Basal Ganglia-Thalamic Interactions in Behaving Songbirds During Learning

描述(申请人提供)：基底节(BG)回路是一组临床上相关的大脑深层结构，在人类和鸟类中似乎发挥着类似的功能-运动序列学习。尽管目前人类的治疗方法包括刺激长期植入大脑皮质结构的电极，但我们仍然不知道电信号是如何通过电路传播来影响行为的。鸣鸟有专门的BG通路，完全致力于单一任务--歌唱学习。在完成了鸣鸟BG不同细胞类别的第一次录音(Goldberg and Fee，2010；Goldberg等人，2010)之后，我现在准备问一些关于BG功能的基本问题：BG输出是如何在丘脑中处理的？不同的BG细胞课程如何实现运动学习？大脑皮层回路中的神经相互作用是什么？在这个提案中，我勾勒出了实现我长期目标的途径：建立一个利用鸣禽模型系统的优势的实验室，研究基底节微电路如何促进正常和异常的运动功能。在我的博士论文中，我使用了细胞生理学和双光子成像来研究大脑皮层微电路中不同的细胞类别。在医学院，我接受了治疗基底节相关神经疾病患者的培训，在博士后培训的第一阶段，我学会了从自由活动的动物基底节连接的神经元进行记录。这份建议中制定的培训计划是专门为我带来新的技术，使我能够进行新的实验并过渡到一个独立的职位。例如，我的近期目标是学习实现新的歌曲条件反射范例所需的计算和数字信号处理技能，开发一种在行为过程中同时从多个神经元进行细胞外记录的新方法，并学习使用最近开发的细胞内微驱动器来记录来自自由移动的动物的细胞内记录。这些目标将在指导阶段完成，然后我将在2011年秋季申请职位。当我掌握这些技术时，我将能够解决有关基底节和丘脑功能的基本问题。首先，我将研究运动丘脑如何通过记录连接的苍白球和丘脑神经元，以及通过在歌唱过程中反向识别的皮质丘脑投射神经元，来整合来自BG和皮质的两个主要输入。接下来，我将通过将神经记录与一种新的条件听觉反馈范式相结合来检查实验控制的运动学习过程中的BG输出信号，该范式可以诱导快速尝试和错误的歌曲学习。最后，我将开始一个长期项目，研究六个主要的BG细胞类别中的每一个在学习过程中如何改变其活动，以及这些神经元的小群体在行为过程中如何相互作用。这一最终目标包括开发一种技术，从鸣禽的BG神经元中进行细胞内记录，这构成了我将在Michale Fee的支持下，在这笔赠款的R00阶段继续进行的研究计划。这项培训和研究将在麻省理工学院麦戈文脑与认知科学研究所的Michale Fee实验室进行，我周围都是有才华的研究生、博士后和教职员工。该部门非常有刺激性，每周有两个研讨会系列，世界知名的演讲者和一流的设施。最后，尽管Michale资金充足(两个R01)，但我是实验室里仅有的两个博士后之一。这意味着我和米歇尔对彼此非常投入，我们经常每天花几个小时在一起，讨论实验，写论文和制造新设备。作为重新提交赠款的一部分，米歇尔和我仔细地制定了实验、培训计划和独立之路，他同意在我过渡到R00阶段时亲自培训和支持我，届时我将开始研究特定的纹状体和苍白球细胞类别在BG功能中所起的作用。这些努力的时间表将构成我的进步基准，在本提案的职业目标部分提供了这些时间表。

DESCRIPTION (provided by applicant): The basal ganglia (BG) circuit is a clinically relevant group of deep brain structures that appear to play similar functions in humans and birds-motor sequence learning. Even though current therapies in humans involve the stimulation of electrodes chronically implanted into BG structures, we still do not understand how electrical signals propagate through the circuit to influence behavior. Songbirds have specialized BG pathway devoted entirely to single task-song learning. Having performed the first recordings from distinct cell classes in the songbird BG (Goldberg and Fee, 2010; Goldberg et al., 2010), I am now poised to ask basic questions of BG function: How are BG outputs processed in the thalamus? How do distinct BG cell classes implement motor learning? What are the neural interactions within the BG circuit? In this proposal, I outline the path to my long term goal: to build a laboratory that harnesses the advantages of the songbird model system to study how basal ganglia microcircuits contribute to normal and abnormal motor function. For my PhD thesis, I used cellular physiology and two-photon imaging to study distinct cell classes in the cortical microcircuit. In medical school, I was trained in the care of patients with basal ganglia-related neurological disease, and in the first phase of my post-doctoral training, I have learned to record from connected neurons in the basal ganglia of freely moving animals. The training plan formulated in this proposal is specifically designed to bring me new techniques that will enable me to execute novel experiments and to transition to an independent position. For example, my immediate goals are to learn the computational, digital signal processing skills required to implement a novel song-conditioning paradigm, to develop a new method for extracellular recording from multiple neurons simultaneously during behavior, and to learn to use a recently developed intracellular microdrive for recording intracellularly from freely moving animals. These goals are to be completed in the mentored phase, before I apply for positions in the fall of 2011. As I acquire these techniques, I will be able to address basic questions of basal ganglia and thalamic function. First, I will examine how the motor thalamus integrates its two major inputs, from the BG and the cortex, by recording from connected pallidal and thalamic neurons, and by recording from antidromically identified corticothalamic projection neurons during singing. Next, I will examine BG output signals during experimentally controlled motor learning by combining neural recordings with a novel conditional auditory feedback paradigm that induces rapid trial and error song learning. Finally, I will embark on a long-term project of studying how each of the six major BG cell classes changes its activity during this learning, and how small groups of these neurons interact during behavior. This final aim includes the development of a technique to record intracellularly from BG neurons in singing birds, and constitutes the research program that I will continue, with Michale Fee's support, in the R00 phase of this grant. This training and research will take place in Michale Fee's laboratory at the McGovern Institute for Brain and Cognitive Sciences at MIT, where I am surrounded by talented graduate students, post-docs and faculty. The department is very stimulating with two weekly seminar series, world-renowned speakers and first rate facilities. Finally, even though Michale is well funded (two R01s), I am one of only two post-docs in the lab. This means Michale and I are very invested in one another and we frequently spend hours per day together, discussing experiments, writing papers and building new devices. As part of this grant resubmission Michale and I carefully formulated the experiments, the training plan, and the path to independence, and he has agreed to personally train and support me as I transition to the R00 phase, when I will begin to pursue the role that specific striatal and pallidal cell classes play in BG function. The timeline for these endeavors, which will constitute my benchmarks for progress, is presented in the Career Goals section of this proposal.