这项工作是支持的外交事务和国际贸易（加拿大政府），多伦多大学，加拿大创新，NSERC，Krembil的基金会和治疗帕金森氏信托基金会诺基金。

<ol>
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作者没有透露。

本协议描述了一个稳定的单方面6-OHDA损毁的帕金森氏症，这是非常重复性高病变的成功率，低死亡率，小鼠模型的生成方法。 6-OHDA损伤手术的成功，可以很容易地估计&gt; 70％&gt; 95％，在27的损毁纹状体多巴胺耗竭的指标ipsiversive旋转自发旋转行为的测量。纹状体多巴胺水平的量化纹状体多巴胺耗竭的程度相比，在黑质致密部TH阳性细胞数量quantificiation是最精确的测量，因为它提供了直接?...

<table border="1" &gt;<tbody&gt;<tr &gt;<td<strong&gt;试剂名称</strong</td&gt;<td<strong&gt;公司</strong</td&gt;<td<strong&gt;产品目录号</strong</td&gt;<td<strong&gt;评论（可选）</strong</td&gt;</tr&gt;<tr &gt;<td&gt; desipramine的盐酸</td&gt;<td&gt;Σ-Aldrich公司，奥克维尔，ON，加拿大</td&gt;<td&gt; D125</td&gt;<td&gt; 25毫克</td&gt;</tr&gt;<tr&gt;<td&gt;优降宁盐酸</td&gt;<td&gt;Σ-Aldrich公司，奥克维尔，ON，加拿大</td&gt;<td&gt; P8013</td&gt;<td&gt;按5mg/kg</td&gt;</tr&gt;<tr&gt;<td&gt; 6 - 羟基多巴胺氢溴酸</td&gt;<td&gt;Σ-Aldrich公司，奥克维尔，ON，加拿大</td&gt;<td&gt; H116</td&gt;<td&gt; 3毫克/鼠标</td&gt;</tr&gt;<tr&gt;<td&gt;立体框架</td&gt;<td&gt; Kopf仪器，图洪加，CA，美国</td&gt;<td&gt;型号900</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;小鼠耳杯</td&gt;<td&gt; Kopf仪器，图洪加，CA，美国</td&gt;<td&gt;型号921颧骨耳罩</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;鼠标切牙酒吧</td&gt;<td&gt; Kopf仪器，图洪加，CA，美国</td&gt;<td&gt;型号923B</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;鼠标麻醉面罩</td&gt;<td&gt; Kopf仪器，图洪加，CA，美国</td&gt;<td&gt;型号923B</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;吸套件（含250毫升注射器）</td&gt;<td&gt;汉密尔顿公司，里诺，内华达州，美国</td&gt;<td&gt; PRMKIT 81120</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt; RN压缩接头套件（1毫米）</td&gt;<td&gt;汉密尔顿公司，里诺，内华达州，美国</td&gt;<td&gt; 55750-01</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt; PEEK管RN压缩接头套件<
 (1/16<sup&gt;日</sup&gt;英寸）</td&gt;<td&gt;汉密尔顿公司，里诺，内华达州，美国</td&gt;<td&gt; 55751-01</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td小双枢纽护士耦合器</td&gt;<td&gt;汉密尔顿公司，里诺，内华达州，美国</td&gt;<td&gt; 55752-01</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;露儿到小枢纽护士适配器</td&gt;<td&gt;汉密尔顿公司，里诺，内华达州，美国</td&gt;<td&gt; 55753-01</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;1毫升25S注射器模型7001KH</td&gt;<td&gt;汉密尔顿公司，里诺，内华达州，美国</td&gt;<td&gt; 80100</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt; * 33G可拆卸的针头（RN）的包6。 。自定义1英寸45 &lt;°斜角</td&gt;<td&gt;汉密尔顿公司，里诺，内华达州，美国</td&gt;<td&gt; 7803-05</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;剪刀</td&gt;<td&gt;精细的科学工具，温哥华，不列颠哥伦比亚省，加拿大。</td&gt;<td&gt; 14084-08</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;手术刀</td&gt;<td&gt;精细的科学工具，温哥华，不列颠哥伦比亚省，加拿大</td&gt;<td&gt; 10003-12</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;手术刀片</td&gt;<td&gt;精细的科学工具，温哥华，不列颠哥伦比亚省，加拿大</td&gt;<td&gt; 10035-20</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;夹钳</td&gt;<td&gt;精细的科学工具，温哥华，不列颠哥伦比亚省，加拿大</td&gt;<td&gt; 11608-15</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;止血</td&gt;<td&gt;精细的科学工具，温哥华，不列颠哥伦比亚省，加拿大。</td&gt;<td&gt; 13004-14</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;异氟醚</td&gt;<td&gt;住持</td&gt;<td&gt; 02241315</td&gt;<td&gt; 2-3％</td&gt;</tr&gt;<tr&gt;<td&gt; Suters（Vicryl 4.0）</td&gt;<td&gt; Syneture</td&gt;<td&gt; SS-683</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;消毒器</td&gt;<td&gt;精细的科学工具，温哥华，不列颠哥伦比亚省，加拿大</td&gt;<td&gt; 18000-45</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;输液泵</td&gt;<td&gt;哈佛仪器</td&gt;<td&gt;博士22/2000</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;针（27G）</td&gt;<td&gt;碧迪</td&gt;<td&gt; 305109</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;针（25G）</td&gt;<td&gt;碧迪</td&gt;<td&gt; 305127</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td注射器（1毫升）</td&gt;<td&gt;屋宇署注射器</td&gt;<td&gt; 309692</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;麻醉手推车</td&gt;<td&gt;雷医疗</td&gt;<td&gt; M2000型</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt; Baytril</td&gt;<td&gt; CDMV，圣圣亚森特，QC</td&gt;<td&gt; 102207</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;利多卡因</td&gt;<td&gt; CDMV，圣圣亚森特，QC</td&gt;<td&gt; 3914</td&gt;<td&gt;</td&gt;</tr&gt;<tr&gt;<td&gt;优碘溶液</td&gt;<td&gt; CDMV，圣圣亚森特，QC</td&gt;<td&gt; 19955</td&gt;<td&gt;</td&gt;</tr&gt;</tbody&gt;</table

