这项工作是由国家神经紊乱和中风研究所（NS - 19108），全国儿童健康与疾病研究所（PO1 - HD09402），偏头痛研究基金会和白基金会的赠款支持。玛西娅体育Kraig女士的协助下在编制和维护文化系统。

<ol>
	<li>Kunkler, P. E., Kraig, R. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Calcium+waves+precede+electrophysiological+changes+of+spreading+depression+in+hippocampal+organ+cultures.">Calcium waves precede electrophysiological changes of spreading depression in hippocampal organ cultures.</a> J Neurosci. 18 (9), 3416-3425 (1998).</li><li>Kunkler, P. E., Hulse, R. E., Schmitt, M. W., Nicholson, C., Kraig, R. 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P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cold+pre-conditioning+neuroprotection+depends+on+TNF-&#x03B1;lpha+and+is+enhanced+by+blockade+of+interleukin-11.">Cold pre-conditioning neuroprotection depends on TNF-&#x03B1;lpha and is enhanced by blockade of interleukin-11.</a> J Neurochem DOI. , (2010).</li><li>Mitchell, H. M., White, D. M., Kraig, R. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Strategies+for+study+of+neuroprotection+from+cold-preconditioning.">Strategies for study of neuroprotection from cold-preconditioning.</a> J Vis Exp. (43), (2010).</li><li>Kunkler, P. E., Kraig, R. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reactive+astrocytosis+from+excitotoxic+injury+in+hippocampal+organ+culture+parallels+that+seen+in+vivo.">Reactive astrocytosis from excitotoxic injury in hippocampal organ culture parallels that seen in vivo.</a> J Cereb Blood Flow Metab. 17 (1), 26-43 (1997).</li><li>Grinberg, Y. Y., Milton, J. G., Kraig, R. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Spreading+depression+sends+microglia+on+Lévy+flights.">Spreading depression sends microglia on Lévy flights.</a> PLoS ONE. 6 (4), (2011).</li><li>Koroleva, V. I., Oitzl, M. S., Bures, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Threshold+of+synaptically+elicited+cortical+spreading+depression:+drug-induced+changes+in+rats.">Threshold of synaptically elicited cortical spreading depression: drug-induced changes in rats.</a> Electroencephalogr Clin Neurophysiol. 60 (1), 55-64 (1985).</li><li>Gubern, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Validation+of+housekeeping+genes+for+quantitative+real-time+PCR+in+in-vivo+and+in-vitro+models+of+cerebral+ischaemia.">Validation of housekeeping genes for quantitative real-time PCR in in-vivo and in-vitro models of cerebral ischaemia.</a> BMC Mol Biol. 10, 57-57 (2009).</li><li>Tian, Y. 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SD是阵发性脑扰动，其在所有物种和大脑区域高度保守的特点研究迄今。 SD通常是在大脑皮层的研究。然而，这种结构的神经回路的复杂性（海马），以及无法保持大脑皮层长期时期的静态免疫功能的体外存活，在体外制备它作为一个有用的定义的长期后果SD的易感性。相比之下，海马不仅是大脑的结构是最敏感到SD的，它也是一个更简化的神经回路的结构和功能，这是适合定义神经活动可以调节的SD易感性neuroimmune手段archicortical结构。

modeling neural immune signaling of episodic and chronic migraine using spreading depression in vitro

