Mapping somatodendritic circuits of midbrain dopamine neurons

绘制中脑多巴胺神经元的体细胞树突回路

• 批准号: 9759351
• 负责人: Sarah Zych
• 金额: $ 3.43万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759351
• 关键词: Amygdaloid structure; Automobile Driving; Autoreceptors; Behavior; Cells; Corpus striatum structure; Data; Dendrites; Dimensions; Disease; Dopamine; Dopamine D2 Receptor; Drug Addiction; Drug usage; Glutamates; Goals; Impulsivity; Label; Lateral; Locomotion; Measures; Mediating; Midbrain structure; Motivation; Movement; Neurons; Nucleus Accumbens; Output; Pattern; Play; Population; Prefrontal Cortex; Property; Rewards; Role; Shapes; Signal Transduction; Site; Substantia nigra structure; Synapses; Synaptic Transmission; Techniques; Testing; Ventral Tegmental Area; Work; addiction; dopamine system; dopaminergic neuron; drug of abuse; experimental study; insight; neuronal cell body; optogenetics; pars compacta; postsynaptic; reinforced behavior; transmission process

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.

项目摘要 中脑皮质边缘多巴胺（DA）系统在获得由多巴胺强化的行为中起着核心作用。 滥用药物。中脑黑质和腹侧被盖的多巴胺神经元 腹侧被盖区（VTA）支配着大量的终末区，以介导多种功能，如运动、奖赏、 编码和动机。由于DA神经元主要投射到单个终末位点，它们形成不同的非- 在主要独立的回路中参与不同功能的重叠群体。先前的工作已经 表明DA细胞可以通过体树突局部调节邻近DA神经元的兴奋性， 多巴胺释放，其作用于位于DA神经元的索马和树突上的抑制性D2自身受体。 这种抑制调节中脑多巴胺神经元的放电，从而调节多巴胺的量和时间 在下游投射地点释放。此外，最近的研究发现，体树突释放 多巴胺以局部点对点的方式起作用，如在突触传递中。这些证据以及 DA群体形成离散的回路，提高了存在特定模式的体树突的可能性。 特定投射DA群体之间的连通性。因为前后之间的局部电路- VTA和SNc内的突触DA神经元尚不清楚，体树突信号在整合中的作用 不同的传入和塑造输出信号的目标网站是不清楚的。此外，由于电磁输入 驱动多巴胺神经元爆发性放电，它们调节末梢和体树突DA的释放。使用 已知滥用药物会改变DA神经元的多巴胺能输入，因此研究了体树突的模式。 由谷氨酸输入驱动的抑制可以提供对可以抑制DA信号传导的电路机制的见解 并抑制滥用药物的强化作用。 这项提议的目标是确定调节神经元活动的局部体树突回路。 中脑内的多巴胺数量。目的1将检查是否有特定的体树突 SNc和VTA中投射特异性DA群体之间的连接。目标2将研究 体树突连接驱动不同的多巴胺能输入中脑DA群体。所有这些 目的将提供有关中脑DA神经元之间的电路组织和 体树突信号在形成输出信号中的作用。鉴于发展援助制度在调解 重要的功能和它在成瘾中的作用，至关重要的是，我们有一个更完整的了解， 多巴胺神经元之间的体树突回路以及这些回路如何被谷氨酸输入激活。