expression, but require chemical architecture that facilitates efficient in vivodelivery. siRNAs are informational drugs, therefore specificity for a target gene is defined by nucleotide sequence. Thus, developing a chemical scaffold that efficiently delivers siRNA to a particular tissue provides an opportunity to target any disease-associated gene in that tissue. The goal of this project was to develop a chemical scaffold that supports efficient siRNA delivery to the brain for the treatment of neurodegenerative diseases, specifically Huntington’s disease (HD).
HD is an autosomal dominant neurodegenerative disorder that affects 3 out of every 100,000 people worldwide. This disorder is caused by an expansion of CAG repeats in the huntingtin gene that results in significant atrophy in the striatum and cortex of the brain. Silencing of the huntingtin gene is considered a viable treatment option for HD. This project: 1) identified a hyper-functional sequence for siRNA targeting the huntingtin gene, 2) developed a fully chemically modified architecture for the siRNA sequence, and 3) identified a new structure for siRNA central nervous system (CNS) delivery—Divalent-siRNA (Di-siRNA). Di-siRNAs, which are composed of two fully chemically-stabilized, phosphorothioate-containing siRNAs connected by a linker, support potent and sustained gene modulation in the CNS of mice and non-human primates. In mice, Di-siRNAs induced potent silencing of huntingtin mRNA and protein throughout the brain one month after a single intracerebroventricular injection. Silencing persisted for at least six months, with the degree of gene silencing correlating to guide strand tissue accumulation levels. In Cynomolgus macaques, a bolus injection exhibited significant distribution and robust silencing throughout the brain and spinal cord without detectable toxicity. This new siRNA scaffold opens the CNS for RNAi-based gene modulation, creating a path towards developing treatments for genetically-defined neurological disorders.
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Chilufya, Jedaidah Y. "Anandamide-Mediated Growth Changes in Physcomitrella patens." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etd/3162.
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Anandamide (NAE 20:4) or arachidonlyethanolamine (AEA) is the most widely studied N-acylethanolamine (NAE) because it mediates several physiological functions in mammals. In vascular plants, 12-18C NAEs inhibit growth in an abscisic acid (ABA)-dependent and -independent manner. Anandamide, which is unique to bryophyte Physcomitrella patens, inhibited gametophyte growth and reduced chlorophyll content when applied exogenously. It is hypothesized that anandamide mediates its responses through morphological and cellular changes. Following growth inhibition by short-term anandamide-treatment, microscopic analyses revealed relocated chloroplasts and depolymerized F-actin in protonemal tips. Long-term treatment showed partially bleached gametophyte cells with degraded and browning chloroplasts. These anandamide-mediated responses have physiological implications as AEA may function as a signal for gametophytes to activate secondary dormancy as seen with ABA. Future studies will investigate the role of AEA in mediating stress responses and possible interaction with ABA.
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Vedala, Krishnatej. "A Novel Signal Processing Method for Intraoperative Neurophysiological Monitoring in Spinal Surgeries." FIU Digital Commons, 2013. http://digitalcommons.fiu.edu/etd/1038.
Full textAbstract:
Intraoperative neurophysiologic monitoring is an integral part of spinal surgeries and involves the recording of somatosensory evoked potentials (SSEP). However, clinical application of IONM still requires anywhere between 200 to 2000 trials to obtain an SSEP signal, which is excessive and introduces a significant delay during surgery to detect a possible neurological damage. The aim of this study is to develop a means to obtain the SSEP using a much less, twelve number of recordings. The preliminary step involved was to distinguish the SSEP with the ongoing brain activity. We first establish that the brain activity is indeed quasi-stationary whereas an SSEP is expected to be identical every time a trial is recorded.
An algorithm was developed using Chebychev time windowing for preconditioning of SSEP trials to retain the morphological characteristics of somatosensory evoked potentials (SSEP). This preconditioning was followed by the application of a principal component analysis (PCA)-based algorithm utilizing quasi-stationarity of EEG on 12 preconditioned trials. A unique Walsh transform operation was then used to identify the position of the SSEP event. An alarm is raised when there is a 10% time in latency deviation and/or 50% peak-to-peak amplitude deviation, as per the clinical requirements. The algorithm shows consistency in the results in monitoring SSEP in up to 6-hour surgical procedures even under this significantly reduced number of trials.
In this study, the analysis was performed on the data recorded in 29 patients undergoing surgery during which the posterior tibial nerve was stimulated and SSEP response was recorded from scalp. This method is shown empirically to be more clinically viable than present day approaches. In all 29 cases, the algorithm takes 4sec to extract an SSEP signal, as compared to conventional methods, which take several minutes.
The monitoring process using the algorithm was successful and proved conclusive under the clinical constraints throughout the different surgical procedures with an accuracy of 91.5%. Higher accuracy and faster execution time, observed in the present study, in determining the SSEP signals provide a much improved and effective neurophysiological monitoring process.
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Zajac, Richard. "From Rainman to Rainmaker: A Presentation of Jim’s Journey and Rapidly Advancing Technologies: Integrating Proven Behavioral Therapies with Emergent Measurement and Testing Advances Will Result in Transformational Progress in Autistic Individuals." Scholarship @ Claremont, 2016. http://scholarship.claremont.edu/cmc_theses/1344.
Full textAbstract:
The autism treatment status quo was reviewed and accompanied by a narrative contextualizing past and present progress with my younger brother Jim’s journey with the condition, sharing proposed next steps for bettering the current state of affairs in the space. The impetus for this piece was to share in the lessons of Jim’s life thus far and the revelations of those who have supported him, as well as to determine ways to create more impactful, lasting change in the limited window of early intervention therapy whilst empowering individuals on the spectrum to optimize for their skills and talents rather than just simply mitigating the downsides of autism spectrum disorder. Feedback as to how to improve the prevailing course of treatment: (education and therapy) was solicited by leading experts in the fields of Applied Behavior Analysis (ABA), Electroencephalography (EEG), and autism more generally in the context of politics, insurability, and savant syndrome and splinter skills. The advice of the various vertical experts were synthesized and distilled into a new proposed course of treatment which were submitted to all respective experts for further feedback and review prior to publication. It was discovered that there is significant feedback to suggest that the prevailing wisdom that splinter skills and savant syndrome are found in a small minority of individuals with autism spectrum disorder may not be true and that further research is warranted that would implement the new proposed course of treatment and attempt to unlock the talents and gifts of these individuals consistent with the success we encountered raising Jim. While our methods were resource-intensive and conducted manually with many hours of intensive in-home therapy, there is significant feedback to suggest that a technology-driven approach to reforming autism treatment would achieve same or greater results with far fewer resources in the near and long term. By unlocking the greatest minds of our society (the majority of savants have historically been autistic) to take on the greatest challenges of our time, we can rapidly accelerate the progress of humanity and exponentially better the trajectory of society’s future at the global scale.
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Vallaster, Markus Parzival. "Intergenerational Effects of Nicotine in an Animal Model of Paternal Nicotine Exposure." eScholarship@UMMS, 2008. http://escholarship.umassmed.edu/gsbs_diss/913.