development of a unilaterally-lesioned 6-ohda mouse model of parkinson's disease

单方面损毁6 hyroxydopamine（6 - 羟基多巴胺），损毁帕金森病大鼠模型（PD）的已证实到是在推进我们基本巴金森氏症症状的机制的理解非常宝贵的，因为它概括在基底神经节电路的变化和药理学观察中帕金森患者1-4。然而，在纹状体内的输出途径，这是基底节的主要输入地区的皮质纹状体突触发生的确切的细胞和分子的变化仍然是难以捉摸的，这被认为是网站，在这里出现潜在的帕金森病症状的病理异常5。 在PD，了解基底节电路以下尼格罗 - 纹状体通路变性的变化机制已大大提前过度表达绿色荧光蛋白，通过促进推动发展由细菌人工染色体（BAC）的小鼠RS具体纹状体两个输出途径（EGFP-D1的直接途径，间接的途径：EGFP-D2和EGFP-A2A）让他们在隔离研究。例如，最近的研究表明，有在突触可塑性的病理变化在帕金森病小鼠9,10。然而，这些研究利用幼年小鼠和急性帕金森模型。目前还不清楚是否与稳定的6 - 羟多巴胺损毁大鼠中所描述的变化也发生在这些模型中。其他团体都试图产生一个稳定的单方面的损毁6-OHDA成年PD小鼠模型，损毁内侧前脑束（MFB），不幸的是，在这项研究中的死亡率是非常高，只有14％存活21手术天或更长时间11。最近的研究已产生内黑质病变与低死亡率&gt; 80％的多巴胺能神经元的损失，但表达左旋多巴引起的运动障碍11,12,13,14变量在这些研究中。另一个PD小鼠模型MPTP的损伤小鼠15。虽然这种模式已被证明在评估潜在神经保护剂16有用的，它是不适合理解机制帕金森病的症状，这种模式往往未能引起运动障碍，在18 17病变程度，显示了一个很大的可变性。 在这里，我们已经开发了6-OHDA直接管理到稳定单方面的PD小鼠模型6-OHDA损毁MFB的，一贯导致95％的损失纹状体多巴胺（高效液相色谱法测定），以及生产的行为，不平衡的特点以及单方面的6-OHDA损毁PD大鼠模型中观察到。这个新开发的PD小鼠模型，将被证明是有价值的工具，在了解帕金森病症状的生成机制。

