Dissecting the basal ganglia's contribution to sensorimotor learning and generalization

描述(申请人提供)：患有基底节疾病或损伤的患者患有广泛的运动障碍，包括纠正运动错误和学习新动作的能力不足。尽管我们知道基底神经节对学习很重要，但我们仍然对它如何促进运动可塑性知之甚少，阻碍了对神经系统疾病和中风后缺陷的理解和治疗。特别是，S并不清楚它是如何引导习得的运动输出调整以应对感觉错误信号的。也不清楚它是否在将学习转移到新的环境中发挥重要作用(“泛化”)。最后，尽管多巴胺信号长期以来一直被认为对学习很重要，但它在学习和推广中的作用仍然知之甚少。拟议的项目将利用一种特别适合于解决这一知识差距的动物模型(鸣鸟)。孟加拉雀表现出复杂的习得运动行为(歌声)，通过感觉运动纠错来维持。他们的歌曲由一系列快速产生的声音手势或音节组成，他们在青少年时期从成人导师那里学习，就像人类婴儿从父母那里学习说话一样。被称为歌曲系统的相互连接的核团网络使歌曲的学习和产生成为可能。基底节核团X区是该系统的组成部分，与人的基底节有许多相似和同源之处。我们的实验室开发了一种新的行为范式，通过改变听觉反馈来唤起孟加拉雀类的适应性发声变化和泛化行为。这一范式将使我们能够追求详细了解基底节和多巴胺在学习和概括中的作用的长期目标。我们的中心假设是，发声学习是由基底节中的多巴胺信号介导的，学习过程中基底节放电模式的变化是获得性歌唱变化的基础。这一假设将通过两个目标进行检验。在目标1中，将确定X区的完全性损伤和投射到X区的多巴胺神经元的选择性损伤如何影响学习能力。在Aim 2区，在驱赶学习的同时，记录到鸣鸟的X区神经元。X区神经活动的变化将与发声输出的变化有关。学习的两个方面将被研究：对发生感觉错误的特定手势的适应性修改，以及将这种学习推广到其他手势。学习将通过改变对歌声中特定发声的听觉反馈来驱动，并观察鸟类如何改变改变的和未改变的发声来进行补偿。总而言之，这些研究将对基底节在运动学习中的作用产生详细的描述。

DESCRIPTION (provided by applicant): Patients with basal ganglia disease or injury suffer from a wide range of motor deficits, including deficiencies in the ability to correct movement errors and learn new movements. Although we know that the basal ganglia is important for learning, we still know relatively little of how it contributes to motor plasticity, hindering the understanding and treatment of deficits after neurological disorders and stroke. In particular, it s not clear how it acts to guide learned adjustments of motor output in response to sensory error signals. It is also unclear whether it plays a major function in transferring learning to new contexts ("generalization"). Finally, although dopamine signaling has long been proposed as being important for learning, its role in learning and generalization remains poorly understood. The proposed project will leverage an animal model (the songbird) uniquely suited for addressing this knowledge gap. Bengalese finches exhibit a complex learned motor behavior (song) maintained via sensorimotor error correction. Their song consists of a series of rapidly produced vocal gestures, or "syllables", which they learn as juveniles from adult tutors, much as human infants learn to speak from parents. A network of interconnected nuclei known as the song system enables song learning and production. The basal ganglia nucleus Area X forms an integral part of this system and has many similarities and homologies to the human basal ganglia. Our lab has developed a novel behavioral paradigm to evoke adaptive vocal changes and generalization behavior in Bengalese finches by altering auditory feedback. This paradigm will allow us to pursue the long-term objective of understanding in detail the basal ganglia's and dopamine's role in learning and generalization. Our central hypothesis is that vocal learning is mediated by dopamine signaling in the basal ganglia and that change in basal ganglia firing patterns during learning underlie learned changes in song. This hypothesis will be tested through two Aims. In Aim 1, it will be determined how complete lesions of Area X, and selective lesions of the dopamine neurons projecting to Area X, affect learning ability. In Aim 2 Area X neurons will be recorded in singing birds while driving learning. Changes in Area X neural activity will be related to the changes in vocal output. Two aspects of learning will be investigated: adaptive modification of the specific gestures during which sensory errors occurred, and generalization of this learning to other gestures. Learning will be driven by altering auditory feedback on specific vocalizations within the song and observing how the bird changes both the altered and unaltered vocalizations to compensate. Together, these studies will yield a detailed characterization of the basal ganglia's role in motor learning.