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1
Tsao, Jack W. "Wallerian degeneration in normal mice and in mutant C57BL/Wld mice." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260174.
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Liu, Hern Choon Eugene. "The central nervous system effects of nocistatin : behavioral effects in mice." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611850.
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Andersson, Sandra. "Nuclear receptor functions in the central nervous system clues for knockout mice /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-661-1/.
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Simpson, Matthew Thomas W. "Caspace-3 deficiency rescues peripheral nervous system defect in pRb nullizygous mice." Thesis, University of Ottawa (Canada), 2002. http://hdl.handle.net/10393/6297.
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The retinoblastoma tumour suppressor protein, pRb, is a key regulator of cell cycle and has been implicated in the terminal differentiation of neuronal cells. Mice nullizygous for pRb die by E14.5 from haematopoietic and neurological defects attributed to failed differentiation (Jacks et al., 1992; Lee et al., 1992; Clarke et al., 1992). Previous studies by Macleod et al., (1996) have demonstrated that the loss of p53 protects pRb-deficient central nervous system (CNS) neurons but not peripheral nervous system (PNS) neurons from cell death. Thus, the mechanisms by which PNS neurons undergo apoptosis in response to pRb deficiency remain unknown. In view of the pivotal role of caspase-3 in the regulation of neuronal apoptosis during development, we examined its function in the execution of the widespread neuronal cell death induced by pRb deficiency. Our results support a number of conclusions: First, we show that caspase-3 becomes activated in all neuronal populations undergoing apoptosis. Second, caspase-3 deficiency does not extend the life span of pRb null embryos, as double null mutants exhibit high rates of liver apoptosis resulting in erythropoietic failure. Third, pRb/caspase-3 double mutant neurons of the CNS exhibit widespread apoptosis similar to that seen in pRb mutants alone, thus caspase-3 deficiency does not protect this population from apoptosis. Finally, in contrast to the CNS, neurons of the PNS including those comprising the trigeminal ganglia (TG) and the dorsal root ganglia (DRG) are protected from apoptosis in pRb/caspase-3 double mutant embryos. Examination of the mechanistic differences between these two cell types revealed that CNS neurons invoke compensatory caspase activity that is not found in PNS neurons. These findings suggest that PNS neurons are dependent upon caspase-3 for the execution of apoptosis and that caspase-3 may serve as a key therapeutic target for neuroprotection following injury of this cell type.
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Lamprianou, Smaragda. "Biological role of nervous system tyrosine phosphatases revealed by analysis of KO mice." Paris 6, 2007. http://www.theses.fr/2007PA066107.
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Le but de ma thèse a été de déterminer le rôle biologique des récepteurs tyrosine phosphatases, -RPTPzeta, et RPTPgamma,- dans le système nerveux, par l’utilisation de souris knockout. Alors que notre laboratoire a précédemment mis en évidence le rôle de RPTP dans la réparation et la myélinisation lors de lésions, nous avons démontré qu’une des formes solubles de RPTP inhibe la prolifération des oligodendrocytes précurseurs. De plus, nous avons déterminé un rôle de RPTP dans la croissance axonale en agissant sur la voie de signalisation des neurégulines. Des souris exprimant le gène rapporteur de la -galactosidase sous le contrôle du promoteur de RPTP nous ont permises de localiser RPTP essentiellement dans les neurones pyramidaux et dans tous les organes sensoriels. L’étude du comportement des souris déficientes pour RPTP a révélé un rôle de RPTP dans des fonctions motrices et sensorielles. Nos résultats démontrent des profils d’expression complémentaires de RPTP et RPTP.
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Marsicano, Giovanni. "Physiological role of the cannabinoid receptor 1 (CB1) in the murine central nervous system." n.p, 2000. http://ethos.bl.uk/.
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邱大安 and Tai-on Yau. "Regulation of the mouse hoxb-3 gene in the neural expression domains during embryogenesis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31242601.
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Lee, King-yiu. "The Ret gene in the enteric nervous system expression analysis and generation of ret deficient mice /." Click to view the E-thesis via HKUTO, 2004. http://sunzi.lib.hku.hk/hkuto/record/B31449669.
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Stromnes, Ingunn Margarete. "T cell determinants of central nervous system autoimmune disease /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8333.
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Lee, King-yiu, and 李景耀. "The Ret gene in the enteric nervous system: expression analysis and generation of ret deficient mice." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B31449669.
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Ho, Wing-lau, and 何穎流. "Investigating neurodegeneration in the retina of tau P301L mice." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B4833392X.
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Neurodegeneration is a collective term for the progressive loss of structure, function or even death of neurons. This includes diseases like Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease and motor neuron disease. Recent researches have shown great interest in the role of tau proteins, which have versatile functions including microtubule stabilization and signal relay in the central nervous system.
Retina and optic nerve, being part of the central nervous system, can also be affected by similar processes. In neurodegenerative diseases visual disturbances including difficulties in reading and finding object, depth perception, perceiving structure from motion, color recognition and impairment in spatial contrast sensitivity have all been observed. Some of these defects may be attributed to changes at ocular level.
The effect of tau mutation was investigated in this study utilizing a transgenic P301L tau mice model. Morphometric analysis has been utilized to quatify the neurodegenerative changes, including the thickness of inner nuclear layer(INL), density of retinal ganglion cells(RGCs) and size of RGCs. Retinal sections stained by hematoxylin and eosin(H&E) were analyzed. Comparisons were made between the P301L tau mice and the control mice in addition to comparisons between different age groups.
The study found that there was a significant decrease of thickness of INL of P301L tau mice when compared with control mice. The effect was more pronounced in the peripheral area and the effect increased with age. Regarding density of RGCs, P301L tau mice showed a similar age-related decline as control mice. And regarding the size of RGCs, the RGCs from P301L tau mice increased in size with age and the RGCs from control mice decreased in size with age.published_or_final_version
Anatomy
Master
Master of Medical Sciences
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羅慧詩 and Wai-sze Law. "Conditional knockout of neural cell adhesion molecule L1 in mouse brain." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B42575266.
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Law, Wai-sze. "Conditional knockout of neural cell adhesion molecule L1 in mouse brain." Click to view the E-thesis via HKUTO, 2000. http://sunzi.lib.hku.hk/hkuto/record/B42575266.
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Tanaka, Hisataka. "Conduction properties of identified neural pathways in the central nervous system of mice in vivo." Kyoto University, 2004. http://hdl.handle.net/2433/145280.
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Kyoto University (京都大学)0048
新制・課程博士
博士(医学)
甲第11099号
医博第2779号
新制||医||877(附属図書館)
22649
UT51-2004-L896
京都大学大学院医学研究科脳統御医科学系専攻
(主査)教授 大森 治紀, 教授 金子 武嗣, 教授 橋本 信夫
学位規則第4条第1項該当
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Colbert, Crystal. "Functional Neural Toxicity and Endocrine Responses in Mice Following Naphthalene Exposure." Thesis, University of North Texas, 2010. https://digital.library.unt.edu/ark:/67531/metadc31529/.
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Polycyclic aromatic hydrocarbons (PAHs) are a well studied and diverse class of environmental toxicants. PAHs act via the aryl hydrocarbon receptor (AhR), and studies have suggested that PAHs may elicit neurological and estrogenic effects. Doses of PAHs between 50 to 150 ppm may elicit neurotoxicity in rodent models. The present study investigated the effects of naphthalene on in vivo steroidogenesis in Swiss Webster male mice, and in vitro neural function of Balb-C/ICR mice frontal cortex neurons. These data suggest that naphthalene may not elicit steroidogenic effects at concentrations ranging from 0.2 to 25 mg/kg/day, following a 7 day subcutaneous dosing regime. In addition, naphthalene may cause functional toxicity of frontal cortex neurons at concentrations of 32 to 160 ppm naphthalene.