Watch this Scientific Journal Video about Development of a Unilaterally-lesioned 6-OHDA Mouse Model of Parkinson's Disease at JoVE.com

Development of a Unilaterally-lesioned 6-OHDA Mouse Model of Parkinson&#039;s Disease

一个6-OHDA单侧病变，内侧前脑束对小鼠进行的协议说明。该方法具有低死亡率与89％的幸存的动物&gt; 95％的损失纹状体多巴胺和90.63率（13.3％）±-4.02％ipsiversive旋转对病灶侧的偏见。

1单侧损毁6  - 羟基多巴胺帕金森病小鼠模型的发展

The unilaterally lesioned 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) has proved to be invaluable in advancing our ...

development-unilaterally-lesioned-6-ohda-mouse-model-parkinson-s

Research

JoVE Journal

Medicine

Development of a Unilaterally-lesioned 6-OHDA Mouse Model of Parkinson's Disease

50.8K 次观看.  University of Toronto at Scarborough. 一个6-OHDA单侧病变，内侧前脑束对小鼠进行的协议说明。该方法具有低死亡率与89％的幸存的动物> 95％的损失纹状体多巴胺和90.63率（13.3％）±-4.02％ipsiversive旋转对病灶侧的偏见。

视频: Development of a Unilaterally-lesioned 6-OHDA Mouse Model of Parkinson's Disease

MALDI Imaging Mass Spectrometry of Neuropeptides in Parkinson's Disease

MALDI imaging mass spectrometry (IMS) is a powerful approach that facilitates the spatial analysis of molecular species in biological tissue samples2 (Fig.1). A 12 &mu;m thin tissue section is covered with a MALDI matrix, which facilitates desorption and ionization of intact peptides and proteins that can be detected with a mass analyzer, typically using a MALDI TOF/TOF mass spectrometer. Generally hundreds of peaks can be assessed in a single rat brain tissue section. In contrast to commonly used imaging techniques, this approach does not require prior knowledge of the molecules of interest and allows for unsupervised and comprehensive analysis of multiple molecular species while maintaining high molecular specificity and sensitivity2. Here we describe a MALDI IMS based approach for elucidating region-specific distribution profiles of neuropeptides in the rat brain of an animal model Parkinson's disease (PD). 
PD is a common neurodegenerative disease with a prevalence of 1% for people over 65 of age3,4. The most common symptomatic treatment is based on dopamine replacement using L-DOPA5. However this is accompanied by severe side effects including involuntary abnormal movements, termed L-DOPA-induced dyskinesias (LID)1,3,6. One of the most prominent molecular change in LID is an upregulation of the opioid precursor prodynorphin mRNA7. The dynorphin peptides modulate neurotransmission in brain areas that are essentially involved in movement control7,8. However, to date the exact opioid peptides that originate from processing of the neuropeptide precursor have not been characterized. Therefore, we utilized MALDI IMS in an animal model of experimental Parkinson's disease and L-DOPA induced dyskinesia. 
MALDI imaging mass spectrometry proved to be particularly advantageous with respect to neuropeptide characterization, since commonly used antibody based approaches targets known peptide sequences and previously observed post-translational modifications. By contrast MALDI IMS can unravel novel peptide processing products and thus reveal new molecular mechanisms of neuropeptide modulation of neuronal transmission. While the absolute amount of neuropeptides cannot be determined by MALDI IMS, the relative abundance of peptide ions can be delineated from the mass spectra, giving insights about changing levels in health and disease. In the examples presented here, the peak intensities of dynorphin B, alpha-neoendorphin and substance P were found to be significantly increased in the dorsolateral, but not the dorsomedial, striatum of animals with severe dyskinesia involving facial, trunk and orolingual muscles (Fig. 5). Furthermore, MALDI IMS revealed a correlation between dyskinesia severity and levels of des-tyrosine alpha-neoendorphin, representing a previously unknown mechanism of functional inactivation of dynorphins in the striatum as the removal of N-terminal tyrosine reduces the dynorphin's opioid-receptor binding capacity9. This is the first study on neuropeptide characterization in LID using MALDI IMS and the results highlight the potential of the technique for application in all fields of biomedical research.

