Pathophysiological studies of Parkinson's disease dementia

帕金森病痴呆的病理生理学研究

• 批准号: 10250919
• 负责人: Huaibin Cai
• 金额: $ 61.64万
• 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/10250919
• 关键词: Ablation; Address; Affect; Agonist; Anatomy; Anxiety; Atrophic; Attention; Autopsy; Axon; Behavioral; Brain; Brain Diseases; Brain region; Calcium; Cholinesterase Inhibitors; Clinical; Cognitive; Complex; Complication; Corpus striatum structure; Data; Dementia; Diagnosis; Disease; Dopamine; Dorsal; Electrophysiology (science); Fiber; Foundations; Fright; Functional disorder; Gene Expression; General Population; Generations; Genes; Genetic; Glutamates; Goals; Hippocampal Formation; Hippocampus (Brain); Human; Image; Impaired cognition; Impairment; Individual; Knowledge; Label; Learning; Levodopa; Location; Memory; Midbrain structure; Molecular Genetics; Morphology; Motor; Movement; Movement Disorders; Mus; Neurons; Neurotransmitter Receptor; Older Population; Parkinson Disease; Parkinson' s Dementia; Pathogenicity; Patients; Pattern; Pharmaceutical Preparations; Phase; Photometry; Physiological; Prefrontal Cortex; Prevalence; Process; Property; Rest Tremor; Rodent; Role; Series; Signal Transduction; Substantia nigra structure; Synapses; Testing; Therapeutic procedure; Ventral Tegmental Area; Visuospatial; aldehyde dehydrogenases; base; behavioral phenotyping; cell type; chemical genetics; cognitive function; cognitive impairment in Parkinson' s; design; dopaminergic neuron; entorhinal cortex; genetic approach; improved; insight; locus ceruleus structure; motor control; motor impairment; motor learning; motor skill learning; motor symptom; nervous system disorder; neural circuit; neuroregulation; neurotransmission; novel therapeutic intervention; optogenetics; pars compacta; posture instability; presynaptic; relating to nervous system; sensor; social; therapeutic target; tool; transmission process; vesicular glutamate transporter 2; walking speed

Parkinsons disease (PD) is typically characterized as a degenerative movement disorder, clinically manifested with distinct motor disturbances, including slowness of movement, resting tremor, rigidity, and postural instability, resulting from extensive loss of nigrostriatal dopaminergic neurons (nDANs) in the substantia nigra pars compacta (SNc) of midbrain. Besides motor symptoms, PD patients often develop cognitive dysfunctions, which leads to Parkinsons disease dementia (PDD). Approximately 75% of PD patients develop dementia within 10 years of diagnosis, and the prevalence of PDD is 0.3-0.5% in general population older than 65 years. There is no cure for PDD. The exact pathogenic mechanisms of PDD are largely unknown. Levodopa, the most effective drug to treat the motor symptoms in PD, however, does not respond well against cognitive dysfunctions. On the other hand, cholinesterase inhibitors can improve the cognitive functions, but exacerbate the motor symptoms. Therefore, an important step in intervening complexed neurological disorder like PDD, is to elucidate the functional roles of different neural circuits responsible for specific behavioral phenotypes. Accumulative evidence supports an association of dopaminergic dysfunction with PDD. PDD is likely resulted from extensive generation of midbrain DANs beyond the SNc regions in the late stages of PD. Midbrain DANs are heterogenous and can be categorized into different subpopulations based on anatomic locations, gene expression, electrophysiological properties, neuronal morphology, axonal projections, physiological functions, and disease vulnerabilities. Which subpopulations of midbrain DANs contribute to PDD remains to be determined. Recently, we discovered that a subpopulation of aldehyde dehydrogenase 1A1-positive (ALDH1A1+) nigrostriatal dopaminergic neuron (nDAN) located in the ventral SNc display the most profound loss in the postmortem human PD brains. The ALDH1A1+ nDANs account for approximately 70% nDANs in human and mouse brains. While ALDH1A1+ nDANs receive diverse monosynaptic inputs from multiple brain regions, their axons project exclusively to the dorsal striatum. The dorsal striatum is generally known for motor control and processing the implicit motor