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Hillard, Kynlee, Matthew Zahner, David Kyle Mounger, Brooke Tipton, and Grayson Jo White. "The effect of leptin on metabolic- and cardiovascular-related pre-sympathetic hypothalamic neurons in mice." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/11.
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Obesity has risen 75% in the United States since 1980 and an estimated 80 million American adults are considered obese. Obesity activates the sympathetic nervous system and is associated with neurogenic hypertension. Leptin is an obesity-related neuropeptide released from fat cells which reduces appetite and increases metabolism. Leptin activates metabolic and cardiovascular responsive pre‑sympathetic neurons within the hypothalamus. Although leptin increases metabolism and curbs appetite, it also increases blood pressure. Considering that one main goal of obesity treatments is to diminish the cardiovascular-related co-morbidities this is an unacceptable side effect for potential treatments. Thus, a better understanding of the role hypothalamic sites involved in obesity-related hypertension is necessary for successful treatments. Our hypothesis is that leptin activates hypothalamic neurons that control metabolic (raphe pallidus) and cardiovascular activity (RVLM, rostroventrolateral medulla) within the brainstem. To test our hypothesis we created a line of transgenic mice using the cre-lox recombination system to express the reporter gene tdTomato under the control of the leptin (ObRb) receptor gene. First, we performed a behavioral study to verify the physiological effect and optimal dose of daily leptin treatment. To do this we implanted mini-osmotic pumps for continuous subcutaneous leptin (400 ng/hr) administration and measured food intake and body weight over 4 weeks. To determine if leptin activates pre‑sympathetic hypothalamic neurons we performed neuroanatomical tracer studies in these mice. At the end of the 4-week period, we injected fluorescent retrograde tracers into the raphe pallidus (green, metabolic center) and RVLM (magenta, cardiovascular). We then performed fluorescence immunohistochemical labelling to identify leptin-induced neuronal activation cFos a marker of neuronal activation of these neurons. Data from this behavioral, neurophysiological and neuroanatomical study will provide a better understanding of the role of the hypothalamus in controlling blood pressure and metabolism in obesity. Information from this study will provide groundwork for a better understanding of central autonomic mechanisms of cardiovascular risk as well as risk introduced by drugs intended to treat obesity.
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Hullmann, Maja [Verfasser]. "Evaluation of the effects of inhaled nanoparticles on the central nervous system of mice / Maja Hullmann." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2013. http://d-nb.info/1030365237/34.
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Ross, Shelley 1973. "Generation and characterization of mice lacking the α4 nicotinic receptor subunit." Monash University, Dept. of Medicine, 2001. http://arrow.monash.edu.au/hdl/1959.1/9180.
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Chan, Yuk-yee. "Tissue-specific expression of cre recombinase in the developing enteric nervous system of a Hoxb3/cre transgenic mouse strain." Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B2510116x.
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Chen, Yuk-shan. "Tissue specific expression studies on a vagal neural crest enhancer element of the mouse Hoxb3 gene in the development of the enteric nervous system /." Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk:8888/cgi-bin/hkuto%5Ftoc%5Fpdf?B23424564.
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Yung, Kin-lam Ken. "Quantification of neuropeptides in the central nervous system of the wobbler mouse during the progression of the motor neuron disease : a study by radioimmunoassay and immunocytochemistry /." [Hong Kong : University of Hong Kong], 1992. http://sunzi.lib.hku.hk/hkuto/record.jsp?B1320502X.
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陳玉儀 and Yuk-yee Chan. "Tissue-specific expression of cre recombinase in the developing enteric nervous system of a Hoxb3/cre transgenic mouse strain." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31970400.
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Gautam, Dinesh Chandra. "Analysis of insulin receptor function in the central nervous system by conditional inactivation of its gene in mice." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=96492353X.
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Li, Yuanfang [Verfasser], and Sabine [Akademischer Betreuer] Steffens. "Arterial wall immunity in hyperlipidemic mice is regulated by the sympathetic nervous system / Yuanfang Li ; Betreuer: Sabine Steffens." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1227840055/34.
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Bolton, Hall Amanda Nicholle. "HISTOLOGICAL AND BEHAVIORAL CONSEQUENCES OF REPEATED MILD TRAUMATIC BRAIN INJURY IN MICE." UKnowledge, 2016. http://uknowledge.uky.edu/physiology_etds/26.
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The majority of the estimated three million traumatic brain injuries that occur each year are classified as “mild” and do not require surgical intervention. However, debilitating symptoms such as difficulties focusing on tasks, anxiety, depression, and visual deficits can persist chronically after a mild traumatic brain injury (TBI) even if an individual appears “fine”. These symptoms have been observed to worsen or be prolonged when an individual has suffered multiple mild TBIs. To test the hypothesis that increasing the amount of time between head injuries can reduce the histopathological and behavioral consequences of repeated mild TBI, a mouse model of closed head injury (CHI) was developed. A pneumatically controlled device with a silicone tip was used to deliver a diffuse, midline impact directly onto the mouse skull. A 2.0mm intended depth of injury caused a brief period of apnea and increased righting reflex response with minimal astrogliosis and axonal injury bilaterally in the entorhinal cortex, optic tract, and cerebellum.
When five CHIs were repeated at 24h inter-injury intervals, astrogliosis was exacerbated acutely in the hippocampus and entorhinal cortex compared to a single mild TBI. Additionally, in the entorhinal cortex, hemorrhagic lesions developed along with increased neurodegeneration and microgliosis. Axonal injury was observed bilaterally in the white matter tracts of the cerebellum and brainstem. When the inter-injury interval was extended to 48h, the extent of inflammation and cell death was similar to that caused by a single CHI suggesting that, in our mouse model, extending the inter-injury interval from 24h to 48h reduced the acute effects of repeated head injuries.
The behavioral consequences of repeated CHI at 24h or 48h inter-injury intervals were evaluated in a ten week longitudinal study followed by histological analyses. Five CHI repeated at 24h inter-injury intervals produced motor and cognitive deficits that persisted throughout the ten week study period. Based upon histological analyses, the acute inflammation, axonal injury, and cell death observed acutely in the entorhinal cortex had resolved by ten weeks after injury. However, axonal degeneration and gliosis were present in the optic tract, optic nerve, and corticospinal tract. Extending the inter-injury interval to 48h did not significantly reduce motor and cognitive deficits, nor did it protect against chronic microgliosis and neurodegeneration in the visual pathway. Together these data suggested that some white matter areas may be more susceptible to our model of repeated mild TBI causing persistent neuropathology and behavioral deficits which were not substantially reduced with a 48h inter-injury interval.
In many forms of TBI, microgliosis persists chronically and is believed to contribute to the cascade of neurodegeneration. To test the hypothesis that post-traumatic microgliosis contributes to mild TBI-related neuropathology, mice deficient in the growth factor progranulin (Grn-/-) received repeated CHI and were compared to wildtype, C57BL/6 mice. Penetrating head injury was previously reported to amplify the acute microglial response in Grn-/- mice. In our studies, repeated CHI induced an increased microglial response in Grn-/- mice compared to C57BL/6 mice at 48h, 7d, and 7mo after injury. However, no differences were observed between Grn-/- and WT mice with respect to their behavioral responses or amount of axonal injury or ongoing neurodegeneration at 7 months despite the robust differences in microgliosis. Dietary administration of ibuprofen initiated after the first injury reduced microglial activation within the optic tract of WT mice 7d after repeated mild TBI. However, a two week ibuprofen treatment regimen failed to affect the extent of behavioral dysfunction over 7mo or decrease chronic neurodegeneration, axon loss, or microgliosis in brain-injured Grn-.- mice when compared to standard diet.