偏头痛和慢性偏头痛的转变是需要改进治疗方案的医疗负担。我们寻求定义神经免疫信号调制易患偏头痛为蓝本， 在体外使用扩散性抑制（SD）作为一种手段来发展新的治疗靶点，为阵发性和慢性偏头痛。 SD是偏头痛先兆偏头痛的可能原因。它是一个由最初增加神经元的活动，慢慢易受影响的大脑区域内传播引发的神经功能阵发性的损失。正常的脑功能是极其敏感，依赖，同步低层次的免疫信号。因此，神经免疫信号可能会影响电活动的SD，因此，偏头痛。 SD疼痛的感知，在整个动物的研究困难重重，但很适合整体动物研究偏头痛的系统生物学方面，因为SD激活三叉神经的痛觉通路。不过，整体动物研究本身不能被用来破译的SD细胞和神经回路机制。相反， 在体外可以控制的环境条件下的准备工作是必要的。在这里，重要的是要承认急性切片和海马脑片培养具有明显的优势的局限性。急性脑切片不能透露，因为准备的片单独触发免疫信号的微妙的变化:亲炎性改变，最后几天，癫痫行为由于高氧张力的水平，需要振兴的切片，和不可逆的细胞损伤，缺氧片中心。 相比之下，我们在成熟的海马脑片培养的免疫信号，因为文化紧密平行在体内对口，具有成熟的trisynaptic功能;显示静态的星形胶质细胞，小胶质细胞和细胞因子水平; SD很容易诱发unanesthetized准备。此外，片长寿命和SD可以连续两天无损伤引起的，这种准备的唯一手段日期建模慢性SD neuroimmune后果，因此也许是慢性偏头痛。我们使用的电生理技术和非侵入性的成像测量神经细胞和电路功能与SD重合。神经免疫基因的表达变量定量PCR筛选，qPCR的阵列，cDNA的前置放大，更重要的是，使用超低水平，如γ-干扰素使用整个区域，或特定的细胞增强的目标检测与测量（通过激光清扫显微镜）抽样检验。细胞因子的级联信号的进一步评估复磷相关的目标与基因的表达，并通过细胞特异性免疫证实磷的变化。药理和siRNA的策略是用来模拟和调节免疫信号的SD 。

Watch this Scientific Journal Video about Modeling Neural Immune Signaling of Episodic and Chronic Migraine Using Spreading Depression In Vitro at JoVE.com

Modeling Neural Immune Signaling of Episodic and Chronic Migraine Using Spreading Depression In Vitro

偏头痛和慢性偏头痛的转变是巨大的医疗负担，需要改进治疗方案。我们寻求神经免疫信号调制易患偏头痛如何定义，建模<em&gt;在体外</em使用在海马脑片培养扩散性抑制，作为一种手段，以开发新的治疗靶点。

使用扩频萧条的情节和慢性偏头痛的神经免疫信号建模<em在体外</em

Migraine and its transformation to chronic migraine are healthcare burdens in need of improved treatment options.  We seek to define how neural immune ...

modeling-neural-immune-signaling-episodic-chronic-migraine-using

Universidad de Cartagena UDEC

Research

JoVE Journal

Neuroscience

Modeling Neural Immune Signaling of Episodic and Chronic Migraine Using Spreading Depression In Vitro

20.0K 次观看.  The University of Chicago Medical Center. 偏头痛和慢性偏头痛的转变是巨大的医疗负担，需要改进治疗方案。我们寻求神经免疫信号调制易患偏头痛如何定义，建模在体外

视频: Modeling Neural Immune Signaling of Episodic and Chronic Migraine Using Spreading Depression In Vitro

3D-Neuronavigation In Vivo Through a Patient's Brain During a Spontaneous Migraine Headache

A growing body of research, generated primarily from MRI-based studies, shows that migraine appears to occur, and possibly endure, due to the alteration of specific neural processes in the central nervous system. However, information is lacking on the molecular impact of these changes, especially on the endogenous opioid system during migraine headaches, and neuronavigation through these changes has never been done. This study aimed to investigate, using a novel 3D immersive and interactive neuronavigation (3D-IIN) approach, the endogenous &#181;-opioid transmission in the brain during a migraine headache attack in vivo. This is arguably one of the most central neuromechanisms associated with pain regulation, affecting multiple elements of the pain experience and analgesia. A 36 year-old female, who has been suffering with migraine for 10 years, was scanned in the typical headache (ictal) and nonheadache (interictal) migraine phases using Positron Emission Tomography (PET) with the selective radiotracer [11C]carfentanil, which allowed us to measure &#181;-opioid receptor availability in the brain (non-displaceable binding potential - &#181;OR BPND). The short-life radiotracer was produced by a cyclotron and chemical synthesis apparatus on campus located in close proximity to the imaging facility. Both PET scans, interictal and ictal, were scheduled during separate mid-late follicular phases of the patient's menstrual cycle. During the ictal PET session her spontaneous headache attack reached severe intensity levels; progressing to nausea and vomiting at the end of the scan session. There were reductions in &#181;OR BPND in the pain-modulatory regions of the endogenous &#181;-opioid system during the ictal phase, including the cingulate cortex, nucleus accumbens (NAcc), thalamus (Thal), and periaqueductal gray matter (PAG); indicating that &#181;ORs were already occupied by endogenous opioids released in response to the ongoing pain. To our knowledge, this is the first time that changes in &#181;OR BPND during a migraine headache attack have been neuronavigated using a novel 3D approach. This method allows for interactive research and educational exploration of a migraine attack in an actual patient's neuroimaging dataset.

