Cholinergic brainstem signaling in striatal circuits

标题：纹状体回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，在动作强化中起着核心作用， 运动规划和运动序列的执行。两种神经调质对 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， 使得它们在解剖学上相互连接并受到神经调节。大量的神经系统 影响基底神经节的疾病与这些神经元中的一个或两个的失调有关 神经调节系统（例如帕金森氏病、抽动秽语综合征）。了解这些系统如何 以及它们如何相互调节是理解正常基底神经节的基础 功能以及它们在患病大脑中是如何改变的。 直到最近，纹状体乙酰胆碱被认为是完全来源于纹状体胆碱能 中间神经元。然而，我们发现纹状体的乙酰胆碱的外源性来源起源于纹状体。 脑桥脚核（PPN）和被盖背外侧核（LDT）。多巴胺，打开 另一方面，起源于中脑并支配大范围的纹状体， 多巴胺神经元受到胆碱能PPN/LDT神经元的轴突侧支的强烈调节。我们 使用光遗传学工具的初步数据显示，PPN和LDT产生了强有力的直接调节作用， 作用于不同类型的纹状体神经元，包括胆碱能中间神经元。因此，PPN/LDT神经元不仅 能够调节多巴胺神经元的活动，这些神经元反过来密集地投射到纹状体，但它们也 能够直接调节纹状体微电路。因此，我们的数据表明，PPN和LDT是一个关键 调节纹状体功能。 拟议研究的目标是表征的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， 优先受脑干胆碱能轴突支配，并确定靶向纹状体神经元的亚型 通过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。 神经化学鉴定单个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胆碱能神经元对纹状体依赖性行为的影响。此外，由于纹状体胆碱能 中间神经元和PPN/LDT胆碱能神经元是两个明显不同的群体，就它们的突触 输入，内在的生理特性和行为过程中的激活模式，我们希望看到关键的 它们如何影响纹状体回路和纹状体功能的差异。因此，我们将比较 以及这两种乙酰胆碱来源的生理组织。 纹状体乙酰胆碱的外源性来源的发现突出了我们在脑内的一个主要空白。 了解神经调质如何调节纹状体活动。目前的基底神经节模型是不完整的 并且需要修改以纳入基底神经节功能的新的主要参与者：胆碱能脑干。 解决这些问题不仅是及时的，对基底神经节研究的进展至关重要， 而是为了理解纹状体依赖性神经病理学。

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.