Together these studies underscore that mild TBIs, when repeated, can result in long lasting behavioral deficits accompanied by neurodegeneration within vulnerable brain regions. Our studies on the time interval between repeated head injuries suggest that a 48h inter-injury interval is within the window of mouse brain vulnerability to chronic motor and cognitive dysfunction and white matter injury. Data from our microglia modulation studies suggest that a chronically heightened microglial response following repeated mild TBI in progranulin deficient mice does not worsen chronic behavioral dysfunction or neurodegeneration. In addition, a two week ibuprofen treatment is not effective in reducing the microglial response, chronic behavioral dysfunction, or chronic neurodegeneration in progranulin deficient mice. Our data suggests that microglia are not a favorable target for the treatment of TBI.
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陳玉珊 and Yuk-shan Chen. "Tissue specific expression studies on a vagal neural crest enhancer element of the mouse Hoxb3 gene in the development of the entericnervous system." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31224088.
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Bovenkamp, Diane Elizabeth. "Eph receptor tyrosine kinases, nervous system development and angiogenesis, cloning and characterization of Eph receptors from zebrafish and mice." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0021/NQ54056.pdf.
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Chaube, Sanjay. "Ubiquitin Expression in the Lumbar Spinal Cord Motoneurons of Postnatal Mice-- an Immunohistochemical Study." Thesis, University of North Texas, 1994. https://digital.library.unt.edu/ark:/67531/metadc332620/.
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Maturation of spinal motoneurons in rodents is characterized by a period of cell loss in the embryo, but researchers have claimed that some cell death occurs postnatally. This form of cell death is called apoptosis and involves active participation of the cell. Apoptotic cells have certain recognizable morphological and molecular features. I have used a monoclonal antibody against ubiquitin, (a putative marker of apoptotic cells), to do immunochemistry on mouse spinal cords at various postnatal ages till early adulthood. Staining is seen in large amotoneurons in the ventral horn. Staining is intense till P28, and faint thereafter. Substantial proportions of motoneurons stain till P21, followed by a sharp decline in the number of immunopositive cells. None of the cells exhibit signs of apoptosis.
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Lowe-Chatham, Janice E. (Janice Elaine). "Effects of 5-hydroxytryptamine on Mouse Lumbar Motor Activity During Postnatal Development." Thesis, University of North Texas, 1998. https://digital.library.unt.edu/ark:/67531/metadc277784/.
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The lumbar motor activity in isolated spinal cords of 72 postnatal Balb/C mice aged 2, 5, 10 and 21 days (PN2-21) was electroneurographically recorded (ENG) via bilateral ventral roots following treatment with three different concentrations (25, 100 and 200 pM) of the neurotransmitter, 5-hydroxytryptamine (5-HT), i.e., serotonin, to determine its effects on spinal pattern generation.
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Brabb, Thea. "The fate of MBP-specific T cells in MBP TCR transgenic mice /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/10853.
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Molina, Leandro. "Efeitos do treinamento e destreinamento físico sobre a manuntenção da memória e funcionamento do sistema colinérgico central de camundongos." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-16062014-095759/.
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A formação da memória envolve aprendizagem, consolidação e recuperação de informações e seus processos envolvem circuitos neuronais do córtex, hipocampo e amígdala. A formação da memória de longa duração ocorre a partir da formação da LTP \'\'long term potentiation\'\' que é modulada por diversos sistemas de neurotransmissores, entre eles o sistema colinérgico. Sabe-se que a atividade física aumenta a produção de neurotrofinas levando à melhora de estados patológicos, aumenta a densidade de receptores nicotínicos alfa7 em células do hipocampo. Já foi relatado que o destreinamento por duas semanas leva à reversão dos efeitos benéficos cardiovasculares. Esse projeto avalia os efeitos do treinamento e do destreinamento físico em piscina, sobre a manutenção da memória de longa duração de camundongos fêmeas por determinação da densidade de receptores nicotínicos alfa7 e da neurotrofina BDNF,na região do hipocampo, que não demonstrou diferença significativa entre os grupos avaliados no trabalho.The processes of memory formation involves learning, consolidation and retrieval of information and processes involving neuronal circuits in the cortex, hippocampus and amygdala. The formation of long term memory occurs through the formation of LTP - \"long term potentiation\" that is modulated by multiple neurotransmitter systems, including the cholinergic system. It is known that physical activity increases the production of neurotrophins leading to an improvement of pathological conditions, increases the density of nicotinic receptors on hippocampal cells alfa7. It has been reported that for two weeks detraining leads to the reversion of beneficial cardiovascular effects. This project evaluates the effects of physical training and detraining on swimming on the maintenance of long-term memory of female mice by determining the density of nicotinic receptors alfa7 and neurotrophin BDNF in hippocampus, than showed no significant differences among the groups at work.
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Cambon, Karine. "Influence of ApoE polymorphism on synaptic morphometry during aging in the dentate gyrus of ApoE knockout and human ApoE transgenic mice." Thesis, [n.p.], 2000. http://oro.open.ac.uk/19118/.
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Shewale, Swapnil Vijay. "LOW DOSE NERVE AGENT SARIN CAUSES DILATED CARDIOMYOPATHY AND AUTONOMIC IMBALANCE IN MICE." Wright State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=wright1316090377.
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翁建霖 and Kin-lam Ken Yung. "Quantification of neuropeptides in the central nervous system of the wobbler mouse during the progression of the motor neuron disease: a study by radioimmunoassay andimmunocytochemistry." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1992. http://hub.hku.hk/bib/B31210673.
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Coiculescu, Olivia Elena. "Mouse cortical cholinergic neurons: Ontogeny of phenotypes in vivo and in vitro." Thesis, University of North Texas, 2005. https://digital.library.unt.edu/ark:/67531/metadc4890/.
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The development of cholinergic neurons in mouse frontal cortex was studied both in vivo and in vitro by immunocytochemistry with an antibody to choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine synthesis. While cortical cholinergic neurons have previously been characterized in rat cortex, up until very recently, intrinsic cortical cholinergic neurons were considered to be absent in mouse, and little is known about their development or phenotypic characteristics. The present study found no ChAT-positive neurons in mouse frontal cortex on postnatal day 0 (P0, the day of birth). On P7 there were few, faintly stained, ChAT-positive neurons. The numerical density of ChAT-positive neurons increased substantially with age, from none on P0, to 9.2 + 1.4 on P7, to 14.8 + 0.9 on P16, and 41.6 + 3.9 in adulthood. Considering that the numerical density of total neurons decreases during this postnatal period, the data represent a marked developmental increase in the percentage of cholinergic neurons. The development of cholinergic neurons showed very similar timelines in rat and mouse frontal cortex. Cultures prepared from mouse frontal cortex on embryonic day 16 were maintained for 25, 76, or 100 days in vitro (div). The percentage of ChAT-positive neurons was considerably higher than in vivo, ranging from a mean 28% to 31% across the three age (div) groups. With increasing age of the cultures, the numerical density of total neurons and ChAT-positive neurons decreased while the percentage of ChAT-positive neurons did not change significantly. These observations suggest some temporal stability in the cultures. Using dual immunofluorescence, ChAT-positive neurons were tested for colocalization with GAD or TH. The majority of ChAT-positive neurons colocalized with GAD, both in vitro and in vivo. However, ChAT did not colocalize with TH, either in vitro or in vivo. Our comparison of intact frontal cortex and cultures suggest that while the percentage of cholinergic neurons was greater in the cultures, the cholinergic neurons developed phenotypic similarities in vitro and in vivo.
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Fridman, Leticia. "Histopathological Characterization of the Dystrophic Phenotype and Development of Therapeutic Candidates for a Gene Therapy Pre-Clinical Study in Dysferlin Deficient Mice." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/881.