MALDI Imaging Mass Spectrometry of Neuropeptides in Parkinson&#039;s Disease

Dopamine replacement pharmacotherapy using L-DOPA is the most commonly used symptomatic treatment of Parkinson&#x2019;s disease, but is accompanied by side effects including involuntary abnormal movements, termed dyskinesia 1. Here, a protocol for MALDI imaging mass spectrometry is presented that detects changes in rat brain neuropeptide levels related to dyskinesia.

MALDI成像帕金森病的神经肽质谱

MALDI imaging mass spectrometry (IMS) is a powerful approach that facilitates the spatial analysis of molecular species in biological tissue samples2 ...

科研

医学

Skin Punch Biopsy Explant Culture for Derivation of Primary Human Fibroblasts

Tissues and cell lines derived from an individual with disease are ideal sources to study disease-related cellular phenotypes. Patient-derived fibroblasts in this protocol have been successfully used in the derivation of induced pluripotent stem cells to model disease1. Early passages of these fibroblasts can also be used for cell-based functional assays to study specific disease pathways, mechanisms2 and subsequent drug screening approaches. The advantage of the presented protocol over enzymatic procedures are 1) the reproducibility of the technique from small amounts of tissue derived from older patients, e.g. patients affected with Parkinson's disease, 2) the technically simple approach over more challenging methodologies using enzymatic treatments, and 3) the time consideration: this protocol takes 15-20 min and can be performed immediately after biopsy arrival. Enzymatic treatments can take up to 4 hr and have the problems of overdigestion, reduction of cell viability and subsequent attachment of cells when not handled properly. This protocol describes the dissection and preparation of a 4-mm human skin biopsy for derivation of a fibroblast culture and has a very high success rate which is important when dealing with patient-derived tissue samples. In this culture, keratinocytes migrate out of the biopsy tissue within the first week after preparation. Fibroblasts appear 7-10 days after the first outgrowth of keratinocytes. DMEM high glucose media supplemented with 20% FBS favors the growth of fibroblasts over keratinocytes and fibroblasts will overgrow the keratinocytes. After 2 passages keratinocytes have been diluted out resulting in relatively homogenous fibroblast cultures which expresses the fibroblast marker SERPINH1 (HSP-47). Using this approach, 15-20 million fibroblasts can be derived in 4-8 weeks for cell banking. The skin dissection takes about 15-20 min, cells are then monitored once a day under the microscope, and media is changed every 2-3 days after attachment and outgrowth of cells.

The fibroblast explant culture protocol from human skin punch biopsies is a technically robust and simple way to derive skin cells within 4-8 weeks for banking of about 15-20 million cells at a low passage number.

推导人类纤维原细胞的皮肤穿刺活检植文化

Tissues and cell lines derived from an individual with disease are ideal sources to study disease-related cellular phenotypes. Patient-derived fibroblasts ...

The Use of Primary Human Fibroblasts for Monitoring Mitochondrial Phenotypes in the Field of Parkinson's Disease

Parkinson's disease (PD) is the second most common movement disorder and affects 1% of people over the age of 60 1. Because ageing is the most important risk factor, cases of PD will increase during the next decades 2. Next to pathological protein folding and impaired protein degradation pathways, alterations of mitochondrial function and morphology were pointed out as further hallmark of neurodegeneration in PD 3-11.
After years of research in murine and human cancer cells as in vitro models to dissect molecular pathways of Parkinsonism, the use of human fibroblasts from patients and appropriate controls as ex vivo models has become a valuable research tool, if potential caveats are considered. Other than immortalized, rather artificial cell models, primary fibroblasts from patients carrying disease-associated mutations apparently reflect important pathological features of the human disease.
Here we delineate the procedure of taking skin biopsies, culturing human fibroblasts and using detailed protocols for essential microscopic techniques to define mitochondrial phenotypes. These were used to investigate different features associated with PD that are relevant to mitochondrial function and dynamics. Ex vivo, mitochondria can be analyzed in terms of their function, morphology, colocalization with lysosomes (the organelles degrading dysfunctional mitochondria) and degradation via the lysosomal pathway. These phenotypes are highly relevant for the identification of early signs of PD and may precede clinical motor symptoms in human disease-gene carriers. Hence, the assays presented here can be utilized as valuable tools to identify pathological features of neurodegeneration and help to define new therapeutic strategies in PD.