Full textAbstract:
Environmental conditions imposed onto organisms during certain phases of their life cycles such as embryogenesis or puberty can not only impact the organisms’ own health, but also affect subsequent generations. The underlying mechanisms causing intergenerational phenotypes are not encoded in the genome, but the result of reversible epigenetic modifications. This work investigates in a mouse model the impact of paternal nicotine exposure on the next generation regarding addictive behavior modulation, metabolic changes, and molecular mechanisms. It provides evidence that male offspring from nicotine-exposed fathers (NIC offspring) is more resistant to lethal doses of nicotine. This phenotype is gender-specific and depends on short-term environmental challenges with low doses of nicotine prior to the LD50 application. The observed survival phenotype is not restricted to nicotine as drug of abuse, but also presents itself, when NIC offspring is challenged with a cocaine LD50 after acclimatization to low doses of either nicotine or cocaine. Functionally, NIC offspring metabolizes nicotine faster than control. Mechanistically, NIC offspring livers show global up-regulation of xenobiotic processing genes (XPG), an effect that is even more pronounced in primary hepatocyte cultures. Being known targets of Constitutive Androstane Receptor (CAR) and Pregnane X Receptor (PXR), these XPGs show higher baseline expression in naïve NIC offspring livers. Nicotine’s action on the brain’s reward circuitry does not appear to be of biological significance in our model system. Taken together, paternal nicotine exposure leads to a non-specific and conditional phenotype in male NIC offspring that may provide a general survival advantage against xenobiotic challenges.
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Vallaster, Markus Parzival. "Intergenerational Effects of Nicotine in an Animal Model of Paternal Nicotine Exposure." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/913.
Full textAbstract:
Environmental conditions imposed onto organisms during certain phases of their life cycles such as embryogenesis or puberty can not only impact the organisms’ own health, but also affect subsequent generations. The underlying mechanisms causing intergenerational phenotypes are not encoded in the genome, but the result of reversible epigenetic modifications. This work investigates in a mouse model the impact of paternal nicotine exposure on the next generation regarding addictive behavior modulation, metabolic changes, and molecular mechanisms. It provides evidence that male offspring from nicotine-exposed fathers (NIC offspring) is more resistant to lethal doses of nicotine. This phenotype is gender-specific and depends on short-term environmental challenges with low doses of nicotine prior to the LD50 application. The observed survival phenotype is not restricted to nicotine as drug of abuse, but also presents itself, when NIC offspring is challenged with a cocaine LD50 after acclimatization to low doses of either nicotine or cocaine. Functionally, NIC offspring metabolizes nicotine faster than control. Mechanistically, NIC offspring livers show global up-regulation of xenobiotic processing genes (XPG), an effect that is even more pronounced in primary hepatocyte cultures. Being known targets of Constitutive Androstane Receptor (CAR) and Pregnane X Receptor (PXR), these XPGs show higher baseline expression in naïve NIC offspring livers. Nicotine’s action on the brain’s reward circuitry does not appear to be of biological significance in our model system. Taken together, paternal nicotine exposure leads to a non-specific and conditional phenotype in male NIC offspring that may provide a general survival advantage against xenobiotic challenges.
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Laws, Brent C. "The Phenomenon of Abstract Cognition Among Scholastic Chess Participants: A Case Study." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etd/2458.
Full textAbstract:
A qualitative investigation was conducted to explore the phenomenon of abstract cognition among a purposive sample of 5 secondary scholastic chess club participants. The case study enabled the researcher to explore the faculties of abstract cognition among students of contrasting skills and abilities in playing chess. The study also allowed for the consideration of potential visual-spatial, logical, academic, social competency and life benefits of chess play. Through analysis of interviews, chess simulations, blindfold chess play, and narration of chess lines and sequences, the investigator was able to extract meaning and code schemata into a holistic understanding of the phenomenon of abstract cognition within the context of Piaget’s Formal Operations Stage.
Scholastic chess systematically engages the student in a stimuli-enriched environment in which the participant must exercise optimal cognitive control in processing and anticipating chess lines and sequences, thus facilitating the manifestation and phenomenon of abstract cognition. Abstract cognition as a phenomenon may elicit increased academic, scholarly, and life potential. Participation in scholastic chess may produce both scholarly and critical thinking individuals. Suggestions for future research include continuing qualitative research in the area of abstract cognition among chess players and developing a stronger understanding of cognitive growth in students.
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Golebiowski, Diane L. "Overcoming Toxicity from Transgene Overexpression Through Vector Design in AAV Gene Therapy for GM2 Gangliosidoses." eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/895.
Full textAbstract:
GM2 gangliosidoses are a family of lysosomal storage disorders that include both Tay-Sachs and Sandhoff diseases. These disorders result from deficiencies in the lysosomal enzyme β-N-acetylhexosaminidase (HexA). Impairment of HexA leads to accumulation of its substrate, GM2 ganglioside, in cells resulting in cellular dysfunction and death. There is currently no treatment for GM2 gangliosidoses. Patients primarily present with neurological dysfunction and degeneration. Here we developed a central nervous system gene therapy through direct injection that leads to long-term survival in the Sandhoff disease mouse model. We deliver an equal mixture of AAVrh8 vectors that encode for the two subunits (α and β) of HexA into the thalami and lateral ventricle. This strategy has also been shown to be safe and effective in treating the cat model of Sandhoff disease. We tested the feasibility and safety of this therapy in non-human primates, which unexpectedly lead to neurotoxicity in the thalami. We hypothesized that toxicity was due to high overexpression of HexA, which dose reduction of vector could not compensate for. In order to maintain AAV dose, and therefore widespread HexA distribution in the brain, six new vector designs were screened for toxicity in nude mice. The top three vectors that showed reduction of HexA expression with low toxicity were chosen and tested for safety in non-human primates. A final formulation was chosen from the primate screen that showed overexpression of HexA with minimal to no toxicity. Therapeutic efficacy studies were performed in Sandhoff disease mice to define the minimum effective dose.
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Golebiowski, Diane L. "Overcoming Toxicity from Transgene Overexpression Through Vector Design in AAV Gene Therapy for GM2 Gangliosidoses." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/895.
Full textAbstract:
GM2 gangliosidoses are a family of lysosomal storage disorders that include both Tay-Sachs and Sandhoff diseases. These disorders result from deficiencies in the lysosomal enzyme β-N-acetylhexosaminidase (HexA). Impairment of HexA leads to accumulation of its substrate, GM2 ganglioside, in cells resulting in cellular dysfunction and death. There is currently no treatment for GM2 gangliosidoses. Patients primarily present with neurological dysfunction and degeneration. Here we developed a central nervous system gene therapy through direct injection that leads to long-term survival in the Sandhoff disease mouse model. We deliver an equal mixture of AAVrh8 vectors that encode for the two subunits (α and β) of HexA into the thalami and lateral ventricle. This strategy has also been shown to be safe and effective in treating the cat model of Sandhoff disease. We tested the feasibility and safety of this therapy in non-human primates, which unexpectedly lead to neurotoxicity in the thalami. We hypothesized that toxicity was due to high overexpression of HexA, which dose reduction of vector could not compensate for. In order to maintain AAV dose, and therefore widespread HexA distribution in the brain, six new vector designs were screened for toxicity in nude mice. The top three vectors that showed reduction of HexA expression with low toxicity were chosen and tested for safety in non-human primates. A final formulation was chosen from the primate screen that showed overexpression of HexA with minimal to no toxicity. Therapeutic efficacy studies were performed in Sandhoff disease mice to define the minimum effective dose.
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Poe, Tyler M., and Francine Marciano-Cabral. "Illumination of the Golgi apparatus of Pathogenic and Nonpathogenic Naegleria species." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/6002.