learning. Correlatively, genetic ablation of ALDH1A1+ nDANs in rodents caused severe impairments in motor skill learning in conjunction with a modest reduction of walking speed. However, those ALDH1A1+ nDAN-ablated mice did not develop any cognitive deficiency (unpublished data), suggesting an involvement of other midbrain DAN subpopulations, especially the ones located in ventral tegmental area (VTA), in the formation of explicit memory. The advancement of gene profiling in individual neurons allows to genetically define DAN subtypes in different SNc and VTA subregions. Using intersectional genetic labeling strategy, a recent study found that a cluster of vesicular glutamate transporter 2-positive (VGLT2+) DANs in the ventral VTA project predominantly to the entorhinal (ENT) and prefrontal cortices (PFC). Interestingly, ENT atrophy is particularly associated with PDD. By contrast, VTA DANs only sparsely project to the hippocampal formation. Instead, hippocampus receives the most dopamine inputs from the afferent fibers of locus coeruleus. Therefore, following our recently established workflow in defining the connectivity and functionality of ALDH1A1+ nDANs in implicit motor learning, we will investigate the synaptic inputs and physiological functions of VTA-VGLT2+ DAN subpopulations in declarative memory formation. The knowledge gained from this study will provide cell type and circuit specific mechanisms of PDD and lay the foundation for designing new therapeutic interventions for treatment of cognitive impairments in PDD. Specific Aims To unravel the contribution of different midbrain DAN subpopulations, especially the VTA-VGLUT2+ DAN subtypes in the formation of declarative memory, we propose the following three specific aims: Aim 1. To investigate the physiological function of VTA-VGLUT2+ DANs in declarative memory formationIn our previous study, we have shown that ALDH1A1+ nDANs are essential for the implicit motor skill learning, but not the explicit cognitive functions. In this proposal, we will test the hypothesis that VTA-VGLUT2+ DANs contribute to the formation of declarative memory. Using intersectional genetic strategy, we will genetically ablate VTA-VGLUT2+ DANs in mouse brains and examine the cognitive functions of the affected mice with a battery of social behavioral, spatial learning and memory, and fear/anxiety tests. Aim 2. To elucidate the underlying transmitter and circuit mechanisms of VTA-VGLUT2+ DANs in declarative memory formationIf the VTA-VGLUT2+ DAN-ablated mice show any specific cognitive abnormalities (investigated in Aim 1), we will further investigate how the VTA-VGLUT2+ DANs execute this function at the transmitter and circuit levels. The VGLUT2+ DANs can release both dopamine and glutamate, and may integrate various presynaptic inputs and undergo either tonic or phasic firing patterns to relay the signals to the downstream neurons in the ENT and PFC12. We will apply series of molecular genetics, chemical genetics and optogenetics tools to identify which neuron transmitters and specific presynaptic inputs are critical for accomplishing the expected behavioral tasks. The alterations of neural activity and transmitter release will be further evaluated by live imaging in behaving mice using fiber photometry and genetically encoded calcium and dopamine sensors. This aim allows us to identify specific presynaptic inputs and transmitter release essential for the memory formation and provides potential therapeutic targets to rescue the memory deficiency. Aim 3. To explore potential therapeutic procedures to mitigate cognitive impairments in the VTA-VGLUT2+ DAN-ablated miceSince levodopa alone is ineffective in treating PDD, to alleviate the cognitive deficiency we will treat the affected mice with levodopa in combination with other neurotransmitter receptor agonists or antagonists as well as neuromodulation. The results from Aim 2 will provide the specific targets for formulating the combinatory treatment paradigms. Taken collectively, this proposed study will unravel the specific cell type and circuit mechanisms of midbrain dopamine transmission in declarative memory formation and provides new insights to address the unmet need of PDD treatment.