The Use of Primary Human Fibroblasts for Monitoring Mitochondrial Phenotypes in the Field of Parkinson&#039;s Disease

Fibroblasts from patients carrying mutations in Parkinson's disease-causing genes represent an easily accessible ex vivo model to study disease-associated phenotypes. Live cell imaging gives the opportunity to study morphological and functional parameters in living cells. Here we describe the preparation of human fibroblasts and subsequent monitoring of mitochondrial phenotypes.

利用人类纤维原细胞线粒体表型的监测领域的帕金森氏病

Parkinson's disease (PD) is the second most  common movement disorder and affects 1% of people over the age of 60 1. Because ageing is  the most important ...

A Simple Method of Mouse Lung Intubation

A simple procedure to intubate mice for pulmonary function measurements would have several advantages in longitudinal studies with limited numbers or expensive animal. One of the reasons that this is not done more routinely is that it is relatively difficult, despite there being several published studies that describe ways to achieve it. In this paper we demonstrate a procedure that eliminates one of the major hurdles associated with this intubation, that of visualizing the trachea during the entire time of intubation. The approach uses a 0.5 mm fiberoptic light source that serves as an introducer to direct the intubation cannula into the mouse trachea. We show that it is possible to use this procedure to measure lung mechanics in individual mice over a time course of at least several weeks. The technique can be set up with relatively little expense and expertise, and it can be routinely accomplished with relatively little training. This should make it possible for any laboratory to routinely carry out this intubation, thereby allowing longitudinal studies in individual mice, thereby minimizing the number of mice needed and increasing the statistical power by using each mouse as its own control.

This paper describes a striaghforward and efficient method of intubating mice for pulmonary function measurements or pulmonary instillation, that allows the mice to recover and be studied at later times. The procedure involves an inexpensive fiberoptic light source that directly illuminates the trachea.

一个简单的方法小鼠肺插管

A  simple procedure to intubate mice for pulmonary function measurements would  have several advantages in longitudinal studies with limited numbers or  ...

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

Lipoxygenase (LOX) activity has been implicated in neurodegenerative disorders such as Alzheimer&#39;s disease, but its effects in Parkinson&#39;s disease (PD) pathogenesis are less understood. Gene-environment interaction models have utility in unmasking the impact of specific cellular pathways in toxicity that may not be observed using a solely genetic or toxicant disease model alone.&#160;To evaluate if distinct LOX isozymes selectively contribute to PD-related neurodegeneration, transgenic (i.e. 5-LOX and 12/15-LOX deficient) mice can be challenged with a toxin that mimics cell injury and death in the disorder.&#160;Here we describe the use of a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces a nigrostriatal lesion to elucidate the distinct contributions of LOX isozymes to neurodegeneration related to PD. The use of MPTP in mouse, and nonhuman primate, is well-established to recapitulate the nigrostriatal damage in PD.&#160;The extent of MPTP-induced lesioning is measured by HPLC analysis of dopamine and its metabolites and semi-quantitative Western blot analysis of striatum for tyrosine hydroxylase (TH), the rate-limiting enzyme for the synthesis of dopamine. To assess inflammatory markers, which may demonstrate LOX isozyme-selective sensitivity, glial fibrillary acidic protein (GFAP) and Iba-1 immunohistochemistry are performed on brain sections containing substantia nigra, and GFAP Western blot analysis is performed on striatal homogenates.&#160;This experimental approach can provide novel insights into gene-environment interactions underlying nigrostriatal degeneration and PD.

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson&#039;s Disease

Lipoxygenase (LOX) isozymes can generate products that may increase or decrease neuroinflammation and neurodegeneration.&#160;A gene-environment interaction study could identify LOX isozyme-specific effects. Using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of nigrostriatal damage in two LOX isozyme-deficient transgenic lines allows for comparison of the contribution of LOX isozymes on dopaminergic integrity and inflammation.

基因-环境相互作用模型揭开帕金森病的隐形易感机制

Lipoxygenase (LOX) activity has been implicated in neurodegenerative disorders such as Alzheimer&#39;s disease, but its effects in Parkinson&#39;s disease ...