Full textAbstract:
In this study, Naegleria fowleri, a pathogenic amoeba and the causative agent of Primary Amebic Meningoencephalitis (PAM), was utilized to determine the presence or absence of classically conserved Golgi molecules featured in the expression of a Golgi apparatus. Previous studies concluded no Golgi expression via light microscopy and transmission electron microscopy, but a recent report on Naegleria gruberi indicated the presence of dispersed Golgi tubules. Non-pathogenic species of the Naegleria genus such as Naegleria gruberi 30540 and Naegleria lovaniensis 30569 were utilized in Western immunoblot analysis compared to reduced whole-cell lysate proteins of two strains of N. fowleri and Vero CCL-81, Chlorocebus sp. kidney epithelial cells, which were utilized as a positive control for Golgi expression. N. fowleri and N. lovaniensis whole-cell lysates had indications of a 110 kDa reduced protein, associated with the predicted molecular weights of the beta-COPI subunit of the COPI cis-Golgi vesicular transport complex with further Western immunoblot indication of a weak band around 25 kDa corresponding to rabbit polyclonal antibodies specific for ARF1. Serial Dilutions of Wheat Germ Agglutinin Alexa Fluor 488TM were performed on Vero cells, Naegleria fowleri 30894, and N. gruberi 30540 with 1:100 dilution of recommended stock dilution of WGA 488 determined for utilization in sequential immunofluorescence. Sequential immunofluorescence with Wheat Germ Agglutinin Alexa Fluor 488TM and then blocked with 3% BSA:PBS [wt/vol] dilution with subsequent incubation in rabbit anti-beta-COPI primary 1:250, and 1:1000 of Alexa Fluor 594 goat anti-rabbit secondary antibody exposure showed strong indications of organized cis- and trans-punctate Golgi body markers in close association in individual and dividing cells of Naegleria fowleri and conserved Golgi expression in the positive control Vero cells, but further experiments are necessary to verify this finding with N. fowleri.
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Ehnert, Samantha L. "Mercury Accumulation and Effects in the Brain of Atlantic Sharpnose Sharks (Rhiszoprionodon Terranovae)." UNF Digital Commons, 2017. http://digitalcommons.unf.edu/etd/736.
Full textAbstract:
Sharks often bioaccumulate mercury (Hg) concentrations in their muscle to levels that threaten the health of human consumers. However, few published studies have examined if the high Hg levels seen in shark muscle also occur in the shark brain, or if Hg accumulation affects shark neurophysiology. Therefore, this study examined if shark brains accumulate significant levels of Hg, if Hg accumulation occurs in certain subcomponents of the brain, and if Hg accumulation is associated with oxidative stress effects on the shark central nervous system, with special focus on the Atlantic sharpnose shark (Rhizoprionodon terraenovae). Sharks were collected along the U.S. Southeastern coast throughout most of the shark’s geographical range. Known biomarkers of Hg-induced neurological effects (markers of glial cell damage, S100b, and markers of oxidative stress) in the shark cerebrospinal fluid were examined. Brain Hg levels were correlated with muscle Hg levels, but were significantly lower and did not exceed most known thresholds for neurological effects, suggesting limited potential for such responses. Data on known biomarkers of Hg-induced neurological effects support this premise, because they were not correlated with brain Hg levels. Organic methylmercury did not compose of a high percentage of the total mercury in the brain, indicating demethylation of Hg is occurring in the brain. Higher Hg levels were measured in the forebrain of the shark in comparison with the midbrain and hindbrain, but levels in both were below threshold levels for effects. This study is the first to demonstrate the correlation and significant difference of Hg in the brain and muscle of sharks, and it identifies significantly higher Hg levels in the forebrain; making this study one of the most extensive analysis of Hg in a single shark species.
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Kennedy, Zachary C. "Optimizing CRISPR/Cas9 for Gene Silencing of SOD1 in Mouse Models of ALS." eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1047.
Full textAbstract:
Mutations in the SOD1 gene are the best characterized genetic cause of amyotrophic lateral sclerosis (ALS) and account for ~20% of inherited cases and 1-3% of sporadic cases. The gene-editing tool Cas9 can silence mutant genes that cause disease, but effective delivery of CRISPR-Cas9 to the central nervous system (CNS) remains challenging. Here, I developed strategies using canonical Streptococcus pyogenes Cas9 to silence SOD1. In the first strategy, I demonstrate effectiveness of systemic delivery of guide RNA targeting SOD1 to the CNS in a transgenic mouse model expressing human mutant SOD1 and Cas9. Silencing was observed in both the brain and the spinal cord. In the second strategy, I demonstrate the effectiveness of delivering both guide RNA and Cas9 via two AAVs into the ventricles of the brain of SOD1G93A mice. Silencing was observed in the brain and in motor neurons within the spinal cord. For both strategies, treated mice had prolonged survival when compared to controls. Treated mice also had improvements in grip strength and rotarod function. For ICV treated mice, we detected a benefit of SOD1 silencing using net axonal transport assays, a novel method to detect motor neuron function in mice before onset of motor symptoms. These studies demonstrate that Cas9-mediated genome editing can mediate disease gene silencing in motor neurons and warrants further development for use as a therapeutic intervention for SOD1-linked ALS patients.
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Lucido, Michael J. "Effects of Neurofeedback on Neuropsychological Functioning in an Adult with Autism." ScholarWorks, 2011. https://scholarworks.waldenu.edu/dissertations/989.
Full textAbstract:
Autism spectrum condition (ASC) is a complex neurodevelopmental disorder that impacts physiological processes, cognition, functional behaviors, social-communication, and often has comorbidities. One approach gaining empirical support for ASC treatment is neurofeedback. Neurofeedback uses operant conditioning to normalize cerebral activity through auditory and visual reinforcement. Live Z-score Training (LZT) has become the latest advancement in neurofeedback. There is no published research to date on LZT neurofeedback in adulthood ASC. The purpose of this study was to evaluate LZT's impact on neuropsychological measures in an adult with ASC. A multiple baseline single-case research design was used with a convenience sample of one adult with ASC to evaluate the effects of 20 LZT sessions using the Conservative Dual Criterion visual inspection method as the primary form analysis. ADHD, mood stability, anxiety, depression, and ASC symptoms were significantly reduced according to the Neuropsych Questionnaire. The participant improved significantly on the CNS Vital Signs (CNVS) Neurocognitive measures of executive function, cognitive flexibility, reaction time, and complex attention. Also, the participant increased intelligence as measured by the Test of Nonverbal Intelligence. Lastly, the participant had changes in brain function according to quantitative electroencephalography and low-resolution brain electromagnetic tomography. CNVS processing speed was the only measure that did not significantly change. No adverse effects were reported. This study may lead to positive social change by providing a technologically advanced intervention for adults with ASC, which may improve their overall quality of life and promote self-sufficiency through adulthood.
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Hattingh, Coenraad Jacobus. "The structural neurobiology of social anxiety disorder : a clinical neuroimaging study." Doctoral thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/15544.
Full textAbstract:
Includes bibliographical references<br>While a number of studies have explored the functional neuroanatomy of social anxiety disorder (SAD), comparatively few studies have investigated the structural underpinnings in SAD. 18 psychopharmacologically and psychotherapeutically naïve adult patients with a primary Axis I diagnosis of generalized social anxiety disorder and 18 demographically (age, gender and education) matched healthy controls underwent 3T structural magnetic resonance imaging. A manual tracing protocol was specifically developed to compute the volume of the most prominent subcortical gray matter structures implicated in SAD by previous functional research. Cortical thickness was estimated using an automated algorithm and whole brain analyses of white matter structure were performed using FSL's tract - based spatial statistics comparing fractional anisotropy (FA), mean diffusivity (MD) in individuals with SAD. Manual tracing demonstrated that compared to controls, SAD patients showed an enlarged right globus pallidus. Cortical thickness analyses demonstrated significant cortical thinning in the left isthmus of the cingulate gyrus, the left temporal pole, and the left superior temporal gyrus. Analyses of white matter tractographic data demonstrated reduced FA in in the genu, splenium and tapetum of the corpus callosum. Additionally reduced FA was noticed in the fornix and the right cingulum. Reduced FA was also noted in bilateral corticospinal tracts and the right corona radiata. The results demonstrate structural alterations in limbic circuitry as well as involvement of the basal glanglia and their cortical projections and input pathways.
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Nyqvist, Ghashghaian Simon. "The Neurobiology of Ketamine and Addiction." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-15610.