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Dysferlin deficient muscular dystrophy is a devastating disease that leads to loss of mobility and quality of life in patients. Dysferlin is a 230 kD protein primarily expressed in skeletal muscle that functions in membrane resealing. Dysferlin loss of function leads to a decrease in the membrane resealing response after injury in skeletal muscle, which is thought to cause degeneration of the musculature over time. Dysferlin cDNA is 7.4 kb and exceeds AAV packaging capacity of ~ 5kb. This thesis focuses on the generation of mini dysferlin mutants that can be packaged in AAV for downstream testing of therapeutic efficacy. In addition, this thesis creates the groundwork for preclinical studies in mice that can potentially be translated to human patients. A mouse model for dysferlin deficiency was characterized and key disease phenotypes were identified. In addition, cell lines carrying a genetically encoded calcium indicator protein, gCaMP, were established to measure mini dysferlin resealing capacity and for downstream testing in vivo.
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Fridman, Leticia. "Histopathological Characterization of the Dystrophic Phenotype and Development of Therapeutic Candidates for a Gene Therapy Pre-Clinical Study in Dysferlin Deficient Mice." eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/881.
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Dysferlin deficient muscular dystrophy is a devastating disease that leads to loss of mobility and quality of life in patients. Dysferlin is a 230 kD protein primarily expressed in skeletal muscle that functions in membrane resealing. Dysferlin loss of function leads to a decrease in the membrane resealing response after injury in skeletal muscle, which is thought to cause degeneration of the musculature over time. Dysferlin cDNA is 7.4 kb and exceeds AAV packaging capacity of ~ 5kb. This thesis focuses on the generation of mini dysferlin mutants that can be packaged in AAV for downstream testing of therapeutic efficacy. In addition, this thesis creates the groundwork for preclinical studies in mice that can potentially be translated to human patients. A mouse model for dysferlin deficiency was characterized and key disease phenotypes were identified. In addition, cell lines carrying a genetically encoded calcium indicator protein, gCaMP, were established to measure mini dysferlin resealing capacity and for downstream testing in vivo.
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Parviz, Maryam. "Evaluation of Zinc Toxicity Using Neuronal Networks on Microelectrode Arrays: Response Quantification and Entry Pathway Analysis." Thesis, University of North Texas, 2007. https://digital.library.unt.edu/ark:/67531/metadc3928/.
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Murine neuronal networks, derived from embryonic frontal cortex (FC) tissue grown on microelectrode arrays, were used to investigate zinc toxicity at concentrations ranging from 20 to 2000 mM total zinc acetate added to the culture medium. Continual multi-channel recording of spontaneous action potential generation allowed a quantitative analysis of the temporal evolution of network spike activity generation at specific zinc acetate concentrations. Cultures responded with immediate concentration-dependent excitation lasting from 5 to 50 min, consisting of increased spiking and enhanced, coordinated bursting. This was followed by irreversible activity decay. The time to 50% and 90% activity loss was concentration dependent, highly reproducible, and formed linear functions in log-log plots. Network activity loss generally preceded morphological changes. 20% cell swelling was correlated with 50% activity loss. Cultures pretreated with the GABAA receptor antagonists bicuculline (40 mM) and picrotoxin (1 mM) lacked the initial excitation phase. This suggests that zinc-induced excitation may be mediated by interfering with GABA inhibition. Partial network protection was achieved by stopping spontaneous activity with either tetrodotoxin (200 nM) or lidocaine (250 mM). However, recovery was not complete and slow deterioration of network activity continued over 6 hrs. Removal of zinc by early medium changes showed irreversible, catastrophic network failure to develop in a concentration-dependent time window between 50% and 90% activity loss. Investigation of entry routes suggested the L-type but not N-type calcium channels to be the main entry pathway for zinc. Data are presented implicating the chloride channel to be an additional entry route.
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Cage, Mary Pauline. "Molecular characterization of mesocorticolimbic brain regions in DBA/2J mice sensitized to the locomotor activating effects of ethanol /." Abstract, 24-page preview and downloadable full-text (PDF format) available to VCU users at:, 2005. http://wwwlib.umi.com/cr/vcu/fullcit?p3196511.
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Millward, Jason Michael 1976. "Interferon-gamma and the regulation of neuroinflammation." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115699.
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Inflammation of the central nervous system (CNS) is important in many human diseases, and is regulated by a multitude of factors, including the cytokine interferon-gamma (IFNgamma). The importance of IFNgamma is highlighted in experimental autoimmune encephalomyelitis (EAE), an animal model of CNS inflammation. Mice lacking IFNgamma show exaggerated disease, with a different pattern of chemokine expression than the wild-type. We administered IFNgamma to the CNS using intrathecal injection of a replication-defective adenoviral vector to ask about direct actions of IFNgamma on chemokine expression without the confounding factors present during CNS inflammation. AdIFNgamma induced expression of CXCL10 and CCL5, two chemokines strikingly absent in Ifng-/- EAE. Chemokine expression was not associated with inflammation, though when an infectious stimulus was administered, an influx of immune cells to the CNS was seen. Using AdIFNgamma to restore IFNgamma to Ifng-/- mice with EAE had a disease-limiting effect. We used vectors encoding CXCL10 or CCL5, to replace these chemokines which are absent during Ifng-/- EAE, attempting to modulate the disease into a form resembling that of the wild-type. AdCCL5 treatment showed a mild reduction in EAE severity in the Ifng-/-, though AdCXCL10 treatment had no effect. A principal inducer of IFNgamma is interleukin-18 (IL 18), and IFNgamma induces IL18-binding protein (IL18bp) which inhibits IL18, establishing a negative feedback loop. We found that ILl8bp expression is upregulated in wild-type mice with EAE, but not in the Ifng-/-, suggesting that the exaggerated disease of the Ifng -/- may be due in part to unrestrained actions of ILI8. Treatment with a vector encoding IL18bp (AdIL18bp) significantly inhibited EAE, without restricting immune cell entry to the CNS. Cytokine expression was shifted away from a pattern favouring Th17 development. AdIL18bp treatment inhibited EAE in Ifng-/- mice, indicating that IFNgamma was not required for this activity. We used a vector encoding M3, a chemokine-binding protein derived from MHV-68, to reduce EAE severity, showing the first use of a viral chemokine-binding protein in EAE.
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Pontes, Renata Bessa. "Envolvimento da endotelina-1, de receptores (TRPV1 E NMDA) e da substÃncia p na neuropatia sensitiva perifÃrica induzida pelo agente antineoplÃsico oxaliplatina." Universidade Federal do CearÃ, 2015. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=15621.
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nÃo hÃIntroduÃÃo: A neurotoxicidade cumulativa à uma toxicidade que pode advir da terapia à base de oxaliplatina (OXL), que à a 3 geraÃÃo de agentes platinos com amplo espectro de atividade antitumoral, incluindo cÃncer colorretal, ovariano e pulmonar. A neurotoxicidade associada à OXL gera uma toxicidade dose-limitante, crÃnica, a neuropatia sensitiva perifÃrica (NSP). Objetivo: Investigar o envolvimento da endotelina-1, de receptores TRPV1 e NMDA e da substÃncia P envolvidos na patogÃnese da neuropatia sensitiva perifÃrica induzida pelo agente antineoplÃsico oxaliplatina. Materiais e mÃtodos: O estudo foi aprovado pelo Comità de Ãtica em Pesquisa Animal da UFC (protocolo n 75/12). Camundongos Swiss machos (20g) foram prÃ-tratados com antagonistas de receptores de endotelina-1 (Bosentana 100mg/kg, VO; BQ-123 e BQ-788 30Âl, intraplantar) e antagonistas do receptor TRPV1 (capsazepina, 5mg/kg, IP), antagonista do receptor NK-1 da Substancia P (apreptanto, 1mg/kg, IP) e antagonista de receptores NMDA (MK-801, 0,5mg/kg, IP) 30 minutos antes da administraÃÃo de OXL (1mg/kg, IV) por 4 semanas e meia. Paralelamente foram realizados testes nociceptivos para avaliar o desenvolvimento da neuropatia sensitiva perifÃrica. A hipernocicepÃÃo foi avaliada pelo teste de imersÃo da cauda (TIC) em Ãgua fria (10ÂC) ou aquecida (43ÂC) e pelo teste Von Frey (HPM). Em seguida, foi realizado imunofluorescÃncia do segmento medular e gÃnglio da raiz dorsal e RT-PCR. Resultados: Como resultados observou-se que com o prÃ-tratamento ao uso de OXL que houve atenuaÃÃo da hiperalgesia da NSP induzida por OXL. Ao realizar a administraÃÃo de antagonistas seletivos de endotelina-1 intraplantar na pata direita observou-se reduÃÃo significativa na hiperalgesia na pata direita (tratada) em comparaÃÃo à pata esquerda (controle). Ao analisar a expressÃo gÃnica para cFos, NK-1 e o receptor de endotelina B, observou-se que houve reduÃÃo significativa da expressÃo dos marcadores no grupo prÃ-tratado com Bosentana ao comparar com o grupo OXL, que demonstrou a expressÃo aumentada para esses marcadores. ConclusÃo: Conclui-se no presente estudo que hà evidÃncias do papel da endotelina-1, de receptores (TRPV1 e NMDA) e da substÃncia P na patogÃnese da NSP induzida pelo agente antineoplÃsico OXL.