Controlling Parkinson's Disease With Adaptive Deep Brain Stimulation

Adaptive deep brain stimulation (aDBS) has the potential to improve the treatment of Parkinson&#39;s disease by optimizing stimulation in real time according to fluctuating disease and medication state. In the present realization of adaptive DBS we record and stimulate from the DBS electrodes implanted in the subthalamic nucleus of patients with Parkinson&#39;s disease in the early post-operative period. Local field potentials are analogue filtered between 3 and 47 Hz before being passed to a data acquisition unit where they are digitally filtered again around the patient specific beta peak, rectified and smoothed to give an online reading of the beta amplitude. A threshold for beta amplitude is set heuristically, which, if crossed, passes a trigger signal to the stimulator. The stimulator then ramps up stimulation to a pre-determined clinically effective voltage over 250 msec and continues to stimulate until the beta amplitude again falls down below threshold. Stimulation continues in this manner with brief episodes of ramped DBS during periods of heightened beta power.
Clinical efficacy is assessed after a minimum period of stabilization (5 min) through the unblinded and blinded video assessment of motor function using a selection of scores from the Unified Parkinson&#39;s Rating Scale (UPDRS). Recent work has demonstrated a reduction in power consumption with aDBS as well as an improvement in clinical scores compared to conventional DBS. Chronic aDBS could now be trialed in Parkinsonism.

Controlling Parkinson&#039;s Disease With Adaptive Deep Brain Stimulation

Adaptive deep brain stimulation (aDBS) is effective for Parkinson&#8217;s disease, improving symptoms and reducing power consumption compared to conventional deep brain stimulation (cDBS). In aDBS we track a local field potential biomarker (beta oscillatory amplitude) in real time and use this to control the timing of stimulation.

控制帕金森氏症与自适应深部脑刺激

Adaptive deep brain stimulation (aDBS) has the potential to improve the treatment of Parkinson&#39;s disease by optimizing stimulation in real time ...

Establishment and Characterization of UTI and CAUTI in a Mouse Model

Urinary tract infections (UTI) are highly prevalent, a significant cause of morbidity and are increasingly resistant to treatment with antibiotics. Females are disproportionately afflicted by UTI: 50% of all women will have a UTI in their lifetime. Additionally, 20-40% of these women who have an initial UTI will suffer a recurrence with some suffering frequent recurrences with serious deterioration in the quality of life, pain and discomfort, disruption of daily activities, increased healthcare costs, and few treatment options other than long-term antibiotic prophylaxis. Uropathogenic Escherichia coli (UPEC) is the primary causative agent of community acquired UTI. Catheter-associated UTI (CAUTI) is the most common hospital acquired infection accounting for a million occurrences in the US annually and dramatic healthcare costs. While UPEC is also the primary cause of CAUTI, other causative agents are of increased significance including Enterococcus faecalis. Here we utilize two well-established mouse models that recapitulate many of the clinical characteristics of these human diseases. For UTI, a C3H/HeN model recapitulates many of the features of UPEC virulence observed in humans including host responses, IBC formation and filamentation. For CAUTI, a model using C57BL/6 mice, which retain catheter bladder implants, has been shown to be susceptible to E. faecalis bladder infection. These representative models are being used to gain striking new insights into the pathogenesis of UTI disease, which is leading to the development of novel therapeutics and management or prevention strategies.

The ability to model urinary tract infections (UTI) is crucial in order to be able to understand bacterial pathogenesis and spawn the development of novel therapeutics. This work&#8217;s goal is to demonstrate mouse models of experimental UTI and catheter associated UTI that recapitulate and predict findings seen in humans.

建立和UTI和CAUTI表征在小鼠模型

Urinary tract infections (UTI) are highly prevalent, a significant cause of morbidity and are increasingly resistant to treatment with antibiotics. ...

A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS

The SOD1-G93A transgenic mouse is the most widely used animal model of amyotrophic lateral sclerosis (ALS). At ALS TDI we developed a phenotypic screening protocol, demonstrated in video herein, which reliably assesses the neuromuscular function of SOD1-G93A mice in a quick manner. This protocol encompasses a simple neurological scoring system (NeuroScore) designed to assess hindlimb function. NeuroScore is focused on hindlimb function because hindlimb deficits are the earliest reported neurological sign of disease in SOD1-G93A mice. The protocol developed by ALS TDI provides an unbiased assessment of onset of paresis (slight or partial paralysis), progression and severity of paralysis and it is sensitive enough to identify drug-induced changes in disease progression. In this report, the combination of a detailed manuscript with video minimizes scoring ambiguities and inter-experimenter variability thus allowing for the protocol to be adopted by other laboratories and enabling comparisons between studies taking place at different settings. We believe that this video protocol can serve as an excellent training tool for present and future ALS researchers.