3D-Neuronavigation In Vivo Through a Patient's Brain During a Spontaneous Migraine Headache

In this study, the authors report for the first time a novel 3D-Immersive &#38; Interactive Neuronavigation (3D-IIN) through the impact of a spontaneous migraine headache attack in the &#956;-opioid system of a patient's brain in vivo.

3D-神经导航<em&gt;在体内</em&gt;通过患者的大脑在一个自发性偏头痛

A growing body of research, generated primarily from MRI-based studies, shows that migraine appears to occur, and possibly endure, due to the alteration ...

科研

医学

Animal Models of Depression - Chronic Despair Model (CDM)

Major depressive disorder is one of the most prevalent forms of mental illnesses and causes tremendous individual suffering and socioeconomic burden. Despite its importance, current pharmacological treatment is limited, and novel treatment options are urgently needed. One key factor in the search for potential new drugs is evaluating their anti-depressive potency in appropriate animal models. The classical Porsolt forced swim test was used for this purpose for decades to induce and assess a depressive-like state. It consists of two short periods of forced swimming: the first to induce a depressed state and the second on the following day to evaluate the antidepressant effect of the agent given in between the two swim sessions. This model might be suitable as a screening tool for potential antidepressive agents but ignores the delayed onset of action of many antidepressants. The CDM was recently established and represented a modification of the classical test with notable differences. Mice are forced to swim for 5 consecutive days, following the idea that in humans, depression is induced by chronic rather than by acute stress. In a resting period of several days (1-3 weeks), animals develop sustained behavioral despair. The standard read-out method is the measurement of immobility time in an additional delayed swim session, but several alternative methods are proposed to get a broader view of the mood status of the animal. Multiple analysis tools can be used targeting behavioral, molecular, and electrophysiological changes. The depressed phenotype is stable for at least 4 weeks, providing a time window for rapid but also subchronic antidepressant treatment strategies. Furthermore, alterations in the development of a depressive-like state can be addressed using this approach. CDM, therefore, represents a useful tool to better understand depression and to develop novel treatment interventions.

Animal Models of Depression - Chronic Despair Model CDM

The chronic despair mouse model (CDM) of depression consists of repetitive forced swim sessions and another delayed swim phase as a read-out. It represents a suitable model for induction of a chronic depressive-like state stable for at least 4 weeks, amendable to evaluate subchronic and acute treatment interventions.

抑郁症的动物模型 - 慢性绝望模型（CDM）

Major depressive disorder is one of the most prevalent forms of mental illnesses and causes tremendous individual suffering and socioeconomic burden. ...

行为学

Investigating Migraine-Like Behavior Using Light Aversion in Mice

Migraine is a complex neurological disorder characterized by headache and sensory abnormalities, such as hypersensitivity to light, observed as photophobia. Whilst it is impossible to confirm that a mouse is experiencing migraine, light aversion can be used as a behavioral surrogate for the migraine symptom of photophobia. To test for light aversion, we utilize the light/dark assay to measure the time mice freely choose to spend in either a light or dark environment. The assay has been refined by introducing two critical modifications: pre-exposures to the chamber prior to running the test procedure and adjustable chamber lighting, permitting the use of a range of light intensities from 55 lux to 27,000 lux. Because the choice to spend more time in the dark is also indicative of anxiety, we also utilize a light-independent anxiety test, the open field assay, to distinguish anxiety from light-aversive behavior. Here, we describe a modified test paradigm for the light/dark and open field assays. The application of these assays is described for intraperitoneal injection of calcitonin gene-related peptide (CGRP) in two mouse strains and for optogenetic brain stimulation studies.

Rodents are not able to report migraine symptoms. Here, we describe a manageable test paradigm (light/dark and open field assays) to measure light aversion, one of the most common and bothersome symptoms in patients with migraines.

使用轻度厌恶研究小鼠偏头痛样行为

Migraine is a complex neurological disorder characterized by headache and sensory abnormalities, such as hypersensitivity to light, observed as ...

