Comprehensive Phenotyping of Specific Populations of Spinal Neurons Processing Cutaneous Information Before and After Injury
损伤前后处理皮肤信息的脊髓神经元特定群体的综合表型
基本信息
- 批准号:10707980
- 负责人:
- 金额:$ 59.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-16 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAgonistAmericanBrainCalciumCapsaicinCatalogsCellsChemicalsChronicCodeCoupledCutaneousDataG-Protein-Coupled ReceptorsGoalsHandHealthHyperalgesiaImageIndividualInjuryKnowledgeLabelMeasuresMechanicsModelingMusNerveNeuronsNeuropathyNociceptionOpticsOutputPainPain managementPatientsPeripheralPersistent painPharmaceutical PreparationsPhenotypePhysiologicalPopulationPreparationProcessPropertyQuality of lifeResearchSensorySeriesSkinSpinalSpinal CordStimulusTestingTetrodotoxinThermal HyperalgesiasTransgenic MiceVertebral columnVisualizationallodyniacalcium indicatorcell typecellular imagingcentral sensitizationchronic paindorsal horneffective therapyexcitatory neuronexperienceheat stimulusimaging approachimaging studyinjuredinnovationinsightmechanical stimulusnerve injuryneuralneural circuitnew therapeutic targetnovelnovel strategiespain chronificationpain sensationpharmacologicprogramsreceptorrecruitresponsesensory inputsensory integrationsensory stimulussomatosensoryspared nervetooltwo-photon
项目摘要
ABSTRACT
Chronic pain is a debilitating condition for which there is a pressing need for safe, effective treatments. These
patients experience enhanced pain sensations and often experience pain when innocuous stimuli are
presented. However, the neural basis for this increased sensitivity is poorly understood. Here, we propose to
investigate the neural circuit basis for central hyperexcitability that may contribute to persistent pain. We will be
combining novel physiological, and pharmacological approaches to address our goals. Using existing
transgenic mouse lines, we can express the calcium indicator GCamp6s in all excitatory spinal neurons. We
can then use our novel ex vivo skin-spinal cord preparation and 2-photon calcium imaging to examine activity
in the spinal dorsal horn activity to cutaneous stimulation in naïve mice and those following injury. While this
approach will allow us to image the responses of many (~200) neurons simultaneously, it does not allow us to
identify different types of neurons, thereby severely hampering the degree to which the data can be
interpreted. Now, we have developed a novel approach to circumvent this limitation through post hoc
pharmacological identification of cell types. The underlying concept is that most neurons express one or more
Gq-coupled G-protein coupled receptors (GPCRs) whose activation results in the release of Ca2+ from internal
stores. In the presence of tetrodotoxin (TTX) to silence neuronal activity, the only neurons that show a Ca2+
transient in response to a given agonist are those that express its receptor. This approach, which we have
termed CICADA (Cell-type Identification by Ca2+-coupled Activity through Drug Activation), allows us to
unambiguously define cell types based on their responses to a series of GPCR agonists. Now we are uniquely
poised to address specific questions about the function of spinal circuitry and how the functional properties of
these circuits are altered following injury. In the first Aim we will extend and validate this analysis with the goal
of developing a complete repertoire dorsal horn subtypes that can be identified in population imaging studies.
While neurons respond to different types of sensory stimuli (e.g., heat, cold, and mechanical), how this coding
is manifest across neuronal populations is unclear. In the second Aim we will catalog functional response
properties across populations of CICADA-defined cell subtypes. In the third Aim we will examine the effects of
capsaicin induced acute central sensitization on these subpopulations. The chronification of pain is thought to
be associated with long-term changes in central network activity that perpetuate hyperalgesic states. In the
fourth Aim we will identify the CICADA-defined cell types that show altered activity in the context of chronic
pain using the spared nerve injury (SNI) as a model. The studies we are proposing here will begin to identify
specific spinal circuitry involved in central sensitization and investigate how these specific microcircuits are
altered in conditions of acute and chronic injury. This knowledge may elucidate new therapeutic targets for the
treatment of pain, which is the long-term goal of research of our program.
