Dissecting the inhibitory architecture governing basal ganglia output

剖析控制基底神经节输出的抑制结构

• 批准号: 10580607
• 负责人: Rebekah Coleman Evans
• 金额: $ 24.9万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580607
• 关键词: Affect; Anatomy; Architecture; Award; Axon; Basal Ganglia; Binding; Brain; Calcium; Cell Nucleus; Cells; Cellular Morphology; Characteristics; Communication; Computer Models; Contralateral; Corpus striatum structure; Deep Brain Stimulation; Dendrites; Disease; Dissection; Electrophysiology (science); Excitatory Synapse; Feedback; Genetic; Globus Pallidus; Glutamates; Goals; Image; Impairment; Interneurons; Knowledge; Learning; Location; Maintenance; Maps; Mentors; Methods; Midbrain structure; Mission; Morphology; Motion; Motor output; Movement; National Institute of Neurological Disorders and Stroke; Neurons; Output; Parkinson Disease; Pattern; Phase; Positioning Attribute; Public Health; Research; Signal Transduction; Source; Structure; Structure of subthalamic nucleus; Substantia nigra structure; Synapses; Techniques; Testing; Training; Work; dopaminergic neuron; expectation; experience; experimental study; imaging study; implantation; inhibitory neuron; insight; motor disorder; motor impairment; nervous system disorder; neural; optogenetics; pars compacta; programs; rabies viral tracing; reconstruction; stem cells; striosome; success; two-photon

The initiation and maintenance of organized movement through the basal ganglia is strongly influenced by its feed-forward and feedback inhibitory architecture. The substantia nigra pars compacta (SNc) and pedunculopontine nucleus (PPN) contribute to the overall output of the basal ganglia. Neurons in both structures degenerate in Parkinson's Disease, resulting in impaired motion. While treatments such as deep brain stimulation in the PPN (Snijders et al., 2016), and the implantation of stem cells into the SNc (Sonntag et al., 2018) have both met with variable success, their potential efficacy is constrained by a fundamental lack of knowledge about the circuitry of these two nuclei. The research proposed here will generate new insights into the function of inhibitory circuitry in these two nuclei and represents the first step toward a full understanding of the local and extended basal ganglia circuits which control organized motion. My long-term goal is to develop an independent research program focused on identifying cellular and network interactions that underlie basal ganglia control of motion. The overall objective of this K99/R00 application is to determine the extent to which local functional connectivity between genetically-defined subpopulations modulates basal ganglia output. My central hypothesis is that inhibition onto SNc and PPN neurons sculpts basal ganglia output by modulating excitatory gain. This hypothesis is based on preliminary two-photon uncaging, calcium imaging, optogenetic experiments, morphological reconstructions, and computational modeling. The rationale for this research is that once the circuit connectivity of the PPN and SNc is functionally mapped, we can begin to define the connections by which the basal ganglia select actions and control coordinated motion. To achieve my overall objective, I will work with my mentor, Dr. Zayd Khaliq and co-mentor, Dr. Chris McBain to learn and implement multi-channel optogenetic techniques and the simultaneous use of spatially-specific optogenetics with two photon glutamate uncaging and calcium imaging. These new techniques, in combination with my computational modeling and electrophysiological experience will allow me to complete my specific aims. During the mentored phase, I will complete aims 1 by performing functional tests of inhibitory inputs onto SNc dopamine neurons, including a comparison of the strength and location of inhibition from the striatal patch (striosome) compartments and the striatal matrix. In aim 2, I will test the functional consequences of dendrite-specific inhibition on the excitatory gain of SNc dopamine neurons. During the independent phase, I will utilize the same techniques to investigate the inhibitory circuitry of the PPN. In aim 3, I will perform functional tests of inhibitory inputs to the glutamatergic neurons of the PPN which have been identified with rabies tracing. In aim 4, I will define the intrinsic and genetic characteristics of a projection-defined subpopulation of PPN neurons. The proposed activities will generate fundamental knowledge about basal ganglia circuitry and will provide training in advanced two-photon and optogenetic techniques to compliment my current expertise in computational modeling and electrophysiology.

