Cholinergic brainstem signaling in striatal circuits

纹状体回路中的胆碱能脑干信号传导

• 批准号: 10164873
• 负责人: Juan MENA-SEGOVIA
• 金额: $ 33.91万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164873
• 关键词: Acetylcholine; Adaptive Behaviors; Address; Affect; Anatomy; Axon; Basal Ganglia; Behavior; Behavioral; Biophysics; Brain Diseases; Brain Stem; Cell Nucleus; Cells; Cognitive deficits; Complex; Corpus striatum structure; Data; Disease; Dopamine; Event; Fire - disasters; Generations; Gilles de la Tourette syndrome; Goals; Impairment; In Vitro; Individual; Interneurons; Label; Link; Methods; Midbrain structure; Modeling; Motor; Motor output; Movement; Mus; Neuromodulator; Neurons; Parkinson Disease; Pathologic; Pathway interactions; Pattern; Pharmacology; Phase; Physiological; Play; Population; Positioning Attribute; Property; Psychological reinforcement; Regulation; Research; Reversal Learning; Role; Sensory; Signal Transduction; Slice; Source; Specificity; Structure; Synapses; System; Time; attentional modulation; awake; base; cell type; cholinergic; cholinergic neuron; dopaminergic neuron; flexibility; genetic approach; in vivo; motor deficit; nerve supply; nervous system disorder; neurochemistry; neuronal circuitry; neuronal excitability; neuropathology; neuroregulation; novel; optogenetics; postsynaptic; receptor; response; tool; transmission process

Title: Cholinergic brainstem signaling in striatal circuits, PI: Juan Mena-Segovia PROJECT SUMMARY The striatum is the main input structure of the basal ganglia and it plays a central role in action reinforcement, movement planning and execution of motor sequences. Two neuromodulators exert powerful control over striatal neuronal circuits: dopamine and acetylcholine. These neuromodulatory systems are inextricably linked, such that they are anatomically interconnected and reciprocally regulated. A significant number of neurological disorders that affect the basal ganglia are associated with the dysregulation of one or both of these neuromodulatory systems (e.g. Parkinson’s disease, Tourette syndrome). Understanding how these systems are regulated and how they modulate each other is fundamental for understanding normal basal ganglia function and how they are altered in the diseased brain. Until recently, striatal acetylcholine was believed to originate exclusively from the striatal cholinergic interneurons. However, we discovered an extrinsic source of acetylcholine to the striatum originating in the pedunculopontine nucleus (PPN) and laterodorsal tegmental nucleus (LDT) of the brainstem. Dopamine, on the other hand, originates from the midbrain and innervate large extents of the striatum, and the activity of dopamine neurons is strongly modulated by the axon collaterals of cholinergic PPN/LDT neurons. Our preliminary data using optogenetic tools show that PPN and LDT produce a robust and direct modulatory effect on distinct types of striatal neurons, including cholinergic interneurons. Thus, PPN/LDT neurons are not only able to modulate the activity of dopamine neurons that in turn project densely to the striatum, but they are also capable of directly modulating striatal microcircuits. Our data thus suggest that the PPN and LDT are in a key position to modulate striatal function. The goal of the proposed studies is to characterize the anatomical organization and functional significance of the brainstem cholinergic innervation of the striatum. First, we will identify the striatal domains that are preferentially innervated by brainstem cholinergic axons and identify the subtypes of striatal neurons targeted by PPN and LDT axons. Second, using optogenetic methods, we will characterize the impact of PPN and LDT axons on neurochemically identified single striatal neurons. Third, we will identify the direct impact of the PPN and LDT cholinergic neurons on striatal-dependent behaviors. Furthermore, because striatal cholinergic interneurons and PPN/LDT cholinergic neurons are two markedly distinct populations in terms of their synaptic inputs, intrinsic physiological properties and pattern of activation during behavior, we expect to see critical differences in how they influence striatal circuits and striatal function. Thus, we will compare the anatomical and physiological organization of these two sources of acetylcholine. The discovery of an extrinsic source of acetylcholine to the striatum highlighted a major gap in our understanding of how neuromodulators regulate striatal activity. Current basal ganglia models are incomplete and need to be revised to incorporate a new major player in basal ganglia function: the cholinergic brainstem. Addressing these issues is not only timely and of critical importance for the progress of basal ganglia research, but for understanding striatal-dependent neuropathology.

标题：纹状体电路中的胆碱能脑干信号传导，PI：Juan Mena-Segovia 项目摘要 纹状体是基底神经节的主要输入结构，它在动作强化中起着核心作用， 运动序列的运动计划和执行。两个神经调节剂对 纹状体神经元回路：多巴胺和乙酰胆碱。这些神经调节系统是密不可分的， 使它们在解剖学上相互联系和相互调节。大量神经系统 影响基底神经节的疾病与其中一个或两个的失调有关 神经调节系统（例如帕金森氏病，图雷特综合症）。了解这些系统如何 受调节以及它们如何相互调节对于理解正常的基底神经节是至关重要的 功能以及如何在患病的大脑中改变它们。 直到最近，纹状体乙酰胆碱被认为仅起源于纹状体胆碱能 中间神经元。但是，我们发现了乙酰胆碱的外在来源，源自纹状体 脑干的花梗核（PPN）和后dodordorsal换段核（LDT）。多巴胺，开 另一方面，起源于中脑，支配纹状体的大量范围，以及 多巴胺神经元受胆碱能PPN/LDT神经元的轴突侧支强烈调节。我们的 使用光遗传学工具的初步数据表明，PPN和LDT产生强大而直接的调节效果 在不同类型的纹状体神经元上，包括胆碱能中间神经元。那，PPN/LDT神经元不仅是 可以调节多巴胺神经元的活性，而多巴胺神经元反过 能够直接调节纹状体微电路。因此，我们的数据表明PPN和LDT在钥匙中 调节纹状体功能的位置。 拟议的研究的目的是表征解剖组织和功能意义 纹状体的脑干胆碱能神经支配。首先，我们将确定纹状体域 优先通过脑干胆碱能轴突支配并识别靶向的纹状体神经元的亚型 由PPN和LDT轴突。其次，使用光遗传学方法，我们将表征PPN和LDT的影响 神经化学鉴定的单纹状体神经元上的轴突。第三，我们将确定PPN的直接影响 和LDT胆碱能神经元在纹状体依赖性行为上。此外，由于纹状体胆碱能 在其突触方面 输入，内在的物理特性和行为过程中的激活模式，我们希望看到关键 它们如何影响纹状体回路和纹状体功能的差异。那，我们将比较解剖学 以及这两个乙酰胆碱来源的物理组织。 在纹状体上发现乙酰胆碱的外部外来来源突出了我们的主要差距 了解神经调节剂如何调节纹状体活性。当前的巴萨神经节模型不完整 并且需要修改以在基本神经节功能中纳入新的主要参与者：胆碱能脑干。 解决这些问题不仅及时，而且至关重要，对于基底神经节研究的进步， 但要理解依赖纹状体的神经病理学。