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Ketamine is a dissociative anesthetic prescription drug and has been used for general anesthesia. The research surrounding this chemical compound has revealed conflicting evidence of its potential use in health care and addiction treatment. On one side, ketamine is a widespread drug of abuse associated with neurocognitive deficits and neurotoxicity, on the other side ketamine has recently been found to have a variety of potential uses, including but not limited to; antidepressant effects, reconsolidation of drug-related memories and disrupting maladaptive rumination. Ketamine’s ability to induce psychedelic and mystic experiences, reconsolidation of memories, antidepressant effects, and its ability to reduce cue-induced drug craving makes it a potentially useful tool in drug abuse therapy. Most of the negative side-effects of ketamine seem to be apparent at high doses and in frequent use but low doses and non-frequent use has a low risk of harm, therefore, careful consideration and extensive research are required before ketamine can be widely used in the public and in health care for treatment strategies. This thesis aims to explore the role of ketamine and its neurobiological effects in the treatment of addiction and depression.
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Petit-Turcotte, Caroline. "The neurobiology of apolipoprotein E : protein interactions in Alzheimer's disease." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84310.
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The epsilon4 allele of apolipoprotein E is now a well-known risk factor for Alzheimer's disease, however there is still much to be learned of the physiology of apoE in the brain, throughout normal aging and AD. To better understand the neurobiology of apoE, the work included in this thesis has focused on some of the key relationships apoE holds with some proteins known or suggested to have a role in the etiology of Alzheimer's disease. The H2 allele of apolipoprotein C-I is associated with Alzheimer's disease (AD). To examine the possibility of a direct role for apoC-I in AD, we compared apoC-I and apoE protein and mRNA levels in post-mortem specimens of frontal cortex and hippocampus from AD patients with levels in non-demented controls. We were able to confirm apoC-I expression in the CNS and identify astrocytes as the source of apoC-I. In addition, we revealed differences in apoC-I expression based on location in the brain, genotype and disease status that may reflect a role for apoC-I in the pathogenesis of AD. Lipoproteins are only efficient if able to access their target cells. ApoER2 is one of the major receptors for ApoE in the brain, and has been shown to be involved not only in lipoprotein endocytosis, but also in various cellular functions such as signalling and cellular guidance. By performing an entorhinal cortex lesion, a model of synaptic plasticity, in mice which express a decreasing number of copies of the apoER2 gene, we investigated the implication of a deficiency of this particular receptor in response to damage. Our results clearly indicate a role for apoER2 in maintaining efficient synaptic plasticity. We have also used the same synaptic plasticity model to compare the reactivity of various proteins associated with Alzheimer's disease, in wild-type C57Bl/6J and apoE-knockout mice. Along with quantifiying the levels of these proteins (APP, amyloid peptides and apoE receptors LRP and apoER2), our results also show that
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Setiawan, Elaine. "Individual differences in the neurobiology of responses to alcohol in humans." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=107730.
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Introduction: Alcohol abuse and dependence represent one of the most substantial burdens worldwide having severe medical, occupational and personal consequences. Animal models have implicated the mesolimbic dopamine and endogenous opioid systems but studies in humans have been less clear, in each case raising the possibility of marked individual differences. To investigate this hypothesis, two studies were conducted. In Study 1, we measured striatal dopamine responses to oral alcohol ingestion in subjects at varying risk for alcohol dependence. In Study 2, we measured individual differences in naltrexone's effects on alcohol reward and self-administration. Methods: Study 1) 26 non-dependent social drinkers at varying risk for alcohol use disorders each received two positron emission tomography scans, one following alcohol (1mL/kg 94% ethanol orally) and the other following a placebo. Changes in [11C]raclopride binding potential were determined as an index of dopamine release and compared in high and low risk individuals. Study 2) 40 healthy social drinkers (20 women), genotyped for the A118G polymorphism of the mu-opioid receptor gene, participated in two alcohol self-administration sessions on a progressive ratio task after receiving a sub-acute dose of naltrexone (1 day at 25mg/day + 5 days at 50mg/day) or placebo (riboflavin). Results: Study 1) High risk individuals showed significant striatal dopamine release in response to alcohol whereas low-risk individuals had significant decreases. The results were similar when risk was defined by the subjective response to alcohol or by personality traits. Study 2) Alcohol self-administration was not significantly affected by naltrexone. However, euphorigenic and stimulatory effects were reduced by naltrexone selectively in women and carriers of the G-allele of the A118G polymorphism.Conclusions: Dopamine release in response to alcohol in high risk individuals may represent a neurobiological vulnerability trait. This differential response may predispose these individuals to greater alcohol seeking and consumption by increasing the incentive salience of alcohol and alcohol-associated cues. In comparison, the opioid system appears to preferentially influence the positive subjective experience of alcohol. In clinical populations, long-term decreases in the positive effects of alcohol might lead to reduced alcohol use. Since the effects of naltrexone occurred only in women and individuals carrying the G-allele of the A118G polymorphism, these features might serve as predictors of greater treatment responsiveness. Together, the results suggest that dopamine and endogenous opioids influence separate, though often covarying, aspects of alcohol reward and reinforcement. These findings may contribute to better identification of at-risk individuals for prevention as well as improving strategies for treatment.<br>Introduction: L'abus d'alcool et la dépendance représentent l'un des fardeaux les plus importantes dans le monde entier associes avec de graves conséquences médicales, professionnelles et personnelles. Les modèles animaux ont mis en cause la dopamine mésolimbique et les systèmes des opioïdes endogènes, mais les études chez l'humain ont été moins clair, qui dans chaque cas soulève la possibilité de différences individuelles marquées. Pour vérifier cette hypothèse, deux études ont été menées. Dans la première étude, nous avons mesuré les réponses dopaminergiques striatales de suite à l'ingestion d'alcool par voie orale chez des sujets à risque variable de la dépendance à l'alcool. Dans la deuxième étude nous avons mesuré les différences individuelles dans les effets de naltrexone sur la récompense associé avec l'alcool et l'auto-administration de l'alcool. Méthodes: Étude 1) 26 buveurs sociaux non dépendants aux risques variables pour les troubles de la consommation d'alcool, ont reçu chacun deux tomographies par émission de positons, un après la consommation de l'alcool (1mL/kg éthanol à 94% par voie orale) et l'autre après placebo. Les changements dans le potentiel de [11C] raclopride contraignantes ont été déterminés comme un indice de la libération de dopamine et comparés chez les personnes à risque élevé et faible. Étude 2) 40 buveurs sociaux sains (20 femmes), génotypés pour le polymorphisme A118G du gène du récepteur mu-opioïde, a participé à deux sessions à l'auto-administration d'alcool en performant une tâche de rationnement progressifs soit après avoir reçu une dose sous-aiguë de la naltrexone (1 jour au 25 mg/jour + 5 jours à 50 mg/jour) ou soit après placebo (riboflavine). Résultats: Étude 1) les personnes à risque élevé ont montré une importante libération de dopamine striatale en réponse à l'alcool tandis que les personnes à faible risque avaient une diminution significative de dopamine. Les résultats étaient similaires lorsque le risque a été défini par la réponse subjective à l'alcool ou par des traits de personnalité. Étude 2) L'auto-administration d'alcool n'a pas été affectée significativement par la naltrexone. Cependant, les effets euphoriques, et de stimulation ont été réduits de manière sélective par naltrexone chez les femmes et les personnes portant l'allèle G du polymorphisme A118G.Conclusions: La libération de dopamine en réponse à l'alcool chez les individus à haut risque peuvent représenter un trait de vulnérabilité neurobiologique. Cette réponse différentielle peut prédisposer ces individus à une plus grande poursuite et consommation d'alcool a cause de l'augmentation de la saillance de l'alcool et des indices associés. En comparaison, le système opioïde semble influencer de façon préférentielle, l'expérience positive subjective de l'alcool. Dans les populations cliniques, la diminution des effets positives associés avec l'alcool peut mener a une réduction de la consommation d'alcool. Comme les effets de la naltrexone s'est produite seulement chez les femmes et les individus porteurs de l'allèle G du polymorphisme A118G, ces caractéristiques pourraient servir comme facteurs prédictifs de la réactivité plus grande suite autraitement. Ensemble, les résultats suggèrent que les systèmes des opioïdes endogènes et le système dopaminergique mésolimbique ont des influences distinctes, malgré souvent en covariance sur les aspects de la récompense d'alcool et de renforcement. Ces résultats peuvent contribuer à une meilleure identification des individus à risque en début de prévention ainsi que l'amélioration des stratégies pour le traitement.