Introduction: The cumulative neurotoxicity is a toxicity that can result from oxaliplatin-based therapy (OXL), which is the 3rd generation platinum agent with broad spectrum of antitumor activity, including colorectal, ovarian and lung cancer. Neurotoxicity associated with OXL generates a dose-limiting toxicity, chronic, peripheral sensory neuropathy (NSP). Objective: To investigate the involvement of endothelin-1, TRPV1 receptors and NMDA and substance P involved in the pathogenesis of peripheral sensory neuropathy induced by oxaliplatin antineoplastic agent. Methods: Male Swiss mice (20g) were pre-treated with antagonists of endothelin-1 receptors (Bosentan 100mg / kg orally; BQ-123 and BQ-788 30μl, intraplantar) and TRPV1 receptor antagonists (capsazepine, 5mg / kg , IP), antagonist of NK-1 receptor for substance P (apreptanto, 1 mg / kg, IP), and a NMDA receptor antagonist (MK-801, 0.5mg / kg, IP) 30 minutes before administration of OXL (1mg / kg, IV) for 4.5 weeks. Parallel nociceptive tests performed to assess the development of peripheral sensory neuropathy. The hyperalgesia assessed by the tail immersion test (ICT) in cold water (10Â C) or warm (43Â C) and test Von Frey (HPM). Then it was performed spinal segment, and the dorsal root ganglion immunofluorescence and RT-PCR the Ethics Committee approved the study for Animal Research UFC (Protocol 75/12). Results: The results observed when using the antagonists, as a pretreatment to the use of OXL there was attenuation of the induced hyperalgesia (NSP) OXL. Upon administration of selective antagonists of endothelin in the right paw was significant reduction in paw hyperalgesia in the right (treated) compared to the left paw (control). By analyzing the gene expression of cFos, NK-1 and endothelin B receptor, it was observed that there was significant reduction of expression of the markers in pre-treated bosentan group versus OXL group that showed increased expression for these markers. Conclusion: It was concluded in this study that there is evidence of the role of endothelin-1 receptors (TRPV1 and NMDA) and substance SP in the pathogenesis of NSP induced antineoplastic agent OXL.
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Bacurau, Aline Villa Nova. "Caracterização fenotípica do músculo esquelético na cardiomiopatia induzida por hiperatividade simpática." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/39/39132/tde-12112007-165712/.
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A insuficiência cardíaca (IC) é uma síndrome clínica de alta incidência e mau prognóstico, caracterizada por fadiga, dispnéia e grande limitação aos esforços físicos. Essas alterações não estão apenas limitadas ao comprometimento cardíaco, mas em parte, são decorrentes também de alterações morfo-funcionais da musculatura esquelética. Para a dissertação foram utilizados camundongos com deleção dos genes para os receptores ?2A e ?2C adrenérgicos (KO) que desenvolvem cardiomiopatia induzida por hiperatividade simpática, associada à sinais clínicos de IC e 50% de mortalidade aos sete meses de idade. Foi objetivo desse estudo realizar a caracterização fenotípica do músculo esquelético por meio de avaliações funcionais e morfológicas em camundongos KO previamente ao desenvolvimento da IC (três meses de idade), e ao longo de sua progressão (cinco e sete meses de idade). Somente na faixa etária de sete meses de idades foi constatado o estabelecimento da miopatia muscular esquelética. Nessa fase, observou-se rarefação vascular, atrofia muscular, aumento na porcentagem de fibras glicolíticas e redução na atividade máxima da enzima citrato sintase, que em conjunto, contribuem para a antecipação da fadiga observada nesse modelo, e como conseqüência, para a redução da tolerância aos esforços. Os resultados sugerem que os camundongos KO apresentam alterações morfo-funcionais da musculatura esquelética semelhantes às observadas nos demais modelos de IC e em indivíduos portadores dessa síndrome. Portanto, sendo um ótimo modelo experimental para estudos de futuras estratégias terapêuticas que visem minimizar as alterações na musculatura esquelética decorrentes da ICHeart failure (HF) is a clinical syndrome with high incidence and bad prognostic, characterized by fatigue, dyspnea, and increased intolerance to exercise. These changes are not only related to the cardiovascular tissue, but are at least in part, consequence of morphofunctional alterations in skeletal muscles. To the present study it was used mice lacking both ?2A/?2C AR subtypes (KO) which develop cardiomyopathy induced by sympathetic hyperactivity, associated to clinical signals of HF and 50% of mortality at seven months of age. The aim of the present study was characterize the phenotype of skeletal muscle by functional and morphological evaluations in KO before (three months of age) and during the HF progression (five and seven months of age). Skeletal muscle alterations due HF were observed only at seven months of age. The alterations were characterized by vascular rarefaction, muscular atrophy, increase in glycolitic fibers percentage and reduction of maximal activity of citrate synthase and contributed with early fatigue observed in this model, and consequently, exercise intolerance. The results of present study suggest that KO mice present morphofunctional changes in skeletal muscles in a similarly to others models of HF and in patients that have this syndrome. Therefore, consisting in an excellent experimental model to future studies related to therapeutic strategies to minimize the skeletal muscle changes due HF
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Oli-Rijal, Sabnam. "Determination of Dissociation Constants for GABAA Receptor Antagonists using Spontaneously Active Neuronal Networks in vitro." Thesis, University of North Texas, 2005. https://digital.library.unt.edu/ark:/67531/metadc4911/.
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Changes in spontaneous spike activities recorded from murine frontal cortex networks grown on substrate-integrated microelectrodes were used to determine the dissociation constant (KB) of three GABAA antagonists. Neuronal networks were treated with fixed concentrations of GABAA antagonists and titrated with muscimol, a GABAA receptor agonist. Muscimol decreased spike activity in a concentration dependent manner with full efficacy (100% spike inhibition) and a 50% inhibitory concentration (IC50) of 0.14 ± 0.05 µM (mean ± SD, n=6). At 10, 20, 40 and 80 µM bicuculline, the muscimol IC50 values were shifted to 4.3 ± 1.8 µM (n=6), 6.8 ± 1.7 µM (n=6), 19.3 ± 3.54 µM (n=10) and 43.5 µM (n=2), respectively (mean ± SD). Muscimol titration in the presence of 10, 20, 40 µM of gabazine resulted in IC50s values of 20.1 (n=2), 37.17 (n=4), and 120.45 (n=2), respectively. In the presence of 20, 80, and 160 µM of TMPP (trimethylolpropane phosphate) the IC50s were 0.86 (n=2), 3.07 (n=3), 6.67 (n=2) µM, respectively. Increasing concentrations of GABAA antagonists shifted agonist log concentration-response curves to the right with identical efficacies, indicating direct competition for the GABAA receptor. A Schild plot analysis with linear regression resulted in slopes of 1.18 ± 0.18, 1.29 ± 0.23 and 1.05 ± 0.03 for bicuculline, gabazine and TMPP, respectively. The potency of antagonists was determined in terms of pA2 values. The pA2 values were 6.63 (gabazine), 6.21 (bicuculline), and 5.4 (TMPP). This suggests that gabazine has a higher binding affinity to the GABAA receptor than bicuculline and TMPP. Hence, using spike rate data obtained from population responses of spontaneously active neuronal networks, it is possible to determine key pharmacological properties of drug-receptor interactions.
