Mapping somatodendritic circuits of midbrain dopamine neurons

项目摘要 大脑中皮质边缘多巴胺(DA)系统在行为习得中起着核心作用。 滥用药物。中脑黑质致密部和腹侧被盖的多巴胺神经元 脑区(VTA)支配大量的终末区域，调节多种功能，如运动、奖赏 编码和激励。由于DA神经元主要投射到单个终末部位，它们形成了不同的非 在以独立为主的电路中，涉及不同功能的重叠种群。以前的工作有 结果表明，DA细胞可通过躯体树突对邻近DA神经元的兴奋性进行局部调制 多巴胺释放，作用于位于DA神经元胞体和树突上的抑制性D2自身受体。 这种抑制调节中脑多巴胺神经元的放电，从而调节多巴胺的数量和时间。 在下游投影点发布。此外，最近的研究发现，躯体树突释放 多巴胺以局部的点对点方式起作用，就像在突触传递中一样。这一证据和事实是 DA群体形成离散的回路，增加了存在特定模式的躯体树突状细胞的可能性 预测特定的DA人群之间的连接性。因为前置和后置之间的本地电路- VTA和SNC内的突触DA神经元尚不清楚，躯体树突信号在整合中的作用 不同的传入和塑造目标部位的输出信号尚不清楚。此外，由于谷氨酸能输入 驱动多巴胺神经元的突发性放电，它们调节终末和躯体树突状细胞DA的释放。对.的使用 已知滥用药物会改变DA神经元上的谷氨酸能输入，从而研究躯体树突状细胞的模式 谷氨酸输入驱动的抑制可以提供对可能抑制DA信号的电路机制的洞察 并遏制毒品滥用的强化属性。 这项建议的目的是确定调节脑组织活动的局部躯体树突回路 中脑内的多巴胺群体。目标1将检查是否有特定的躯体树突状细胞 SNC和VTA中预测特定DA人群之间的连通性。目标2将研究 不同谷氨酸能输入驱动的躯体树突连接至中脑DA种群。加在一起，这些 AIMS将提供有关中脑DA神经元之间的回路组织和 躯体树突信号在整形输出信号中的作用。鉴于发展议程系统在调解方面的关键作用 重要的功能及其在成瘾中的作用，我们有必要对成瘾有一个更完整的了解 多巴胺神经元之间的躯体树突回路以及谷氨酸输入如何激活这些回路。

Project Summary The mesocorticolimbic dopamine (DA) system plays a central role in the acquisition of behaviors reinforced by drugs of abuse. Dopamine neurons in the midbrain substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) innervate a vast number of terminal regions to mediate diverse functions such as locomotion, reward encoding, and motivation. Because DA neurons largely project to a single terminal site, they form distinct non- overlapping populations involved in different functions in predominantly separate circuits. Previous work has shown that DA cells can locally modulate the excitability of neighboring DA neurons via somatodendritic dopamine release, which acts on inhibitory D2 autoreceptors located on the soma and dendrites of DA neurons. This inhibition regulates midbrain dopamine neuron firing and thus regulates the amount and timing of dopamine released at downstream projection sites. Furthermore, recent work has found that somatodendritically released dopamine acts in a localized point-to-point manner, as in synaptic transmission. This evidence and the fact that DA populations form discrete circuits, raises the likelihood that there exists a specific pattern of somatodendritic connectivity between projection-specific DA populations. Because the local circuitry between pre- and post- synaptic DA neurons within the VTA and SNc is unknown, the role of somatodendritic signaling in integrating diverse afferents and shaping output signals to target sites is unclear. Additionally, since glutamatergic inputs drive dopamine neuron burst firing, they regulate both terminal and somatodendritic DA release. The use of drugs of abuse is known to alter glutamatergic inputs on DA neurons, thus studying the pattern of somatodendritic inhibition driven by glutamate inputs could provide insights into circuit mechanisms that can dampen DA signaling and curb the reinforcing properties of drugs of abuse. The goal of this proposal is to determine the local somatodendritic circuitry that modulates the activity of dopamine populations within the midbrain. Aim 1 will examine whether there is specific somatodendritic connectivity between projection-specific DA populations in the SNc and VTA. Aim 2 will examine the pattern of somatodendritic connectivity driven by different glutamatergic inputs to midbrain DA populations. Together, these aims will provide critical information about the circuit organization between midbrain DA neurons and the role of somatodendritic signaling in shaping output signals. In view of the critical role of the DA system in mediating important functions and its role in addiction, it is essential that we have a more complete understanding of the somatodendritic circuitry between dopamine neurons and how these circuits are activated by glutamate inputs.