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Todi, Sokol. "Investigating auditory transduction functions of myosin VII in Drosophila melanogaster." Diss., University of Iowa, 2005. http://ir.uiowa.edu/etd/92.
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Wen, Jing. "Experience-dependent plasticity of layer 2/3 circuits in developing somatosensory neocortex." Research Showcase @ CMU, 2012. http://repository.cmu.edu/dissertations/121.
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Experience-dependent plasticity is the adaptability of brain circuits as a result of changes in neural activity, a phenomenon that has been proposed as the neural basis for important brain function in health and disease. The underlying mechanisms of experience-dependent plasticity can take different forms, depending on the organisms and brain areas under investigation. A better understanding of these mechanisms will help to interpret normal brain function as well as to guide therapies for neurological diseases. Mouse vibrissa system offers great experimental advantages to studying experience-dependent plasticity and the underlying molecular mechanisms at different levels.
Using sensory experience paradigms of unbalanced whisker activity, we find that sensory experience induces rapid synaptic strengthening at excitatory synapses converged onto single layer 2/3 pyramidal neurons, although the plasticity at these synapses displays remarkable input specificity. Furthermore, we discover that recently potentiated layer 4-2/3 excitatory synapses are labile and subject to activity-dependent weakening in vitro. Calcium-permeable AMPARs (CP-AMPARs) that are sometimes associated with synaptic strengthening are not essential for activity-induced synaptic weakening. Finally, we demonstrate that ongoing sensory experience triggers distinct phases of synaptic plasticity, which are tightly correlated with changes in NMDAR properties and function. Taken together, the results from this thesis show distinct manifestations and mechanisms of how sensory experience modulates synaptic properties and neuronal function that may provide insights into information processing and coding in the neocortex.
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Stump, Madeliene. "The role of brain PPAR[gamma] in regulation of energy balance and glucose homeostasis." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/6000.
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The Peroxisome Proliferator-Activated Receptor gamma (PPARγ), a master regulator of adipogenesis, has been shown to influence energy balance through its actions in the brain rather than in the adipose tissue alone. Deletion of PPARγ in mouse brain results in resistance to weight gain in response to high fat diet. Activation of PPARγ leads to change in the firing pattern of melanocortin system neurons (POMC and AgRP), which are critical for energy homeostasis. To determine the effects of modulation of brain PPARγ on food intake and energy expenditure we generated a novel transgenic mouse model in which a dominant-negative (DN) mutant form of PPARγ (P467L) or a wild type (WT) form that is conditionally expressed in either the entire central nervous system (CNS) or specifically in POMC or AgRP neurons. Interference with brain PPARγ results in impaired insulin and glucose regulation. This in turn has significant implications in altering the growth rate and metabolic homeostasis. In light of the well-established role of PPARγ in regulating insulin sensitivity, this is the first report implicating brain PPARγ in controlling peripheral insulin levels. Overexpression of the WT PPARγ in the CNS leads to failure to thrive and early death due to microcephaly and severe distortion of brain architecture with notable agenesis of the corpus callosum. Our results show that the levels of PPARγ in the brain are tightly regulated and perturbations leading to “too much” or “too little” functional PPARγ result in major shifts in structural organization of the brain or metabolic balance.
The herein presented data show that chronic interference with the function of neuronal PPARγ affects energy balance only under certain dietary conditions and through specific neuronal populations. We show that POMC, but not AgRP neurons, are particularly sensitive to modulation of PPARγ activity. These observations give support to the notion that cellular adaptations in POMC neurons, driven by PPARγ, represent critical components in the regulation of metabolic homeostasis.
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Wernett, Pamela Joy. "The effects of Med12 variation upon cell cycle progression and differential gene expression." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/2787.
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MED12 is an X– chromosome member of the Mediator complex that is a key regulator of tissue specific gene expression and moderates intracellular signaling via multiple developmental pathways. Sequence variation in the carboxy– terminus of MED12, which contains a PQL and Opa domain, is associated with X– linked mental retardation behavioral syndromes and schizophrenia. Unfortunately, the mechanism(s) through which sequence variation in the carboxy– terminus could alter vulnerability to neurodevelopmental and neuropsychiatric illnesses is yet unclear.
In order to elucidate a better understanding of this process, we examined the role of the MED12 carboxy– terminus in cell cycle and gene expression with a full– length overexpression construct, domain deleted overexpression constructs and RNA interference using a HEK293 cell model. Our results show that MED12 overexpression leads to G1 cell cycle exit, whereas deletion of the PQL domain and MED12 RNA interference results in cell cycle progression. Our data also show that MED12 expression level differentially affects early response antiviral gene expression and stress response mechanisms. These results are consistent with prior studies showing that MED12 has a key role in determining neuronal cell fate and with the theoretical understanding of the biological basis of psychosis. These results also lend further insight upon the pathways through which MED12 exerts its effects upon differentiation and disease pathogenesis, which may lead to new approaches to the treatment of MED12– related disorders.
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Lobas, Mark Albert. "Novel roles for y-Protocadherins in the choroid plexus." Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/5017.
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Γ-protocadherins (Γ-Pcdhs) are important for neuronal development and regular nervous system patterning. Much of this work is based on the assumption that this family of 22 cadherin-like adhesion molecules acts in the manner of Roger Sperry's hypothesized "molecular code", with homophilic adhesion allowing neurons to find their proper neuronal partners during development. Therefore, most research has focused on the expression and roles of these adhesion molecules in neurons and glia. Although these molecules have been almost exclusively studied in neurons, there is evidence that Γ-Pcdhs are also expressed and play important roles in other cells. The work done for this thesis focuses on the roles of Γ-Pcdhs in the choroid plexus (CP), a brain epithelial tissue that produces the cerebrospinal fluid, as well as potential roles in neuro-immune interactions.
The importance of the CP for proper nervous system development, maintenance, function, and neuro-immunosurveillance has largely been overlooked in the past. Prior to this research, the presence, let alone the function of Γ-Pcdhs in the CP was not documented. Here, we show that each epithelial cell of the CP expresses a subset of Γ-Pcdhs at high levels, and that restricted disruption of this gene family in the CP and in the adjacent ependymal epithelia of mice results in reduced cerebroventricular volume. Furthermore, we show that CP-restricted mutant mice have altered gene expression in the CP, including groups of genes associated with immune function and with TGFΒ signaling pathways, suggesting novel roles for the Γ-Pcdhs. Finally, we present preliminary data indicating that expression of the Γ-Pcdhs is up-regulated in the CP following an immune challenge (experimental autoimmune encephalomyelitis, a mouse model for multiple sclerosis) and that they are expressed in other non-neuronal tissues, which, like the CP, play roles in immunosurveillance.
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Alberico, Stephanie Lorraine. "Striatal neurons in the development of levodopa-induced dyskinesias in Parkinson’s disease." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5903.
