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: 10913169
• 负责人: Huaibin Cai
• 金额: $ 58.93万
• 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/10913169
• 关键词: Affect; Aging; Anatomy; Autopsy; Aversive Stimulus; Behavioral; Brain; Categories; Cells; Classification; Compensation; Complex; Cues; Disease; Dopamine; Exhibits; Gene Expression; Gene Expression Profile; Genetic Markers; Genetic Variation; Genetic study; Individual; Investigation; Knowledge; Lead; Memory; Midbrain structure; Molecular; Molecular Genetics; Motivation; Motor; Movement; Neuronal Dysfunction; Neurons; Outcome; Parkinson Disease; Pathway interactions; Patients; Pattern; Pharmacology Study; Procedures; Regulation; Research; Resolution; Rewards; Role; SOX6 gene; Sensory; Stimulus; Substantia nigra structure; Technology; Ventral Striatum; Ventral Tegmental Area; behavioral study; design; dopaminergic neuron; improved; innovation; insight; molecular marker; motor control; motor skill learning; motor symptom; neuron loss; neuroregulation; non-motor symptom; novel; pars compacta; presynaptic; response; reward processing; segregation; single-cell RNA sequencing

Various genetic, behavioral, and pharmacological studies have established the involvement of the nigrostriatal dopamine pathway in motor function, while reward is predominantly associated with the mesolimbic dopamine pathway. The mesolimbic pathway comprises dopaminergic connections projecting from the ventral tegmental area (VTA) to the ventral striatum. However, research also supports the significance of the nigrostriatal dopamine pathway in reward processing, indicating that both the substantia nigra pars compacta (SNc) and VTA midbrain dopaminergic neurons (DANs) exhibit altered firing patterns in response to reward prediction and prediction errors. Studies have demonstrated that stimuli predicting rewards lead to activation in the SNc, highlighting that midbrain DAN activity changes are not solely confined to the VTA. Specifically, SNc DANs, particularly those located in the ventromedial part adjacent to the VTA, show neuronal activation in response to reward or sensory cues predicting reward, as well as inhibition in the presence of aversive stimuli. Conversely, there are also SNc DANs located in the dorsolateral part of the SNc that are activated by aversive stimuli or cues predicting aversive outcomes. This raises the need for more definitive genetic markers to better distinguish between these two DAN subpopulations. Moreover, the role of dopamine is continuously expanding to include responses to novel, salient, and even aversive stimuli. However, further characterization of different DAN subtypes and their distinctive connectivity and functionality requires the use of molecular genetic markers. Fortunately, the advent of single-cell RNA sequencing technology has enabled multiple studies to reveal diverse gene expression profiles of midbrain DANs at the single-cell level. These high-resolution gene expression studies have unveiled more complex gene expression patterns in individual midbrain DANs, identified additional DAN subtypes with unique genetic markers, and improved our understanding of the genetic diversity of midbrain DANs. Based on these distinct gene expression patterns, the DANs in the substantia nigra pars compacta may be categorized into at least three subtypes: Aldh1a1+/Sox6+, Aldh1a1-/Sox6+, and Aldh1a1-/Vglut2+. This study is specifically designed to explore the connectivity and functionality of Aldh1a1-/Sox6+ and Aldh1a1-/Vglut2+ SNc DANs in the context of motor control and PD.

各种遗传、行为和药理学研究已经证实黑质纹状体多巴胺通路参与运动功能，而奖赏主要与中脑边缘多巴胺通路相关。中脑边缘通路包括从腹侧被盖区（VTA）投射到腹侧纹状体的多巴胺能连接。然而，研究也支持黑质纹状体多巴胺通路在奖励处理中的重要性，表明黑质致密部 (SNc) 和 VTA 中脑多巴胺能神经元 (DAN) 表现出响应奖励预测和预测错误的改变的放电模式。 研究表明，预测奖励的刺激会导致 SNc 激活，这凸显出中脑 DAN 活动的变化不仅仅局限于 VTA。具体来说，SNc DAN，特别是位于 VTA 附近腹内侧部分的 SNc DAN，显示出响应奖励或预测奖励的感觉线索的神经元激活，以及在存在厌恶刺激时的抑制。相反，也有位于 SNc 背外侧部分的 SNc DAN，它们被厌恶刺激或预测厌恶结果的线索激活。这就需要更明确的遗传标记来更好地区分这两个 DAN 亚群。 此外，多巴胺的作用不断扩大，包括对新奇的、显着的、甚至令人厌恶的刺激的反应。然而，进一步表征不同 DAN 亚型及其独特的连接性和功能性需要使用分子遗传标记。 幸运的是，单细胞 RNA 测序技术的出现使得多项研究能够在单细胞水平上揭示中脑 DAN 的不同基因表达谱。这些高分辨率基因表达研究揭示了个体中脑 DAN 中更复杂的基因表达模式，识别了具有独特遗传标记的其他 DAN 亚型，并提高了我们对中脑 DAN 遗传多样性的理解。 基于这些不同的基因表达模式，黑质致密部中的 DAN 可以分为至少三个亚型：Aldh1a1+/Sox6+、Aldh1a1-/Sox6+ 和 Aldh1a1-/Vglut2+。本研究专门旨在探索 Aldh1a1-/Sox6+ 和 Aldh1a1-/Vglut2+ SNc DAN 在运动控制和 PD 背景下的连接性和功能。

项目成果

Tau knockout exacerbates degeneration of parvalbumin-positive neurons in substantia nigra pars reticulata in Parkinson's disease-related α-synuclein A53T mice.

• DOI: 10.1096/fj.202000017rr
• 发表时间: 2020-09
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Jiao L;Zheng M;Duan J;Wu T;Li Z;Liu L;Xiang X;Tang X;He J;Li X;Zhang G;Ding J;Cai H;Lin X
• 通讯作者: Lin X