Induction of Experimental Autoimmune Encephalomyelitis in Mice and Evaluation of the Disease-dependent Distribution of Immune Cells in Various Tissues

Multiple sclerosis is presumed to be an inflammatory autoimmune disease, which is characterized by lesion formation in the central nervous system (CNS) resulting in cognitive and motor impairment. Experimental autoimmune encephalomyelitis (EAE) is a useful animal model of MS, because it is also characterized by lesion formation in the CNS, motor impairment and is also driven by autoimmune and inflammatory reactions. One of the EAE models is induced with a peptide derived from the myelin oligodendrocyte protein (MOG)35-55 in mice. The EAE mice develop a progressive disease course. This course is divided into three phases: the preclinical phase (day 0 - 9), the disease onset (day 10 - 11) and the acute phase (day 12 - 14). MS and EAE are induced by autoreactive T cells that infiltrate the CNS. These T cells secrete chemokines and cytokines which lead to the recruitment of further immune cells. Therefore, the immune cell distribution in the spinal cord during the three disease phases was investigated. To highlight the time point of the disease at which the activation/proliferation/accumulation of T cells, B cells and monocytes starts, the immune cell distribution in lymph nodes, spleen and blood was also assessed. Furthermore, the levels of several cytokines (IL-1&#946;, IL-6, IL-23, TNF&#945;, IFN&#947;) in the three disease phases were determined, to gain insight into the inflammatory processes of the disease. In conclusion, the data provide an overview of the functional profile of immune cells during EAE pathology.

This manuscript describes the methods for induction and scoring of the experimental autoimmune encephalomyelitis (EAE) model, together with the assessment of immune cell distribution and mRNA cytokine levels in lymph nodes, spleen, blood and spinal cord using flow cytometry and quantitative PCR, respectively, at various disease phases.

在免疫细胞在不同组织与疾病相关的分布和小鼠实验评价性自身免疫性脑脊髓炎的诱导

Multiple sclerosis is presumed to be an inflammatory autoimmune disease, which is characterized by lesion formation in the central nervous system (CNS) ...

免疫与感染

<meta charset="utf8"></head><body>使用 DeepLabCut 实时小鼠斜视检测偏头痛追踪

An Automated Squint Method for Time-syncing Behavior and Brain Dynamics in Mouse Pain Studies

Spontaneous pain has been challenging to track in real time and quantify in a way that prevents human bias. This is especially true for metrics of head pain, as in disorders such as migraine. Eye squint has emerged as a continuous variable metric that can be measured over time and is effective for predicting pain states in such assays. This paper provides a protocol for the use of DeepLabCut (DLC) to automate and quantify eye squint (Euclidean distance between eyelids) in restrained mice with freely rotating head motions. This protocol enables unbiased quantification of eye squint to be paired with and compared directly against mechanistic measures such as neurophysiology. We provide an assessment of AI training parameters necessary for achieving success as defined by discriminating squint and non-squint periods. We demonstrate an ability to reliably track and differentiate squint in a CGRP-induced migraine-like phenotype at a sub second resolution.

<meta charset="utf8"></head><body>作者聚焦：破译复杂大脑活动和疾病背后的电网

This protocol provides a method for tracking automated eye squint in rodents over time in a manner compatible with time-locking to neurophysiological measures. This protocol is expected to be useful to researchers studying mechanisms of pain disorders such as migraine.

一种用于小鼠疼痛研究中时间同步行为和大脑动力学的自动斜视方法

Spontaneous pain has been challenging to track in real time and quantify in a way that prevents human bias. This is especially true for metrics of head ...

Visualizing Impairment of the Endothelial and Glial Barriers of the Neurovascular Unit during Experimental Autoimmune Encephalomyelitis In Vivo

The neurovascular unit (NVU) is composed of microvascular endothelial cells forming the blood-brain barrier (BBB), an endothelial basement membrane with embedded pericytes, and the glia limitans composed by the parenchymal basement membrane and astrocytic end-feed embracing the abluminal aspect of central nervous system (CNS) microvessels. In addition to maintaining CNS homeostasis the NVU controls immune cell trafficking into the CNS. During immunosurveillance of the CNS low numbers of activated lymphocytes can cross the endothelial barrier without causing BBB dysfunction or clinical disease. In contrast, during neuroinflammation such as in multiple sclerosis or its animal model experimental autoimmune encephalomyelitis (EAE) a large number of immune cells can cross the BBB and subsequently the glia limitans eventually reaching the CNS parenchyma leading to clinical disease. 
Immune cell migration into the CNS parenchyma is thus a two-step process that involves a sequential migration across the endothelial and glial barrier of the NVU employing distinct molecular mechanisms. If following their passage across the endothelial barrier, T cells encounter their cognate antigen on perivascular antigen-presenting cells their local reactivation will initiate subsequent mechanisms leading to the focal activation of gelatinases, which will enable the T cells to cross the glial barrier and enter the CNS parenchyma. Thus, assessing both, BBB permeability and MMP activity in spatial correlation to immune cell accumulation in the CNS during EAE allows to specify loss of integrity of the endothelial and glial barriers of the NVU. 
We here show how to induce EAE in C57BL/6 mice by active immunization and how to subsequently analyze BBB permeability in vivo using a combination of exogenous fluorescent tracers. We further show, how to visualize and localize gelatinase activity in EAE brains by in situ zymogaphy coupled to immunofluorescent stainings of BBB basement membranes and CD45+ invading immune cells.