This video protocol describes a sensitive, reliable, and quick method for evaluating the neuromuscular deficits in a transgenic mouse model of amyotrophic lateral sclerosis.

一个快速的表型神经评分系统在ALS的SOD1-G93A小鼠模型评估疾病进展

The SOD1-G93A transgenic mouse is the most widely used animal model of amyotrophic lateral sclerosis (ALS). At ALS TDI we developed a phenotypic screening ...

A Neonatal Mouse Spinal Cord Compression Injury Model

Spinal cord injury (SCI) typically causes devastating neurological deficits, particularly through damage to fibers descending from the brain to the spinal cord. A major current area of research is focused on the mechanisms of adaptive plasticity that underlie spontaneous or induced functional recovery following SCI. Spontaneous functional recovery is reported to be greater early in life, raising interesting questions about how adaptive plasticity changes as the spinal cord develops. To facilitate investigation of this dynamic, we have developed a SCI model in the neonatal mouse. The model has relevance for pediatric SCI, which is too little studied. Because neural plasticity in the adult involves some of the same mechanisms as neural plasticity in early life1, this model may potentially have some relevance also for adult SCI. Here we describe the entire procedure for generating a reproducible spinal cord compression (SCC) injury in the neonatal mouse as early as postnatal (P) day 1. SCC is achieved by performing a laminectomy at a given spinal level (here described at thoracic levels 9-11) and then using a modified Yasargil aneurysm mini-clip to rapidly compress and decompress the spinal cord. As previously described, the injured neonatal mice can be tested for behavioral deficits or sacrificed for ex vivo physiological analysis of synaptic connectivity using electrophysiological and high-throughput optical recording techniques1. Earlier and ongoing studies using behavioral and physiological assessment have demonstrated a dramatic, acute impairment of hindlimb motility followed by a complete functional recovery within 2 weeks, and the first evidence of changes in functional circuitry at the level of identified descending synaptic connections1.

This article describes a method for generating a reproducible spinal cord compression injury (SCI) in the neonatal mouse. The model provides an advantageous platform for studying mechanisms of adaptive plasticity that underlie spontaneous functional recovery.

新生儿小鼠脊髓压迫损伤模型

Spinal cord injury (SCI) typically causes devastating neurological deficits, particularly through damage to fibers descending from the brain to the spinal ...

Development of an Alpha-synuclein Based Rat Model for Parkinson's Disease via Stereotactic Injection of a Recombinant Adeno-associated Viral Vector

In order to study the molecular pathways of Parkinson&#39;s disease (PD) and to develop novel therapeutic strategies, scientific investigators rely on animal models. The identification of PD-associated genes has led to the development of genetic PD models. Most transgenic &#945;-SYN mouse models develop gradual &#945;-SYN pathology but fail to display clear dopaminergic cell loss and dopamine-dependent behavioral deficits. This hurdle was overcome by direct targeting of the substantia nigra with viral vectors overexpressing PD-associated genes. Local gene delivery using viral vectors provides an attractive way to express transgenes in the central nervous system. Specific brain regions can be targeted (e.g. the substantia nigra), expression can be induced in the adult setting and high expression levels can be achieved. Further, different vector systems based on various viruses can be used. The protocol outlines all crucial steps to perform a viral vector injection in the substantia nigra of the rat to develop a viral vector-based alpha-synuclein animal model for Parkinson&#39;s disease.

Development of an Alpha-synuclein Based Rat Model for Parkinson&#039;s Disease via Stereotactic Injection of a Recombinant Adeno-associated Viral Vector

This manuscript describes how viral vector-mediated local gene delivery provides an attractive way to express transgenes in the central nervous system. The protocol outlines all crucial steps to perform a viral vector injection in the substantia nigra of the rat to develop a viral vector-based animal model for Parkinson's disease.

通过重组腺相关病毒载体注射立体的α-突触核蛋白基于大鼠模型为帕金森氏病的发展

In order to study the molecular pathways of Parkinson&#39;s disease (PD) and to develop novel therapeutic strategies, scientific investigators rely on ...