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Simões, Gustavo Ferreira 1978. "Plasticidade sináptica em motoneurônios alfa medulares de camundongos MDX tratados com fator estimulador de colônias granulocitárias (GCSF)." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/316412.
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Orientador: Alexandre Leite Rodrigues de OliveiraTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Atualmente, muito se sabe sobre o acometimento muscular na DMD, mas poucos estudos estão voltados para os efeitos no Sistema Nervoso Central (SNC), mais especificamente no microambiente do motoneurônio medular. Sabe-se que durante a evolução da doença, o terminal axonal, na junção neuromuscular, entra em um ciclo de denervação (retração) e reinervação (brotamento). A possibilidade de modulação do MHC I se apresenta como uma nova estratégia de influenciar positivamente o processo de plasticidade sináptica após lesões do Sistema Nervoso Periférico (SNP) e SNC. Tal modulação pode ser realizada através da utilização ou desenvolvimento de drogas específicas. O fator estimulador de colônias glanulocitárias (G-CSF) é uma glicoproteína que foi descrita há mais de vinte anos, possui aprovação do ANVISA (Agência Nacional de Vigilância Sanitária) e é comumente utilizada para tratar neutropenia, ou para transplantes de medula óssea. O GCSF possui um efeito neuroprotetor aparentemente multimodal, incluindo-se a atividade anti-apoptóptica em neurônios, regeneração da vascularização, efeito antiinflamatório e estimulação de neurogênese endógena, sendo capaz de atuar efetivamente no processo de regeneração do sistema nervoso. No presente trabalho, foram utilizados camundongos MDX. Os camundongos foram distribuídos em 4 grupos (axotomia + G-CSF; Axotomia; Controle + G-CSF e Controle), com n=10. Incluiu-se para imunoistoquímica o grupo placebo, onde os animais receberam uma dose diária de 200?m, via subcutânea, de glicose a 25%. Nossos resultados indicam que redução de sinapses nos motoneurônios alfamedulares e aumento da astrogliose circunjacente aos neurônios alfa-medulares, seja decorrente da desconexão parcial entre o orgão alvo e o corpo neuronal durante o período de ciclos de degeneração/regeneração muscular que ocorrem a partir das primeiras semanas de vida nos camundongos MDX. Estes ciclos podem repercutir retrogradamente nos corpos celulares dos motoneurônios alfa-medulares, provocando uma série de alterações denominadas cromatólise. A axotomia do nervo isquiático resulta num aumento significativo da expressão de MHC I nas duas linhagens estudadas. Contudo, nos animais MDX, este aumento é menor, comparativamente à linhagem C57BL/10. Quando tratados com G-CSF a expressão de MCH I ficou maior em relação aos grupos não tratados e, isso pode indicar um papel ativo da droga no potencial regenerativo após a lesão. Também podemos sugerir que, apesar dos animais MDX apresentarem uma menor função motora em relação aos animais controle, os resultados indicam que o tratamento com G-CSF é capaz de reduzir os efeitos inflamatórios e atuar positivamente no processo de regeneração nervosa periférica após esmagamento do nervo isquiático
Abstract: Currently, much is known about the muscular involvement in DMD, but few studies have focused on the effects on the central nervous system (CNS), specifically in the microenvironment of spinal motor neurons. It is known that during the course of the disease, the axon terminal at the neuromuscular junction, enters a cycle of denervation (retraction) and reinnervation (sprouting). The possibility of modulation of MHC I presents itself as a new strategy to positively influence the process of synaptic plasticity after injury Peripheral Nervous System (PNS) and CNS. Such modulation may be accomplished through the use or development of special drugs. The granulocyte colony-stimulating factor (G-CSF) is a glycoprotein which was first described more than twenty years, has approval from ANVISA (Agência Nacional de Vigilância Sanitária) and is commonly used to treat neutropenia, or bone marrow transplants. The G-CSF has a multimodal neuroprotective effect l, including the anti-apoptotic activity in neurons, regeneration of vascularization, anti-inflammatory effect and stimulation of endogenous neurogenesis, being able to act effectively in the process of regeneration of the nervous system. In this study, we used MDX mice. The mice were divided into 4 groups (axotomy + G-CSF; axotomy, Control + G-CSF and Control), with n = 10. Included immunohistochemistry to the placebo group, where the animals received a daily dose of 200?m, subcutaneously, glucose 25%. Our results indicate that reduction of synapses in the alpha motoneurosn and increased astrogliosis , either due to partial disconnection between the target organ and the neuronal body during the cycles of degeneration /regeneration muscle that occur from first weeks of life in MDX mice. These cycles can pass retrogradely in alpha motoneurons cell bodies, causing a series of changes called chromatolysis. The sciatic nerve axotomy results in a significant increase of MHC I expression in both strains studied. However, in MDX strain, this increase is smaller, compared to C57BL/10. After treatment with G-CSF the expression of MCH I got bigger compared to untreated groups, and this may indicate an active role in the regenerative potential of the drug after injury. Also we suggest that while the animals present MDX a smaller motor function compared to control animals, the results indicate that treatment with G-CSF is capable of reducing the inflammatory effects and act positively on peripheral nerve regeneration process after nerve crush sciatic. Also our results indicate that treatment with G-CSF is able to reduce the inflammatory effects and act positively on peripheral nerve regeneration process after nerve crush sciatic
Doutorado
Anatomia
Doutor em Biologia Celular e Estrutural
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Moraes, Oscar Albuquerque de. "Avaliação da modulação autonômica cardiovascular de camundongos diabéticos não obesos." Universidade Nove de Julho, 2013. http://bibliotecadigital.uninove.br/handle/tede/1146.
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Introduction: It is known that diabetes is associated with autonomic dysfunction and this is a severe complication that increases the risk of cardiovascular mortality. The non-obese diabetic mice (NOD) is an experimental model of type 1 diabetes which develops insulitis at the 4th week and diabetes between the 14th and the 20th week of life. However, data about autonomic function in these mice remain scarce. Objective: To investigate the cardiovascular autonomic profile of NOD mice. Methods: Female mice (24-28 week old) were divided in two groups: NOD (n=6) and control (n=6, swiss mice). NOD mice with glycemia ≥300 mg/dl were used in this study. Heart rate variability (HRV) was evaluated in time and frequency domains and also through symbolic analysis. Were also analyzed the variability of the blood pressure, and baroreflex sensitivity by means of the bradycardic and tachycardic responses induced by infusion of phenylephrine and sodium nitroprusside. Student t test for independent samples and Pearson's correlation coefficient were used for statistical analyses. The data were described as means and standard error. Results: The heart rate and arterial pressure were similar between the groups, however HRV (total variance of RR interval: NOD = 21.07 ± 3.75 vs. C = 42.02 ± 6.54 ms2) and RMSSD (NOD = 4.01 ± 0.32 vs. C = 8.28 ± 0.97 ms), a vagal modulation index, were lower in NOD group when compared to control group. Moreover, the low frequency component was higher in NOD group (normalized LF: NOD = 61.0 ± 4.0 vs. C = 20.0 ± 4.0%), while the high frequency of HR component was lower in NOD compared with the control group (normalized HF: NOD = 39.0 ± 4.0% vs. C = 80.0 ± 4.0%). Similarly, the 0V pattern of symbolic analysis, indicative of sympathetic activity, was increased in NOD group when compared to the control group (NOD = 11.9 ± 1.4 vs. C = 6.06 ± 0.90%) and the 2LV pattern, indicative of parasympathetic activity, was reduced in the NOD group (NOD = 7.98 ± 1.3 vs. C = 21.2 ± 3.36%). Both responses to arterial pressure changes, tachycardic (NOD = 3.01 ± 0.72 vs. C = 4.54 ± 0.36 bpm/mmHg) and bradycardic (NOD = 2.49 ± 0.31 vs. C = 3.43 ± 0.33 bpm/mmHg) were lower in NOD when compared to the control group. A negative correlation between the indices of vagal modulation (RMSSD, normalized high frequency component and 2LV pattern of symbolic analysis) and blood glucose levels was also observed. Conclusions: The NOD mice present cardiovascular autonomic dysfunction and that is probably associated with glycemic levels.