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Levodopa-induced dyskinesias (LIDs) are abnormal involuntary movements that limit the effectiveness of treatments for Parkinson’s disease. Although dyskinesias involve the striatum, it is unclear how striatal neurons are involved in dyskinetic movements. Here we record from striatal neurons in mice during levodopa-induced axial dyskinesias. We developed an automated 3-dimensional motion tracking system to capture the development of axial dyskinesias at ~10 ms resolution, and correlated these movements with neuronal activity of striatal medium spiny neurons and fast spiking interneurons. The average firing rate of medium spiny neurons increased as axial dyskinesias developed, and both medium spiny neurons and fast spiking interneurons were modulated around axial dyskinesias. We also found that delta field potential power increased in the striatum with dyskinesia, and that this increased delta power coupled with striatal neurons.
Secondly, we studied the role of the two main types of dopamine receptors. We pharmacologically inhibited either the D1 or D2 receptors while recording from neuronal ensembles in the striatum and measuring LIDs in high temporal resolution. We found that inhibiting the D1, but not the D2, receptor led to a decrease in axial dyskinesias. Interestingly, both types of antagonist attenuated the strong modulation of MSNs around axial dyskinesias when compared to levodopa alone. These results suggest that LIDs are modulated through activity in D1-MSNs.
Lastly, we selectively targeted the D1 receptor expressing neurons (D1-MSNs) with optogenetics. With this technique, we can specifically activate or inhibit certain neuronal populations. We found that stimulating the D1-MSNs led to dyskinetic events only after levodopa priming. However, inhibiting these neurons was not sufficient to attenuate dyskinesias following levodopa administration. We also found that putative D1-MSNs are more strongly modulated around axial dyskinesias than other MSNs.
Together, our findings provide novel insight into how striatal networks change as LIDs develop, and suggest that increased medium spiny neuron firing, that D1-MSNs are strongly modulated around LIDs, and that D1-MSN activity is sufficient to drive dyskinesias. These data could help clarify the role of the striatum in the pathogenesis of dyskinesias in Parkinson’s disease.
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D'Alberto, Nicholas C. "Examining Inter- And Intra-Individual Differences In The Neurobiological Mechanisms Associated With Inhibitory Control." ScholarWorks @ UVM, 2018. https://scholarworks.uvm.edu/graddis/962.
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Adolescence is an ideal time to measure the development of the neural mechanisms associated with inhibitory control because this age period is marked by impulsive and risk taking behaviors. Maturational brain changes in the prefrontal cortex that are associated with the emergence of inhibitory control are thought to occur during this age. With knowledge of how this system develops, it may be possible to identify the development of disorders that arise from poor inhibitory control such as attention deficit hyperactivity disorder (ADHD) and substance use. The goal of the current dissertation is to examine the neurobiological correlates associated with individual differences in inhibitory ability, and examine the age-related changes in neurobiological mechanisms of inhibitory control. This report will be the first of its size (n = 538) to examine within-subject changes longitudinally over five years of adolescent development (age 14 to 19). Furthermore, we supplement the longitudinal data with findings from a split-brain patient on the lateralization of inhibitory control, and we explore a subtle nuance that may have large implications on how to best measure inhibition-related brain activity.
In the second chapter of the dissertation, we examine the lateralization of inhibitory control by measuring hemispheric differences in the ability to inhibit a motor response in a split-brain patient. Here, we found patient J.W.’s right hemisphere performed better than his left hemisphere on three different inhibitory control tasks. Interestingly, although inferior to the performance of the right hemisphere, the left hemisphere still performed relatively well on the three tasks, suggesting the left hemisphere can perform response inhibition independently.
The third chapter examines both the functional correlates of Stop Signal Task performance, and the age-related differences in the functional mechanisms of response inhibition. At age 14 and age 19, similar patterns of activation were associated with performance, however relatively little overall activity exhibited performance-related effects. Superior performance was associated with greater right inferior frontal gyrus (rIFG) activation, as well as greater activation in a set of regions potentially involved with a stimulus-detection and attention-orienting system. However, at age 14 performance was also negatively associated with default mode network activity, and at age 19 performance was also positively associated with left amygdala activity. In the absence of within-subject differences in performance between ages 14 to 19, there were significant decreases in functional activation associated with successful inhibition. The potential mechanisms by which activity decreases over time while performance remains stable are discussed.
The fourth chapter of the dissertation examines the effect of objective task difficulty on the magnitude of activation associated with successful inhibition. The Stop Signal Task employs an adaptive algorithm that alters task difficulty to meet participants’ abilities. Typically, when capturing functional activation associated with response inhibition, activation is extracted from all successful trials. Here, we find that individual differences in activation are expanded when using the activation from the extreme, rather than average, aspects of task performance variables. Individual differences in performance may best be captured by examining the maximum difficultly at which a participant is able to inhibit a response, rather than the average of all successful inhibitions. These results also lend support to the minimal activity associated with performance in Chapter 3, and we discuss how improving the measure of stop-related activity may help explain both inter- and intra-individual differences in inhibitory control.
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Williams, Brittany Nicole. "Characterization of the modulatory effects of alternative splicing on Cav1.4 Ca2+ channels." Diss., University of Iowa, 2019. https://ir.uiowa.edu/etd/6883.
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In synaptic terminals of retinal photoreceptors, Cav1.4 (L-type) Ca2+ channels mediate Ca2+ influx that promotes neurotransmitter release. Mutations in Cav1.4 are associated with multiple vision disorders including congenital stationary night blindness type 2(CSNB2). Cav1.4 undergoes weak Ca2+-dependent inactivation (CDI) – a negative feedback mechanism seen for other L-type channels (e.g., Cav1.2 and Cav1.3) mediated by calmodulin (CaM) binding to a consensus IQ domain in the proximal C-terminal domain (CT) of the pore-forming a1 subunit. The lack of CDI in Cav1.4 is due to a C-terminal automodulatory domain (CTM), located in the distal CT of Cav1.4. The CTM is thought to suppress CDI of Cav1.4 channels by competing with CaM binding to sites in the proximal CT. A CSNB2-causing mutation (K1591X) in Cav1.4 that deletes the CTM promotes CaM binding and CDI, but also causes channel activation at more negative potentials than full-length channels (Cav1.4FL).
We have identified a human-specific Cav1.4 splice variant that removes part of the CTM due to the deletion of exon 47 (Cav1.4Δex47). In electrophysiological recordings of transfected HEK 293T cells, we found that Cav1.4Δex47 channels undergo robust CDI and activates at more negative potentials, like K1591X. The presence of CDI and very negative activation thresholds in a naturally occurring variant of Cav1.4 are perplexing considering that these properties are expected to be maladaptive for visual signaling and result in night blindness in the case of K1591X. Here we show that Cav1.4Δex47 and K1591X exhibit fundamental differences in their regulation by CaM. In Cav1.4Δex47, CDI requires both the N-terminal (N lobe) and C-terminal (C lobe) lobes of CaM to bind Ca2+, whereas CDI in K1591X is driven mainly by Ca2+ binding to the C lobe. Moreover, the CaM N lobe causes a Ca2+-dependent enhancement of activation of Cav1.4Δex47 but not K1591X. We conclude that the residual CTM in Cav1.4Δex47 enables a form of CaM N lobe regulation of activation and CDI that is absent in K1591X. Interaction with the N lobe of CaM, which is more sensitive to global elevations in cytosolic Ca2+ than the C lobe, may allow Cav1.4Δex47 to be modulated by a wider range of synaptic Ca2+ concentrations than K1591X; this may distinguish the normal physiological function of Cav1.4Δex47 from the pathological consequences of K1591X.
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Keeler, Austin Byler. "Branching out by sticking together: elucidating mechanisms of gamma-protocadherin control of dendrite arborization." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/2230.
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Growth of a properly complex dendrite arbor is a vital step in neuronal differentiation and a prerequisite for normal neural circuit formation; likewise, overly dense or sparse dendrite arbors are a key feature of abnormal neural circuit formation and characteristic of many neurodevelopmental disorders. Thus, identifying factors involved in aberrant dendrite complexity and therefore aberrant circuit formation, are necessary to understanding these disorders. In my doctoral work I have elucidated both intracellular and extracellular aspects to the gamma-protocadherins (γ-Pcdhs) that regulate dendrite complexity.
