Dissecting the inhibitory architecture governing basal ganglia output

剖析控制基底神经节输出的抑制结构

基本信息

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
项目类别：
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

项目摘要

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很大程度上受其影响前馈和反馈抑制架构。黑质致密部 (SNc) 和桥脚核（PPN）有助于基底神经节的总体输出。两种结构中的神经元帕金森病中的退化，导致运动障碍。而治疗如深脑 PPN 刺激（Snijders 等，2016），以及将干细胞植入 SNc（Sonntag 等， 2018）都取得了不同程度的成功，但它们的潜在功效因根本性缺乏而受到限制有关这两个原子核电路的知识。这里提出的研究将产生新的见解抑制电路在这两个核中的功能，代表着全面理解的第一步控制有组织运动的局部和扩展基底神经节回路。我的长期目标是开发一个独立研究计划专注于识别基础细胞和网络相互作用神经节控制运动。该 K99/R00 应用程序的总体目标是确定基因定义的亚群之间的局部功能连接调节基底神经节的输出。我的中心假设是对 SNc 和 PPN 神经元的抑制通过调节来塑造基底神经节的输出兴奋性增益。该假设基于初步的双光子解笼、钙成像、光遗传学实验、形态重建和计算建模。这项研究的理由是一旦 PPN 和 SNc 的电路连接在功能上得到映射，我们就可以开始定义连接基底神经节通过它选择动作并控制协调运动。为了实现我的总体目标，我将与我的导师 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以及同时使用两个光子谷氨酸的空间特异性光遗传学解笼和钙成像。这些新技术与我的计算模型相结合电生理经验将使我能够完成我的特定目标。在辅导阶段，我会通过对 SNc 多巴胺神经元进行抑制输入的功能测试来完成目标 1，包括纹状体斑块（纹状体）区室和纹状体矩阵。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 多巴胺神经元的增益。在独立阶段，我将使用相同的技术来调查 PPN 的抑制电路。在目标 3 中，我将进行谷氨酸能抑制输入的功能测试已通过狂犬病追踪鉴定出 PPN 神经元。在目标 4 中，我将定义内在的和遗传的 PPN 神经元投影定义亚群的特征。拟议的活动将产生有关基底神经节电路的基础知识，并将提供高级双光子和光遗传学技术补充了我目前在计算建模和电生理学方面的专业知识。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

ALDH1A1 阳性黑质纹状体多巴胺能神经元在运动控制和帕金森病中的功能和调节。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Carmichael, Kathleen;Evans, Rebekah C;Lopez, Elena;Sun, Lixin;Kumar, Mantosh;Ding, Jinhui;Khaliq, Zayd M;Cai, Huaibin
通讯作者：
Cai, Huaibin

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.

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

树突参与健康和病理条件下脆弱的多巴胺能神经元的抑制和去抑制。