Genetic, Molecular and Anatomical Characterization of VTA Cell Types Involved in Pain and Addiction
与疼痛和成瘾相关的 VTA 细胞类型的遗传、分子和解剖学特征
基本信息
- 批准号:10198888
- 负责人:
- 金额:$ 24.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAnatomyBehavioralBrainBypassCalciumCellsCharacteristicsCommon CoreDataDevelopmentDorsalDrug abuseExhibitsExpression ProfilingFoundationsGene ExpressionGene Expression ProfileGene Expression ProfilingGenesGeneticGlutamatesGoalsHeterogeneityHippocampus (Brain)HumanImageIndividualLabelLateralLightMapsMedialModelingMolecularMolecular ProfilingMolecular TargetMusNeurogliaNeuronsNucleus AccumbensOpiate AddictionOpioidOutputPainPathologicPathway interactionsPhysiologicalPhysiologyPopulationPositioning AttributeProcessPropertyRabies virusRewardsRodentSOX6 geneSliceSourceStructureSurveysUnited States National Institutes of HealthValidationVentral Tegmental AreaWorkaddictionbasebrain abnormalitiescandidate validationcell typechronic painchronic pain managementchronic painful conditiondopaminergic neurongenetic approachhuman subjectin vivomorphine administrationmouse modelnovelopioid usepain modelreceptorresponsetooltranscriptomics
项目摘要
Abstract
The VTA is a central hub for two prevalent pathological conditions - chronic pain and opioid addiction. In
both these conditions, the physiological properties of neurons in the VTA are significantly altered. Recent
evidence suggests that in the case of opioid addiction, not all VTA neurons respond equally, and in the case of
pain, different VTA neurons display complementary responses. A clear description of cell types in the VTA, their
cognate projections and inputs, and which of these might be involved in these two conditions has not been well
elucidated, and is essential to understand these pathological conditions. Here, we propose to determine the
cellular, molecular and anatomical landscape of VTA cell types and how these are altered in chronic pain and
addiction models.
The VTA displays enormous cellular heterogeneity, being comprised of DA neurons, GABAergic neurons
and Glutamatergic neurons, as well as non-neuronal cells. Further, among the DA neurons there is additional
layer of heterogeneity, and at least four VTA DA subtypes have been demonstrated. This immense heterogeneity
presents a problem for understanding VTA circuitry as well as its alterations in these conditions. Here, our goal
is to disentangle the murine VTA into its constituent cellular components, towards understanding how these
individual components are altered in pain and addiction. In Specific Aim 1, we will use single cell transcriptomics
to analyze VTA cells in conditions of chronic pain, morphine administration, or both. We expect to first subdivide
the VTA into its constituent cell types, and then evaluate the molecular changes within each cell type, in each
condition. This aim will facilitate discovery of new molecular targets towards treatment of chronic pain. In
Specific Aim 2, using newly developed intersectional genetic tools to access VTA cell types, we will determine
the projections of several classes of VTA DA and non-DA neurons. Next, we will develop an intersectional rabies
virus labeling approach to determine the inputs of distinct VTA cell types. This aim will provide a neuroanatomical
foundation for understanding circuits involved in these pathological conditions. Finally, in Specific Aim 3, guided
by data from Aim 1 and 2, we will identify and validate novel targets in specific DA cell types, with the goal of
reversing the hypo-dopaminergic state that is characteristic of chronic pain.
The results of these Aims will provide a molecular, cellular and anatomical framework for understanding
VTA cell types, that will be relevant to all projects in this P50. Additionally, the discovery and validation of
candidate receptors in distinct VTA cell types, will provide an excellent entry point towards developing
alternatives to opioids in the management of chronic pain.
摘要
腹侧被盖区是两种常见病理状态的中心枢纽-慢性疼痛和阿片类药物成瘾。在
在这两种情况下,腹侧被盖区神经元的生理特性显著改变。最近
有证据表明,在阿片类药物成瘾的情况下,并非所有VTA神经元的反应都是一样的,
疼痛时,不同的腹侧被盖区神经元表现出互补的反应。VTA中细胞类型的清晰描述,
同源预测和输入,以及其中哪些可能涉及这两个条件一直没有很好
阐明,并且对于理解这些病理条件是必不可少的。在这里,我们建议确定
VTA细胞类型的细胞、分子和解剖学景观,以及这些在慢性疼痛和
成瘾模型
腹侧被盖区显示出巨大的细胞异质性,由DA能神经元、GABA能神经元、
和谷氨酸能神经元,以及非神经元细胞。此外,在DA神经元中,
层的异质性,和至少四个VTA DA亚型已被证明。这种巨大的异质性
提出了一个问题,了解VTA电路,以及其在这些条件下的变化。在这里,我们的目标
是将鼠腹侧被盖区分解成其组成细胞成分,
在疼痛和成瘾中个别成分会发生改变。在特定目标1中,我们将使用单细胞转录组学
分析慢性疼痛、吗啡给药或两者兼而有之条件下的腹侧被盖区细胞。我们希望首先细分
将VTA分为其组成细胞类型,然后评估每种细胞类型内的分子变化,
条件这一目标将有助于发现治疗慢性疼痛的新分子靶点。在
具体目标2,使用新开发的交叉遗传工具来访问VTA细胞类型,我们将确定
VTA DA和非DA神经元的几类投射。接下来,我们将制定一个交叉狂犬病
病毒标记方法来确定不同VTA细胞类型的输入。这一目标将提供一个神经解剖学
这是理解这些病理状态所涉及的电路的基础。第三,明确目标,引导
通过目标1和目标2的数据,我们将在特定的DA细胞类型中识别和验证新的靶点,目标是
逆转作为慢性疼痛特征的低多巴胺能状态。
这些目标的结果将提供一个分子,细胞和解剖学框架的理解
VTA细胞类型,这将与本P50中的所有项目相关。此外,发现和验证
不同VTA细胞类型中的候选受体,将提供一个很好的切入点,
阿片类药物在慢性疼痛管理中的替代品。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Rajeshwar B Awatramani其他文献
Rajeshwar B Awatramani的其他文献
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黑质脆弱性的发育基础
- 批准号:
10322048 - 财政年份:2021
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$ 24.89万 - 项目类别:
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$ 24.89万 - 项目类别:
Genetic, Molecular and Anatomical Characterization of VTA Cell Types Involved in Pain and Addiction
与疼痛和成瘾相关的 VTA 细胞类型的遗传、分子和解剖学特征
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10440297 - 财政年份:2018
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