Here, we present protocols to investigate impairment of the neurovascular unit during experimental autoimmune encephalomyelitis in vivo. We specifically address how to determine blood-brain barrier permeability and gelatinase activity involved in leukocyte migration across the glia limitans.&#160;

体内自身免疫性脑髓炎实验性神经血管内障碍和胶质屏障的可视化

The neurovascular unit (NVU) is composed of microvascular endothelial cells forming the blood-brain barrier (BBB), an endothelial basement membrane with ...

脊髓组织学染色用于评估 EAE 疾病严重程度

Scoring Central Nervous System Inflammation, Demyelination, and Axon Injury in Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a common immune-based model of multiple sclerosis (MS). This disease can be induced in rodents by active immunization with protein components of the myelin sheath and Complete Freund&#39;s adjuvant (CFA) or by the transfer of myelin-specific T effector cells from rodents primed with myelin protein/CFA into na&#239;ve rodents. The severity of EAE is typically scored on a 5-point clinical scale that measures the degree of ascending paralysis, but this scale is not optimal for assessing the extent of recovery from EAE. For example, clinical scores remain high in some EAE models (e.g., myelin oligodendrocyte glycoprotein [MOG] peptide-induced model of EAE) despite the resolution of inflammation. Thus, it is important to complement clinical scoring with histological scoring of EAE, which also provides a means to study the underlying mechanisms of cellular injury in the central nervous system (CNS).
Here, a simple protocol is presented to prepare and stain spinal cord and brain sections from mice and to score inflammation, demyelination, and axonal injury in the spinal cord. The method for scoring leukocyte infiltration in the spinal cord can also be applied to score brain inflammation in EAE. A protocol for measuring soluble neurofilament light (sNF-L) in the serum of mice using a Small Molecule Assay (SIMOA) assay is also described, which provides&#160;feedback on the extent of overall CNS injury in live mice.

作者聚焦：揭示多发性硬化症中肥胖与自身免疫性炎症之间的通路 

Experimental autoimmune encephalomyelitis (EAE) serves as an animal model of multiple sclerosis. This article describes an approach for scoring spinal cord inflammation, demyelination, and axonal injury in EAE. Additionally, a method to quantify soluble neurofilament light levels in the mice serum is presented, facilitating the assessment of axonal injury in live mice.

对实验性自身免疫性脑脊髓炎中的中枢神经系统炎症、脱髓鞘和轴突损伤进行评分

Experimental autoimmune encephalomyelitis (EAE) is a common immune-based model of multiple sclerosis (MS). This disease can be induced in rodents by ...

使用扩频萧条的情节和慢性偏头痛的神经免疫信号建模

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3D-神经导航

抑郁症的动物模型 - 慢性绝望模型（CDM）

使用轻度厌恶研究小鼠偏头痛样行为

在免疫细胞在不同组织与疾病相关的分布和小鼠实验评价性自身免疫性脑脊髓炎的诱导

一种用于小鼠疼痛研究中时间同步行为和大脑动力学的自动斜视方法

一种用于小鼠疼痛研究中时间同步行为和大脑动力学的自动斜视方法

一种用于小鼠疼痛研究中时间同步行为和大脑动力学的自动斜视方法

体内自身免疫性脑髓炎实验性神经血管内障碍和胶质屏障的可视化

对实验性自身免疫性脑脊髓炎中的中枢神经系统炎症、脱髓鞘和轴突损伤进行评分

对实验性自身免疫性脑脊髓炎中的中枢神经系统炎症、脱髓鞘和轴突损伤进行评分