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: 10263060
• 负责人: ZAYD M KHALIQ
• 金额: $ 13.4万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10263060
• 关键词: Anatomy; Architecture; Aversive Stimulus; Award; BRAIN initiative; Back; Basal Ganglia; Catecholamines; Cells; Characteristics; Computer Models; Corpus striatum structure; Dendrites; Dopamine; Educational workshop; Electrophysiology (science); Faculty; GABA-B Receptor; Globus Pallidus; Goals; Image; Location; Maps; Midbrain structure; National Institute of Neurological Disorders and Stroke; Output; Paper; Parvalbumins; Pathway interactions; Phase; Positioning Attribute; Prize; Property; Publications; Publishing; Receptor Activation; Research; Series; Signal Transduction; Source; Substantia nigra structure; Synapses; Training Programs; United States National Institutes of Health; Workplace; career; computational neuroscience; data visualization; dopaminergic neuron; experimental study; gamma-Aminobutyric Acid; in vivo; optogenetics; pars compacta; posters; reward processing; striosome; symposium; two-photon

This year I have made excellent progress on my scientific goals. For this project, I developed a functional map of four genetically and anatomically defined inhibitory inputs onto the dopamine neurons of the substantia nigra pars compacta (SNc). I found that the striosome and matrix compartments of the striatum and the parvalbumin and lhx6 subpopulations of the globus pallidus differ in their impact on dopamine neuron activity. Specifically, striosomes selectively activate the ventrally-projecting SNr dendrite of SNc dopamine neurons. While a dendritic location suggests weak inhibitory control over a cell, we found that the striosomes effectively pause firing and hyperpolarized the cell. We found this to be due to both GABA-A and GABA-B receptor activation on the SNc dopamine neuron dendrites. This type of input strongly induces a rebound in activity when the inhibition is released. By contrast, the inputs from the globus pallidus did not strongly hyperpolarize the dopamine neurons and did not induce rebound activity. Together these findings delineate a specific striatonigral circuit for inducing dopamine neuron rebound activity. Because these dopamine neurons inhibited by the striosomes project back to the striatum, this circuit represents a way for the striatum to control the timing of phasic dopamine signals back onto itself. These findings have been well-received at conferences this year. I was selected from the poster abstracts for a talk at the Catecholamines Gordon Research Seminar and, from there, was selected as a talk for the Catecholamines Gordon Research Conference. I also presented this project at the organization for computational neuroscience (OCNS) conference in Barcelona and this project was selected for a poster prize at the annual NINDS retreat. This project is being prepared for publication and I am currently following up these findings with in vivo optogenetic experiments. I have also made good progress in my career goals this year, receiving the BRAIN Initiative K99/R00 pathway to independence award and publishing a co-authored paper with collaborator Huaibin Cai. In addition, I have taken advantage of several training programs offered by NIH including sessions in the workplace dynamics series, the seminar on applying for academic faculty positions, and a hands-on data visualization workshop.

今年我在科学目标上取得了很大的进步。对于这个项目，我开发了一个功能图的四个基因和解剖学定义的抑制性输入到黑质的多巴胺神经元的pars腹侧部（SNc）。我发现纹状体的纹状体和基质区室以及苍白球的小白蛋白和lhx 6亚群对多巴胺神经元活性的影响不同。具体而言，纹状体选择性地激活腹侧投射SNc多巴胺神经元的SNr树突。虽然树突的位置表明对细胞的抑制控制较弱，但我们发现纹状体有效地暂停了放电并使细胞超极化。我们发现这是由于SNc多巴胺神经元树突上的GABA-A和GABA-B受体激活所致。当抑制被释放时，这种类型的输入强烈地诱导活动的反弹。相比之下，苍白球的输入并没有强烈的多巴胺神经元，并没有引起反弹活动。这些发现一起描绘了一个特定的纹状体黑质回路诱导多巴胺神经元反弹活动。因为这些被纹状体抑制的多巴胺神经元会投射回纹状体，所以这个回路代表了纹状体控制多巴胺信号反馈到自身的时机。这些研究结果在今年的会议上受到好评。我从海报摘要中被选为在儿茶酚胺戈登研究研讨会上的演讲，并从那里被选为儿茶酚胺戈登研究会议的演讲。我还在巴塞罗那的计算神经科学组织（OCNS）会议上介绍了这个项目，这个项目被选为年度NINDS务虚会的海报奖。该项目正在准备出版，我目前正在通过体内光遗传学实验跟踪这些发现。 今年，我在职业目标方面也取得了很好的进展，获得了BRAIN Initiative K99/R 00独立之路奖，并与合作者蔡淮滨共同发表了一篇论文。此外，我还利用了NIH提供的几个培训项目，包括工作场所动态系列课程，申请学术教师职位的研讨会，以及动手数据可视化研讨会。