Introdução: O diabetes está associado com disfunção autonômica e esta é uma grave complicação que eleva o risco de mortalidade cardiovascular. O camundongo não obeso diabético (NOD) é um modelo experimental de diabetes tipo 1 que desenvolve insulinite na quarta semana de vida e diabetes entre a 14ª e 20ª semana de vida. Contudo, dados sobre a função autonômica cardiovascular em camundongos NOD permanecem escassos. Objetivos: Investigar a função autonômica cardiovascular do camundongo NOD. Métodos: Camundongos fêmeas (24-28 semanas de vida) foram divididas em dois grupos: NOD (n = 6) e controle (C, camundongo suiço, n=6). Foram incluídos no grupo NOD animais com glicemia igual ou superior a 300 mg/dl. Foi avaliada a variabilidade da frequência cardíaca no domínio do tempo e da frequência e também por meio de análise simbólica. Além disso, foram avaliados a variabilidade da pressão arterial, bem como a sensibilidade barorreflexa, por meio das respostas bradicárdicas e taquicárdicas induzidas pela infusão de fenilefrina e nitroprussiato de sódio. Para análise estatística foi utilizado o teste t de Student para amostras independentes e o coeficiente de correlação de Pearson. Os dados foram descritos como média e erro padrão. Resultados: A frequência cardíaca e a pressão arterial foram similares entre os grupos, no entanto a variabilidade da frequência cardíaca (variância do intervalo de pulso: NOD = 21,07 ± 3,75 vs. C = 42,02 ± 6,54 ms2) e o RMSSD (NOD = 4,01 ± 0,32 vs. C = 8,28 ± 0,97 ms), um índice de modulação vagal, foram menores no grupo NOD quando comparados ao grupo controle. Além disso, o componente de baixa frequência foi maior no grupo NOD (BF normalizado: NOD = 61,0 ± 4,0 vs. C = 20,0 ± 4,0%), enquanto que o componente de alta frequência foi menor no grupo NOD quando comparado com o grupo controle (AF normalizado: NOD = 39,0 ± 4,0% vs. C = 80,0 ± 4,0%). De forma semelhante, na análise simbólica o padrão 0V, indicativo da atividade simpática, estava aumentado no grupo NOD em comparação com o grupo controle (NOD= 11,9 ± 1,4 vs. C = 6,06 ± 0,90%) e o padrão 2LV, indicativo da atividade parassimpática, estava reduzido no grupo NOD (NOD = 7,98 ± 1,3 vs. C = 21,2 ± 3,36%). Ambas as respostas reflexas comandadas pelos barorreceptores, taquicárdica (NOD = 3,01 ± 0,72 vs. C = 4,54 ± 0,36 bpm/mmHg) e bradicárdica (NOD = 2,49 ± 0,31 vs. C = 3,43 ± 0,33 bpm/mmHg) foram menores no grupo NOD quando comparadas com o grupo controle. Ainda, observamos uma correlação negativa entre os índices de modulação vagal (RMSSD, componente de alta frequência normalizado e padrão 2LV da análise simbólica) e os níveis glicêmicos. Conclusão: Os camundongos NOD apresentam disfunção autonômica cardiovascular e essa disautonomia está associada com os níveis glicêmicos.
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Pan-Montojo, Francisco, Oleg Anichtchik, Yanina Dening, Lilla Knels, Stefan Pursche, Roland Jung, Sandra Jackson, et al. "Progression of Parkinson's Disease Pathology is Reproduced by Intragastric Administration of Rotenone in Mice." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-185435.
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In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system.
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Maduna, Tando Lerato. "Vasoactive intestinal peptide (VIP) controls the development of the nervous system and its functions through VPAC1 receptor signalling : lessons from microcephaly and hyperalgesia in VIP-deficient mice." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ009/document.
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Mes études doctorales ont permis de démontrer que les souris déficientes en VIP présentent une microcéphalie ayant principalement une origine maternelle qui affecte secondairement le développement de la substance blanche. Cette production placentaire par les lymphocytes T pourrait être affectée dans des pathologies du système immunitaire. De plus, nos données indiquent qu’une déficience en VIP prédispose à l'apparition de troubles sensoriels, en particulier de la nociception. Il est donc possible que les déficits précoces de développement du cerveau murin et l'apparition de l'hypersensibilité cutanée mécanique et thermique froide soient deux facettes d'une même pathologie. Des mesures d'activité de décharge spontanée des neurones dans le thalamus sensoriel chez des mâles adultes anesthésiés ont montré que les neurones des animaux KO sont hyper-excités, ce qui suggère un traitement aberrant des informations, notamment nociceptives, ou que l'activité inhibitrice des interneurones des réseaux locaux est réduiteThe studies carried out during my PhD demonstrate that VIP-deficient mice suffer from microcephaly and as well as white matter deficits mainly due to the absence of maternal VIP during embryogenesis, Placental secretion of VIP is dependent on T lymphocytes and could be altered in pathologies of the immune system. Moreover, our data links VIP deficiency to sensory alterations, specifically, the nociceptive system. Thus, it is possible that early developmental defects and hypersensitivity to mechanical and cold stimuli are two manifestations of the same pathology. This hypothesis was reinforced following analysis of spontaneous firing patterns of neurons in the sensory thalamus of anesthetized adult males. Neurons from VIP-KO mice are hyperactive, which suggests aberrant local processing of nociceptive input or that the inhibitory inputs from local interneuron networks is reduced
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Sicot, Géraldine. "Conséquences pathologiques des expansions CTG sur le système nerveux central d’un modèle murin de la dystrophie myotonique de Steinert : approches moléculaires, protéomiques et cellulaires." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T084/document.