帕金森氏病（PD）通常以退化性运动障碍为特征，在临床上表现出明显的运动障碍，包括运动，静止震颤，僵硬，僵硬和姿势不稳定，这是由于Nigrostriatal多巴胺能神经元（Ndans）的广泛丧失而导致的。中脑的PARS CMPCACTA（SNC）。除运动症状外，PD患者经常会出现认知功能障碍，从而导致帕金森氏病痴呆症（PDD）。大约75％的PD患者在诊断后的10年内患痴呆症，PDD的患病率在65岁以上的普通人群中为0.3-0.5％。 PDD无法治愈。 PDD的确切致病机制在很大程度上未知。但是，左旋多巴是治疗PD中运动症状的最有效药物，但对认知功能障碍的反应不佳。另一方面，胆碱酯酶抑制剂可以改善认知功能，但会加剧运动症状。因此，干预PDD等复杂神经系统疾病的重要一步是阐明负责特定行为表型的不同神经回路的功能作用。 累积证据支持多巴胺能功能障碍与PDD的关联。 PDD很可能是由于PD晚期的SNC地区以外的大脑DAN产生的。中脑dan是异质的，可以根据解剖位置，基因表达，电生理特性，神经元形态，轴突预测，生理功能和疾病脆弱性分类为不同的亚群。中脑DAN的哪些亚群有助于PDD。最近，我们发现位于腹侧SNC中的醛脱氢酶1A1阳性（Aldh1a1+）二神素多巴胺能神经元（NDAN）的亚群显示出最深刻的损失。在人和小鼠大脑中，ALDH1A1+ NDAN约占NDAN的70％。尽管Aldh1a1+ Ndans从多个大脑区域接收多种单突触输入，但其轴突仅投射到背侧纹状体。背侧纹状体通常以运动控制和处理隐式运动学习而闻名。相关的是，啮齿动物中Aldh1a1+ NDAN的遗传消融导致运动技能学习的严重损害，并降低步行速度。但是，那些ALDH1A1+ NDAN燃烧的小鼠没有发展出任何认知缺陷（未发表的数据），这表明其他中脑Dan亚群，尤其是位于腹侧段（VTA）（VTA）中的参与。 单个神经元中基因分析的进步允许在不同的SNC和VTA子区域中遗传定义DAN亚型。一项最新研究发现，使用遗传标记策略，发现一组腹侧VTA项目中的一组水泡谷氨酸转运蛋白2个阳性（VGLT2+）DAN，主要是到内嗅（ENT）和前额叶皮层（PFC）。有趣的是，ENT萎缩尤其与PDD有关。相比之下，VTA DAN仅稀疏地将海马形成投影。取而代之的是，海马从基因座的传入纤维接收最多的多巴胺输入。因此，遵循我们最近建立的工作流程，以在隐式运动学习中定义ALDH1A1+ NDAN的连通性和功能，我们将研究声明记忆形成中VTA-VGGLT2+ DAN亚群的突触输入和生理功能。从这项研究中获得的知识将提供PDD的细胞类型和电路特定机制，并为设计新的治疗干预措施设计用于治疗PDD的认知障碍的基础。 具体目标 为了揭示不同中脑Dan亚群的贡献，尤其是在声明性记忆形成中的VTA-VGLUT2+ DAN子类型的贡献，我们提出了以下三个具体目标： 目的1。研究在先前的研究中，在声明性记忆形成中VTA-VGLUT2+ DAN的生理功能，我们表明ALDH1A1+ NDAN对于隐式运动技能学习是必不可少的，但不是明确的认知功能。在此提案中，我们将检验以下假设：VTA-VGLUT2+ DAN有助于声明性记忆的形成。使用交叉遗传策略，我们将在遗传上消除小鼠大脑中的VTA-VGLUT2+ DAN，并通过一系列社交行为，空间学习和记忆和恐惧/焦虑测试来检查受影响小鼠的认知功能。 目的2。为了阐明声明性记忆形成中VTA-VGLUT2+ DAN的基本发射器和电路机制，如果VTA-VGGLUT2+ dAN驱动的小鼠显示任何特定的认知异常（在AIM 1中进行了研究），我们将如何进一步研究VTA-VGGLUT2+ DANS2+ DANS2+ DANS2+ DANS2+ DANS2+ DANS2+ DANS2+ DANS在发射器和电路级别执行此功能。 VGLUT2+ DAN可以同时释放多巴胺和谷氨酸，并且可以整合各种突触前输入并经历滋补或阶段性射击模式，以将信号传递到ENT和PFC12中的下游神经元。我们将应用一系列分子遗传学，化学遗传学和光遗传学工具来确定哪些神经元发射机和特定突触前输入对于完成预期的行为任务至关重要。通过使用纤维光度法和遗传编码的钙和多巴胺传感器在行为小鼠中实时成像，将进一步评估神经活动和发射器释放的改变。这个目标使我们能够确定特定的突触前输入和发射器释放，这对于记忆形成必不可少，并提供了潜在的治疗目标来挽救记忆力不足。 AIM 3。探索潜在的治疗程序来减轻VTA-VGLUT2+ dan启动的MICESINCE LEVODOPA中的认知障碍，无法治疗PDD，以减轻认知缺陷，以减轻我们与其他神经疗法受体或其他Neurotransmitter剂量的患者的治疗小鼠，拮抗剂和神经调节。 AIM 2的结果将为制定组合治疗范例的特定目标提供。 这项拟议的研究集体将在声明性记忆形成中揭示中脑多巴胺传播的特定细胞类型和电路机制，并提供了新见解，以满足PDD处理的未满足需求。