Pathophysiological Study of ALDH1A1-negative Nigrostriatal Dopaminergic Neuron Subtypes in Parkinson's disease

帕金森病 ALDH1A1 阴性黑质纹状体多巴胺能神经元亚型的病理生理学研究

• 批准号: 10688881
• 负责人: Huaibin Cai
• 金额: $ 70.12万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688881
• 关键词: Affect; Aversive Stimulus; Cells; Complex; Cues; DNA; Deep Brain Stimulation; Dopamine; Dyskinetic syndrome; Elderly; Gene Expression; Gene Expression Profile; Genetic; Genetic Markers; Genetic Variation; Genetic study; Impulsivity; Individual; Midbrain structure; Molecular Genetics; Motor; Muscle; Musculoskeletal Equilibrium; Neurodegenerative Disorders; Neurons; Operative Surgical Procedures; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology Study; Quality of life; Research; Resolution; Rest Tremor; Rewards; Role; SOX6 gene; Stimulus; Substantia nigra structure; Syndrome; Technology; Therapeutic Agents; Ventral Striatum; Ventral Tegmental Area; base; behavioral study; design; disorder control; dopaminergic neuron; improved; insight; motor control; motor impairment; motor symptom; novel; pars compacta; response; sensory stimulus; side effect; single-cell RNA sequencing

Various genetic, behavioral, and pharmacological studies have established a role of the nigrostriatal dopamine pathway in motor function, with reward largely associated with the mesolimbic dopamine pathway, which consists of dopaminergic connections that project from the ventral tegmental area (VTA) to the ventral striatum. However, research also supports the importance of the nigrostriatal dopamine pathway in reward, suggesting that both substantia nigra pars compacta (SNc) and VTA midbrain dopaminergic neurons (DANs) have altered firing in response to reward prediction and prediction errors. Studies show that reward-predicting stimuli result in SN activation, highlighting the fact that changes in midbrain DAN activity are not limited to the VTA. When considering SNc DANs specifically, there is again support for neuronal activation in response to reward or sensory stimuli that predict reward and inhibition by aversive stimuli. These DANs are located within the ventromedial part of the SNc adjacent to VTA, which raises the need to better define those two DAN subpopulations with more definitive genetic makers. On the other hand, there are also some SNc DANs that are activated by aversive stimuli or cues that predict aversive stimuli, which are located in the dorsolateral part of the SNc. The role of dopamine is expanding further to include response to novel, salient, and even aversive stimuli. However, molecular genetic makers are needed to better characterize different DAN subtypes, and their distinctive connectivity and functionality. By employing the newly available single cell RNA sequencing technology, recently multiple studies have been performed to reveal the diverse gene expression profiles of midbrain DNAs at single cell level. These high-resolution gene expression studies demonstrate more complex gene expression patterns in individual midbrain DANs, identify more DAN subtypes with additional genetic markers, and improve our understanding of the genetic diversity of midbrain DANs. Based on distinct gene expression patterns, the DANs in substantia nigra pars compacta may constitute at least three subtypes: Aldh1a1+/Sox6+, Aldh1a1-/Sox6+, and Aldh1a1-/Vglut2+. This study is particularly designed to characterize the connectivity and functionality of Aldh1a1-/Sox6+ and Aldh1a1-/Vglut2+ SNc DANs in motor control and Parkinson's disease.

各种遗传、行为和药理学研究已经确定了黑质纹状体多巴胺通路在运动功能中的作用，其奖励很大程度上与中边缘多巴胺通路相关，该通路由从腹侧被盖区（VTA）投射到腹侧纹状体的多巴胺能连接组成。然而，研究也支持黑质纹状体多巴胺通路在奖励中的重要性，表明黑质致密部 (SNc) 和 VTA 中脑多巴胺能神经元 (DAN) 都改变了放电以响应奖励预测和预测错误。研究表明，奖赏预测刺激会导致 SN 激活，这凸显了中脑 DAN 活动的变化不仅限于 VTA。当具体考虑 SNc DAN 时，再次支持神经元激活以响应奖赏或感觉刺激，从而预测厌恶刺激的奖赏和抑制。这些 DAN 位于 SNc 的腹内侧部分，毗邻 VTA，这就需要用更明确的遗传标记来更好地定义这两个 DAN 亚群。另一方面，也有一些 SNc DAN 被厌恶刺激或预测厌恶刺激的线索激活，这些 DAN 位于 SNc 的背外侧部分。多巴胺的作用正在进一步扩大，包括对新奇的、显着的、甚至令人厌恶的刺激的反应。然而，需要分子遗传标记来更好地表征不同的 DAN 亚型及其独特的连接性和功能。 通过采用新的单细胞RNA测序技术，最近进行的多项研究揭示了单细胞水平上中脑DNA的多样化基因表达谱。这些高分辨率基因表达研究证明了个体中脑 DAN 中更复杂的基因表达模式，通过额外的遗传标记鉴定了更多 DAN 亚型，并提高了我们对中脑 DAN 遗传多样性的理解。基于不同的基因表达模式，黑质致密部中的DAN可能构成至少三种亚型：Aldh1a1+/Sox6+、Aldh1a1-/Sox6+和Aldh1a1-/Vglut2+。本研究专门用于表征 Aldh1a1-/Sox6+ 和 Aldh1a1-/Vglut2+ SNc DAN 在运动控制和帕金森病中的连接性和功能。