Loss of the 22 γ-Pcdhs, adhesion molecules that interact homophilically and are expressed combinatorially in neurons and astrocytes, leads to aberrantly high activity of focal adhesion kinase (FAK) and reduced dendrite complexity in cortical neurons. Little is known, however, about how γ-Pcdh function is regulated by other factors. Here I show that PKC phosphorylates a serine residue situated within the shared γ-Pcdh C-terminus; PKC phosphorylation disrupts the γ-Pcdhs’ inhibition of FAK. Additionally, γ-Pcdh phosphorylation or a phosphomimetic mutant reduce dendritic arbors, while blocking γ-Pcdh phosphorylation increases dendrite complexity. Together, these data identify a novel intracellular mechanism through which γ-Pcdh control of a signaling pathway important for dendrite arborization is regulated.
Although specific interactions between diverse cell surface molecules are proposed to regulate circuit formation, the extent to which these promote dendrite growth and branching is unclear. Here, using transgenic mice to manipulate expression in vivo, I and my colleagues show that the complexity of a cortical neuron’s dendritic arbor is regulated by γ-Pcdh isoform matching with surrounding cells. Expression of the same single γ-Pcdh isoform leads to exuberant or minimal arbor complexity depending on matched expression of surrounding cells. Additionally, loss of γ-Pcdhs in astrocytes, or induced mis-matching between astrocytes and neurons, reduces dendrite complexity in a cell non-autonomous manner. Thus, these data support our proposal that γ-Pcdhs create a rare neuronal identity that, depending on the identities of surrounding cells, specifies the complexity of that neuron’s dendritic arbor.
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Croft, Katie Elizabeth. "Exploring the role of ventromedial prefrontal cortex in human social learning: a lesion study." Diss., University of Iowa, 2009. https://ir.uiowa.edu/etd/350.
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Converging evidence suggests a critical role for the ventromedial prefrontal cortex (vmPFC) in social cognition, but its specific contribution to various aspects of social cognition, including the acquisition and updating of complex social information, is not well understood or documented via a systematic experimental approach. The primary aim of this dissertation is to determine whether the vmPFC is necessary for the integration of complex social information in order to form normal moral and social judgments about people. In the first of two studies presented here, I examined the roles of the vmPFC and the hippocampus in updating one's moral judgment of others. I hypothesized that both the vmPFC and the hippocampus are critical--but in different ways--for updating character judgments in light of new social and moral information. To test this hypothesis, I used a novel moral "updating" task and compared the performances of patients with bilateral vmPFC damage to patients with bilateral hippocampal damage (HC), and brain-damaged comparison (BDC) patients. The results suggest that the vmPFC may attribute emotional salience to moral information, whereas the hippocampus may provide necessary contextual information from which to make appropriate character judgments. In the second study, I specifically examined whether the vmPFC is necessary for the integration of simple versus complex, and social versus nonsocial information in order to form normal judgments about people. I hypothesized that patients with circumscribed damage to the vmPFC would be impaired in integrating complex social information. To test this prediction, I employed a novel decision making task and compared the performances of vmPFC patients with BDC patients, and a group of normal, healthy individuals. I also explored which anatomical sectors within the vmPFC system are responsible for normal social information integration. Going against my predictions, most participants were better at making the best choice when more information was available. On the whole, all groups were more accurate in choosing the best nonsocial choice versus the social choice, and this is attributed to the fact that the nonsocial trials were much easier for the participants. Overall, vmPFC patients were inferior to the other groups in choosing the best option for both the social and nonsocial conditions, which suggests that vmPFC patients may have a general impairment in integrating information. The subjective ratings data revealed that the vmPFC patients: perceived the choices to be more difficult overall, had difficulty discriminating between the best and worse options, did not provide the same subjective influence weights as the comparison groups, and endorsed social choices being overall more difficult than nonsocial choices. The neuroanatomical data revealed that unilateral left vmPFC damage may have contributed the most to impairment in making the correct choice for the social condition, and overall, left hemisphere vmPFC lesion volume correlated negatively with percentage correct on my experimental task.
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Thomas, Jessica René. "Elucidating the molecular and biophysical determinants that suppress Ca2+-dependent facilitation of Cav2.2 Ca2+ channels." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6307.
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Cav2.2 channels are presynaptic voltage-gated Ca2+ channels that regulate neurotransmitter release. In addition, they are major therapeutic targets from neuropathic pain, a chronic pain disorder caused by injury to the nerve. Pain-relieving drugs such as opioids and ziconotide block Cav2.2 channels. Unfortunately, these drugs are associated with severe adverse side effects. Therefore, there is a need to understand the factors that regulate Cav2.2 channels to design more effective therapies. My dissertation uses electrophysiological techniques to understand the factors that regulate Cav2.2 channel function. My research will provide insights into how Cav2.2 channels integrate diverse cellular signals to shape neurotransmission. This knowledge can be used to treat neurological disorders, such as chronic pain and Myoclonus- Dystonia syndrome, a movement disorder associated with a mutation in the gene that encodes Cav2.2.
A variety of regulatory mechanisms modulate Ca2+ entry through Cav2.2 channels. One prominent from of regulation is Ca2+-dependent inactivation, a negative feedback mechanism. Incoming Ca2+ ions bind to the Ca2+ sensor calmodulin, which is tethered to the channel. The interaction between Ca2+ and calmodulin is thought to induce a conformational change in the structure of Cav2.2 to reduce further Ca2+ entry. The related voltage-gated Ca2+ channel Cav2.1 undergoes an additional and opposing form of regulation, Ca2+-dependent facilitation, which enhances Ca2+ entry. Ca2+-dependent inactivation and facilitation of Cav2.1 can adjust the amount of neurotransmitter released at a synapse in ways that modify information processing in the nervous system. Unlike Cav2.1, Cav2.2 does not undergo Ca2+-dependent facilitation, but the mechanism underlying this difference is unknown.
One possibility is that Cav2.2 channels do not contain the molecular components necessary to support Ca2+-dependent facilitation, which have been identified in Cav2.1 in previous studies. I hypothesized that the analogous regions of Cav2.2 contain slight modifications, which prevents Ca2+-dependent facilitation. In support of this hypothesis, I found that Cav2.2 channels can undergo Ca2+-dependent facilitation upon transferring portions of the C-terminal domain of Cav2.1 to Cav2.2. A second possibility is that Cav2.2 undergoes other forms of regulation that oppose Ca2+-dependent facilitation. Cav2.2 is strongly inhibited by ligands for some G protein-coupled receptors, which helps prevent excess release of neurotransmitters in the nervous system. I hypothesized that strong G protein modulation of Cav2.2 opposes Ca2+-dependent facilitation. I found that Cav2.2 channels could undergo a form of Ca2+-dependent facilitation upon inhibiting G-protein signaling, which supported my hypothesis.
Taken together, my results demonstrate that multiple factors contribute the lack of Ca2+-dependent facilitation observed for Cav2.2 channels. My results provide new insights into the intrinsic and extrinsic forces that regulate Cav2.2 function, which expands our understanding of how Cav2.2-mediated Ca2+ signals can modified by normal patterns of neuronal activity. This knowledge will aid our understanding of the pathogenic mechanisms underlying neurological conditions associated with Cav2.2 dysfunction and how to treat them.
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Garrett, Andrew. "Control of synaptogenesis and dendritic arborization by the γ-Protocadherin family of adhesion molecules". Diss., University of Iowa, 2009. https://ir.uiowa.edu/etd/362.