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La dystrophie myotonique de type I (DM1) constitue la plus fréquente des pathologies musculaires héréditaires chez l’adulte. Bien qu’initialement considérée comme une maladie musculaire, la DM1 présente une atteinte neurologique très handicapante. Cette maladie autosomique dominante résulte de l’expansion anormale d’un triplet CTG dans la partie 3’UTR du gène DMPK. Un effet trans du transcrit DMPK muté entraine une dérégulation de l‘épissage alternatif dans de nombreux tissus. Cependant, les mécanismes pathologiques de la DM1 dans le cerveau restent encore peu compris. Afin de disséquer ce mécanisme, notre laboratoire a créé des souris transgéniques exprimant le transcrit DMPK avec de larges expansions CUG dans de nombreux tissus. Ces souris nommées DMSXL, recréent d’importants aspects pathologiques de la DM1, comme des anomalies du comportement et électrophysiologiques du cerveau. Elles représentent donc un excellent outil pour explorer l’effet pathologique de la mutation dans le SNC. En m’appuyant sur ce modèle, j’ai exploré dans un premier temps l’effet trans des ARNs toxiques et l’ampleur de la splicéopathie dans le SNC. De façon intéressante, certains défauts d’épissage sont régions spécifiques, et ne montrent pas d’aggravation avec l’âge des souris DMSXL. Mes résultats démontrent que les ARNs mutés sont capables de déréguler l’épissage alternatif dans l’ensemble du SNC. La région du cervelet a aussi montré des anomalies de l’épissage dans les souris DMSXL, qui, en plus, présentent des perturbations cognitives dépendantes de cette région cérébrale. Le cervelet des souris DMSXL présente aussi des déficits électrophysiologiques suggérant une dysfonction cérébelleuse et plus précisément une dysfonction des cellules de Purkinje. Dans la recherche des populations cellulaires les plus affectées dans le cervelet, j’ai démontré la présence de signes de la toxicité de l’ARN plus marqués dans la glie de Bergman, entourant les cellules de Purkinje. Pour trouver les voies moléculaires perturbées dans le cervelet, et disséquer le mécanisme derrière les anomalies observées, j’ai réalisé une approche protéomique globale et trouvé une sévère baisse de l’expression du transporteur glial de glutamate GLT1/EAAT2, suggérant une dysfonction du cervelet, en conséquence d’un possible métabolisme anormal du glutamate. L’analyse protéomique globale du cerveau des souris DM1 a aussi identifié des différences d’expression et des modifications post-traductionnelles de protéines impliquées dans la signalisation du calcium. L’étude du métabolisme des ARNm dans la DM1 a mis en évidence la dérégulation de l’épissage de gènes impliqués dans le métabolisme du calcium, soutenant l’hypothèse d’une dysfonction calcique dans le SNC. Pour étudier les conséquences de la mutation sur les variations calciques cellulaires, j’ai caractérisé un modèle cellulaire astrocytaire de la DM1. Ce modèle m’a permis de démontrer une localisation anormale du récepteur GRIN1/NMDAR1, ainsi qu’une réponse calcique anormale dans les astrocytes primaires porteurs des amplifications CTG. Malgré les avancés thérapeutiques dans le muscle, on ne sait pas à quel point les stratégies en cours de développement sont efficaces dans le SNC. Pour étudier ce problème, j’ai utilisé le modèle astrocytaire de la DM1 afin de valider in cellulo une stratégie thérapeutique qui vise à rétablir une activité normale du facteur d’épissage MBNL1 endogène. Mes travaux de thèse ont permis d’avancer dans la compréhension de la neuropathologie de la DM1. Ils ont mis en évidence pour la première fois une dysfonction du cervelet, ainsi que la possible dérégulation de la voix calcique dans le SNC. Mes résultats ont donc contribué à mieux comprendre le mécanisme de la DM1 dans le SNC, pour, à long terme, développer des approches thérapeutiques ciblant des évènements moléculaires précisMyotonic dystrophy type 1 (DM1) is the most frequent inherited muscular disorder in adults. Although traditionally regarded as a muscle disease, DM1 presents debilitating neurological manifestations. DM1 is an autosomic dominant disease caused by the abnormal expansion of a CTG triplet within the 3’UTR of the DMPK gene. Many molecular aspects of the DM1 are mediated by a trans effect of the expanded DMPK transcripts, whose accumulation leads to splicing deregulation in many tissues. Despite recent progress in the understanding of DM1 pathogenesis in muscle and central nervous system (CNS), the detailed molecular disease mechanism operating in the brain is still poorly understood. In order to investigate the pathophysiology, our laboratory has generated DMSXL transgenic mice expressing DMPK transcripts containing large CUG expansions in many tissues. DMSXL mice mimic important features of the DM1, notably in the CNS, showing behaviour as well as electrophysiological abnormalities. Therefore, this mouse line represents an excellent tool to investigate the toxic effects of the mutation in the CNS. Taking advantages of this transgenic model, I have first explored the trans effect of the toxic RNA and the extent of DM1-associated spliceopathy in the CNS. Interestingly, some splicing defects were region-specific, and their severity did not increase with the age of the DMSXL mice. My data demonstrate that CUG-containing RNAs have a wide deleterious effect and deregulate alternative splicing in many areas of the CNS. In addition to splicing abnormalities in cerebellum, DMSXL mice also displayed deficits in cerebellum-dependant motor coordination. Plus, DMSXL cerebellum showed electrophysiological abnormalities, suggesting cerebellar dysfunction and more precisely Purkinje cell dysfunction. In the search for the cellular populations showing the greatest susceptibility to RNA toxicity in the cerebellum, I have found extensive foci accumulation as well as pronounced splicing defects in the Bergman glia, surrounding Purkinje cells, in DMSXL and DM1 patients cerebellum. In order to identify molecular pathways and mechanisms behind the behaviour and electrophysiological abnormalities detected, I have performed a global proteomics approach and found a severe decrease in the expression of a glial glutamate transporter GLT1/EAAT2, suggesting that DM1 causes cerebellum dysfunction, through abnormal glutamate metabolism. Global proteomic analysis of DMSXL cerebellum also identified expression and post-translational changes of several proteins involved in calcium signalling. Missplicing of different transcripts involved in calcium metabolism reinforces the idea of calcium dysfunction in the neuropathogenesis of the DM1. To study the effects of toxic RNA on calcium homeostasis and flux, I have established and characterised a brain cell model of DM1. DMSXL primary astrocyte cultures allowed me to show the mislocalisation of the glutamate receptor GRIN1/NMDAR1, as well as abnormal calcium responses to stimulation. Despite recent therapeutic advances in muscle, we do not know the CNS efficiency of the therapeutic strategies currently being developed. To address this problem, I have used the DM1 astrocyte cell model to validate in cellulo a therapeutic strategy aiming to restore the activity of the endogenous splicing factor MBNL1. My thesis work provided a significant step in the understanding of the DM1 pathology in the CNS. My results revealed for the first time signs of cerebellum dysfunction in DM1, as well as signs of calcium homeostasis deregulation in the SNC. My work contributed to better understand the pathological mechanisms of DM1, the brain pathways and cell types most susceptible to toxic RNA. In the long term, my data will contribute to the rational development of therapeutic strategies targeting precise and deleterious molecular events
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Wolf, Amy. "In Vitro Studies of Nuclear Changes in Mammalian CNS Neurons Subjected to Rapid Acceleration Impact Injury." Thesis, University of North Texas, 1995. https://digital.library.unt.edu/ark:/67531/metadc278044/.
Full textAbstract:
An in vitro model of Rapid Acceleration Impact (RAI) Injury was used to study the effects of multiple impact (220 g/impact, 3-5 sec intervals) trauma on cultures of murine CNS cells. Investigations with spinal cord cultures showed that 1) multiple impacts delivered tangential to the plane of cell growth caused neuronal death (12% after 3 impacts to 46% after 10 impacts); 2) multiple impacts delivered normal to the plane of cell growth were much less effective (8% dead after 10 impacts); 3) most neuronal death occurred within 15 minutes after injury 4) morphological changes observed included increased nuclear prominence and somal swelling; and 5) pretreatment with ketamine (0.1mM) reduced cell death from 51 to 14% and reduced somal swelling. Identical studies performed on cortical cultures revealed minimal differences between the two tissues in their response to multiple tangential impacts.
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Pan-Montojo, Francisco, Oleg Anichtchik, Yanina Dening, Lilla Knels, Stefan Pursche, Roland Jung, Sandra Jackson, et al. "Progression of Parkinson's Disease Pathology is Reproduced by Intragastric Administration of Rotenone in Mice." PloS ONE, 2010. https://tud.qucosa.de/id/qucosa%3A29010.
Full textAbstract:
In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system.