抽象的
慢性疼痛是一种使人衰弱的疾病,迫切需要安全、有效的治疗方法。这些
患者会感到疼痛感增强,并且当受到无害刺激时常常会感到疼痛。
提出。然而,人们对这种敏感性增加的神经基础知之甚少。在此,我们建议
研究可能导致持续性疼痛的中枢过度兴奋的神经回路基础。我们将会
结合新颖的生理学和药理学方法来实现我们的目标。使用现有的
在转基因小鼠品系中,我们可以在所有兴奋性脊髓神经元中表达钙指示剂GCamp6s。我们
然后可以使用我们新型的离体皮肤脊髓制剂和 2 光子钙成像来检查活性
幼稚小鼠和受伤后的小鼠的脊髓背角活动对皮肤刺激的影响。虽然这
方法将允许我们同时对许多(~200)神经元的反应进行成像,但它不允许我们
识别不同类型的神经元,从而严重阻碍了数据的可识别程度
解释了。现在,我们开发了一种新颖的方法来通过事后规避这一限制
细胞类型的药理学鉴定。基本概念是大多数神经元表达一种或多种
Gq 偶联的 G 蛋白偶联受体 (GPCR) 的激活导致内部 Ca2+ 的释放
商店。在存在河豚毒素 (TTX) 来抑制神经元活动的情况下,唯一显示 Ca2+ 的神经元
对给定激动剂的瞬时响应是那些表达其受体的激动剂。我们有这种方法
称为 CICADA(通过药物激活通过 Ca2+ 偶联活性进行细胞类型识别),使我们能够
根据细胞对一系列 GPCR 激动剂的反应,明确定义细胞类型。现在我们是独一无二的
准备解决有关脊髓回路功能的具体问题以及脊髓回路的功能特性如何
这些电路在受伤后会发生改变。在第一个目标中,我们将扩展并验证此分析,目标是
开发可以在群体成像研究中识别的完整的背角亚型。
虽然神经元对不同类型的感觉刺激(例如热、冷和机械)做出反应,但这种编码如何
是否在神经元群体中表现出来尚不清楚。在第二个目标中,我们将对功能响应进行分类
CICADA 定义的细胞亚型群体的特性。在第三个目标中,我们将研究以下效果:
辣椒素对这些亚群引起急性中枢敏化。疼痛的慢性化被认为是
与维持痛觉过敏状态的中枢网络活动的长期变化有关。在
第四个目标,我们将识别 CICADA 定义的细胞类型,这些细胞类型在慢性疾病背景下表现出改变的活性
使用幸存神经损伤(SNI)作为模型来缓解疼痛。我们在这里提出的研究将开始确定
参与中枢敏化的特定脊髓回路并研究这些特定微回路的作用
急性和慢性损伤的情况下会发生变化。这些知识可能会阐明新的治疗靶点
治疗疼痛,这是我们项目研究的长期目标。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Beyond lidocaine: selective voltage-gated sodium channel blockade for vaginal pain.
超越利多卡因:选择性电压门控钠通道阻断治疗阴道疼痛。
- DOI:10.1097/j.pain.0000000000002037
- 发表时间:2021
- 期刊:
- 影响因子:7.4
- 作者:Holland,RubyA;Ross,SarahE
- 通讯作者:Ross,SarahE
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H Richard Koerber其他文献
H Richard Koerber的其他文献
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{{ truncateString('H Richard Koerber', 18)}}的其他基金
Molecular genetic dissection of the spinal microcircuits of wind-up
缠绕脊髓微电路的分子遗传学解剖
- 批准号:
9246779 - 财政年份:2016
- 资助金额:
$ 59.99万 - 项目类别:
Comprehensive Phenotyping of Specific Populations of Spinal Neurons Processing Cutaneous Information Before and After Injury
损伤前后处理皮肤信息的脊髓神经元特定群体的综合表型
- 批准号:
10211006 - 财政年份:2016
- 资助金额:
$ 59.99万 - 项目类别:
Molecular genetic dissection of the spinal microcircuits of wind-up
缠绕脊髓微电路的分子遗传学解剖
- 批准号:
10011884 - 财政年份:2016
- 资助金额:
$ 59.99万 - 项目类别:
Molecular genetic dissection of the spinal microcircuits of wind-up
缠绕脊髓微电路的分子遗传学解剖
- 批准号:
9334948 - 财政年份:2016
- 资助金额:
$ 59.99万 - 项目类别:
Molecular genetic dissection of the spinal microcircuits of wind-up
缠绕脊髓微电路的分子遗传学解剖
- 批准号:
9767876 - 财政年份:2016
- 资助金额:
$ 59.99万 - 项目类别:
Primary and Secondary Nociceptors in Persistent Pain
持续性疼痛中的初级和次级伤害感受器
- 批准号:
7394912 - 财政年份:2006
- 资助金额:
$ 59.99万 - 项目类别:
Primary and Secondary Nociceptors in Persistent Pain
持续性疼痛中的初级和次级伤害感受器
- 批准号:
7797315 - 财政年份:2006
- 资助金额:
$ 59.99万 - 项目类别:
Primary and Secondary Nociceptors in Persistent Pain
持续性疼痛中的初级和次级伤害感受器
- 批准号:
7103893 - 财政年份:2006
- 资助金额:
$ 59.99万 - 项目类别:
Primary and Secondary Nociceptors in Persistent Pain
持续性疼痛中的初级和次级伤害感受器
- 批准号:
7224226 - 财政年份:2006
- 资助金额:
$ 59.99万 - 项目类别:
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