Full textAbstract:
During development, the mammalian nervous system wires into a precise network of unrivaled complexity. The formation of this network is regulated by an assortment of molecular cues, both secreted molecules and cell-surface proteins. The ã-Protocadherins (ã-Pcdhs) are particularly good candidates for involvement in these processes. This family of adhesion molecules consists of 22 members, each with diverse extracellular adhesive domains and shared cytoplasmic domains. Thus, cellular interactions with varied adhesive partners can trigger common cytoplasmic responses. Here we investigated the functions of the ã-Pcdhs in two processes involved in neural network formation: dendrite arborization and synaptogenesis.
We first asked how ã-Pcdhs regulate synaptogenesis in the spinal cord. We found that the ã-Pcdhs are differentially expressed by astrocytes as well as neurons. In astrocytes, the proteins localize to perisynaptic processes where they can mediate contacts between neurons and astrocytes. In an in vitro co-culture system in which either only astrocytes or only neurons were null for the ã-Pcdhs, we found that astrocytic ã-Pcdh is required for an early stage of synaptogenesis in a contact-dependent manner, while neuronal ã-Pcdh is sufficient for later stages. Conversely, if neurons lacked the adhesion molecules, very few synaptic contacts formed at all. By deleting the ã-Pcdhs from astrocytes in vivo, we demonstrated that these contacts are required for the normal progression of synaptogenesis.
We also investigated the function of the ã-Pcdhs in the cerebral cortex. We found that cortical-restricted loss of the adhesion molecules resulted in a severe reduction in thickness of layer 1. By crossing the mutant mice to a line in which scattered layer 5 neurons express YFP, we saw that this thinning resulted from a reduced complexity in the apical tufts of dendrites from layer 5 neurons. Sholl analysis demonstrated that the arbor reduction existed throughout the cell, a phenotype that was recapitulated in vitro. Using the in vitro system, we found that the arborization defect was caused by hyperphosphorylation of the PKC substrate, MARCKS, indicating that the ã-Pcdhs may function by inhibiting PKC activity. Thus, we provide new information about the mechanisms through which the ã-Pcdhs influence neural network development.
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Johnson, Shane Benjamin. "An analysis of prefrontal cortex pathways and their assembly of stress coping responses." Diss., University of Iowa, 2019. https://ir.uiowa.edu/etd/6965.
Full textAbstract:
Stress is characterized by the deployment of response systems to promote adaptation in the face of threats. Among these, the neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis has received considerable attention due to the potent acute and chronic effects of its glucocorticoid end-products, including cortisol in humans and corticosterone (CORT) in rodents. Stress also simultaneously elicits conserved behavioral responses that may be key to understanding how animals and humans cope with ongoing threats. Both neuroendocrine and behavioral responses to psychological stress are thought to originate from, and are modulated by, complex neurocircuitry residing within the limbic forebrain. However, to date these responses have largely been studied in functional and neuroanatomical isolation. The experiments here described are intended to shed light on the circuitry underlying the dual modulation of behavioral and HPA output.
Chapter 2 investigates a pathway from the prelimbic subfield (PL) of the medial prefrontal cortex (mPFC) to the anteroventral bed nuclei of the stria terminalis (avBST). Using an optogenetic approach, we found that this pathway simultaneously suppresses both immobility behavior and HPA output during an acute psychological stressor (tail suspension, TS). We go on to show that this pathway also suppresses behavioral passivity in the shock probe defensive burying test (SPDB), a test of coping behavior. Furthermore, endogenous activity in this pathway, as measured by Fos immunoreactivity in avBST–projecting PL neurons, was negatively correlated with passive coping behavior in the SPDB. Follow-up experiments found that PL axonal terminals within avBST were glutamatergic and photoexcitation of these terminals produced excitatory post-synaptic potentials in avBST neurons. Next, a downstream pathway from avBST to the ventrolateral periaqueductal gray (vlPAG) was investigated as a candidate mediator of the observed effects on passive coping. Photoinhibition of avBST terminals in vlPAG recapitulated the effects of PL–avBST photoinhibition. Finally, avBST terminals within vlPAG were found to be GABAergic, consistent with a role for avBST inputs in inhibiting passive coping-related activity in this region.
Chapter 3 expands on the role of avBST and its output pathways in modulating behavioral and neuroendocrine stress responses. Photoinhibition of avBST cell bodies during TS produced a marked increase in both immobility and HPA output while photoexcitation was sufficient to suppress the neuroendocrine stress axis. Follow-up studies found that the HPA-modulatory effects of avBST cell body manipulations were likely mediated by direct avBST inputs to the paraventricular nucleus of the hypothalamus (PVH). We found that avBST terminals within PVH terminated in close proximity to putatively neurosecretory corticotropin releasing factor (CRF)-immunoreactive neurons. Photoinhibition of avBST terminals in PVH during TS produced elevations in HPA output that were comparable to those observed follow avBST cell body inhibition. Finally, photoinhibition of avBST terminals in vlPAG was associated with increased immobility during both TS and acute exposure to the forced swim test, consistent with a role for this pathway in suppressing passive behaviors across a variety of behavioral tests.
Chapter 4 studies parallel pathways from mPFC to distinct cell columns within the periaqueductal gray (PAG). The PAG is a highly conserved region of the midbrain that surrounds the cerebral aqueduct and has been implicated in the regulation of defensive behaviors. Prior work suggests that ventrolateral aspects of the structure promote passive defensive behaviors (e.g., freezing and immobility), whereas activation of the dorsal (d) cell column produces active behavior (threat confrontation or flight). In these experiments, we again utilized the SPDB; rats are exposed to an electrified probe mounted on their cage wall, whereby after receiving electric shock, they display both active (probe burying with cage bedding) and passive (immobility) coping behavior. Consistent with previous reports, we found that rostral mPFC provided dense innervation of ventrolateral PAG, whereas caudal mPFC provided innervation of dorsal PAG. Using an optogenetic approach we found that photoinhibition enhanced, and photoexcitation of the rostral mPFC–ventrolateral PAG pathway diminished passive coping during the SPDB, but active coping behavior was unaffected. Next, we investigated the contributions of the caudal mPFC–dorsal PAG pathway during the SPDB. Here, pathway photoexcitation enhanced probe burying behavior, the primary measure of active coping, while other behaviors remained unaffected. This result suggested that activation of a single pathway was sufficient to drive active coping. Finally, we tested the effects of caudal mPFC–dorsal PAG pathway photoexcitation under conditions where active coping behavior is prohibited, by removal of the cage bedding to prevent rats from the ability to bury the shock probe. In control animals acutely deprived of bedding during the SPDB, we observed increased immobility behavior and ultrasonic vocalizations, as well as autonomic and HPA output, while each of these were decreased in bedding-deprived animals that received caudal mPFC–dPAG pathway photoexcitation. This final series of experiments implicate separate prefrontal-PAG pathways in either the suppression of passive, or promotion of active coping behavior. They further suggest that the caudal mPFC-dorsal PAG pathway provides a neural basis linking active coping with stress-buffering effects, marked by decreases in displacement behavior and neuroendocrine activation.
These results show that separate pathways from the medial prefrontal cortex to the bed nuclei of the stria terminalis and periaqueductal gray are simultaneously and differentially able modulate passive and active coping in response to aversive stimuli in rats. The prefrontal–avBST pathway coordinates the inhibition of something akin to a “passive response set” – i.e., by gating passive coping behavior and restraining neuroendocrine activation. Complementary, parallel prefrontal–periaqueductal gray pathways are able to independently support either the suppression of passive, or promotion of active coping behavior. The discussion will consider the naturalistic contexts accounting for how activity in mPFC may provide for the cooperative engagement of an active behavioral response set, and how differentially engaging these pathways may promote distinct adaptative strategies as based upon changing environmental conditions. Finally, we will consider how these data offer a neural basis linking active coping with stress-buffering effects, and how perturbations in these circuits may lead to chronic stress-related dysfunction of multiple systems and inform disease susceptibility in humans.