通过基底神经节的有组织运动的启动和维持受到其 前馈和反馈抑制架构。黑质腹侧部（SNc）和 脚桥核（PPN）有助于基底神经节的总输出。两种结构中的神经元 帕金森氏病的退化，导致运动受损。虽然像脑深部这样的治疗 PPN中的刺激（Snijders等人，2016），以及将干细胞植入SNc（Sonntag等人， 2018）都取得了不同的成功，但它们的潜在功效受到根本缺乏 关于这两个原子核的电路的知识。这里提出的研究将产生新的见解， 这两个核团中抑制回路的功能，代表了全面理解 控制有组织运动的局部和扩展基底神经节回路。我的长期目标是发展一个 一项独立的研究计划，重点是确定细胞和网络的相互作用，基础 神经节控制运动本K99/R 00应用程序的总体目标是确定 遗传上确定的亚群之间的局部功能连接调节基底神经节输出。我 中心假设是对SNc和PPN神经元的抑制通过调节基底神经节的输出来塑造基底神经节的输出， 兴奋性增益这一假设是基于初步的双光子uncaging，钙成像，光遗传学 实验、形态重建和计算建模。这项研究的基本原理是， 一旦PPN和SNc的电路连通性在功能上得到映射，我们就可以开始定义连接 基底神经节选择动作并控制协调运动。为了实现我的总体目标，我将 我与我的导师Zayd Khaliq博士和共同导师Chris McBain博士一起学习和实施多渠道 光遗传学技术和空间特异性光遗传学与双光子谷氨酸的同时使用 血管造影和钙成像。这些新技术，结合我的计算模型， 电生理学的经验会让我完成我的特定目标。在学习阶段，我将 通过对SNc多巴胺神经元进行抑制性输入的功能测试，完成目标1，包括 比较来自纹状体斑（纹状体）隔室的抑制的强度和位置， 纹状体基质在目标2中，我将测试树突特异性抑制对兴奋性神经元的功能影响。 SNc多巴胺神经元的获得。在独立阶段，我将利用同样的技术来调查 PPN的抑制回路在目标3中，我将对脑电的抑制性输入进行功能测试 PPN的神经元已被狂犬病追踪。在目标4中，我将定义内在和遗传 PPN神经元的投影定义的亚群的特征。拟议的活动将产生 关于基底神经节电路的基本知识，并将提供先进的双光子和 光遗传学技术来补充我目前在计算建模和电生理学方面的专业知识。

项目成果

Dendritic involvement in inhibition and disinhibition of vulnerable dopaminergic neurons in healthy and pathological conditions.

• DOI: 10.1016/j.nbd.2022.105815
• 发表时间: 2022-10-01
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Evans, R. C.

Comparing tonic and phasic calcium in the dendrites of vulnerable midbrain neurons.

比较脆弱中脑神经元树突中的强直性和阶段性钙。

• DOI: 10.1101/2023.08.28.555184
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Chen,RitaYu-Tzu;Evans,RebekahC
• 通讯作者: Evans,RebekahC

Functional Dissection of Basal Ganglia Inhibitory Inputs onto Substantia Nigra Dopaminergic Neurons.

基底神经节抑制输入对黑质多巴胺能神经元的功能剖析。

• DOI: 10.1016/j.celrep.2020.108156
• 发表时间: 2020-09-15
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Evans, Rebekah C.;Twedell, Emily L.;Zhu, Manhua;Ascencio, Jefferson;Zhang, Renshu;Khaliq, Zayd M.
• 通讯作者: Khaliq, Zayd M.

Function and Regulation of ALDH1A1-Positive Nigrostriatal Dopaminergic Neurons in Motor Control and Parkinson's Disease.

• DOI: 10.3389/fncir.2021.644776
• 发表时间: 2021
• 期刊: Frontiers in neural circuits
• 影响因子: 3.5
• 作者: Carmichael K;Evans RC;Lopez E;Sun L;Kumar M;Ding J;Khaliq ZM;Cai H
• 通讯作者: Cai H