Synaptic processing in the basal ganglia

描述（申请人提供）：鸣禽的声乐学习是人类声乐学习的一种独特的、可通过实验获得的模型，也体现了复杂社会行为的习得。雄性鸣禽通过首先记住父亲的歌声来学习求爱的歌声，然后用听觉反馈来匹配自己的歌声和父亲的歌声。这个模型系统的一个主要优点是存在独立的前脑回路，参与产生歌曲和学习歌曲。学习唱歌所需的途径涉及基底神经节，这是哺乳动物大脑中已知的一组对运动控制、运动学习和各种认知功能很重要的区域。由于歌唱学习的电路相对简单，我们假设理解鸣禽的声乐学习将为包括人类在内的哺乳动物的学习机制提供一般的见解。具体而言，我们建议通过学习回路探索信息传递和处理的细胞机制。这里提出的实验将使用电生理学和神经解剖学的方法来理解这条通路的结构、功能和分子组成部分。我们将：(1)确定学习回路中异常强大的抑制性突触背后的细胞特化；(2)在体内验证“抑制性”突触是否能驱动突触后神经元的活动；(3)确定学习所必需的基底神经节结构关键神经元中的多巴胺受体和神经肽；(4)对一种新的解剖学特征通路的功能连接进行测试，该通路可以向多巴胺系统的神经元提供与歌曲相关的信息；(5)测量多巴胺在学习回路中的释放时间，作为多巴胺是否在歌曲学习中发挥作用的第一个测试。这些实验将为鸟类学习回路如何完成其正常功能提供必要的基础信息。由于我们和其他人已经建立了比较鸟类鸣叫学习回路与哺乳动物基底神经节回路的坚实基础，结果将更广泛地了解基底神经节回路如何有助于复杂行为的学习。他们将为更高层次的实验奠定基础，这些实验旨在操纵学习回路中的信息处理，以可预测的方式改变学习。虽然本研究的重点是认知功能的基本机制，但由于自闭症谱系障碍、精神分裂症、帕金森病和亨廷顿病等多种疾病都涉及基底神经节，因此本研究也有可能对这些疾病产生长期影响。这些实验利用了我们已经证明的鸣禽基底神经节回路与哺乳动物之间的强烈相似之处。他们共同研究了基底节区信息处理的细胞机制，基底节区是青少年学习复杂社会行为和成人改变这种行为的基础。研究结果将指导人们理解基底神经节在认知过程（如学习）中的作用，并最终可能阐明与基底神经节有关的疾病，如自闭症和精神分裂症。

DESCRIPTION (provided by applicant): Vocal learning in songbirds is a unique, experimentally accessible model of human vocal learning that also exemplifies the acquisition of complex social behavior. A male songbird learns his courtship song by first memorizing his father's song, and later using auditory feedback to match his own song to his memory of his father's song. One major advantage to this model system is the existence of separate forebrain circuits involved in producing the song and in learning it. The pathway needed for learning song involves the basal ganglia, a set of brain regions known in mammals to be important for motor control, motor learning and a variety of cognitive functions. Because of the relatively simple circuitry for song learning, we hypothesize that understanding vocal learning in songbirds will provide general insights into learning mechanisms in mammals, including humans. Specifically, we propose to explore cellular mechanisms underlying information transfer and processing through the learning circuit. The experiments proposed here will use electrophysiological and neuroanatomical approaches to understand the structural, functional and molecular components of the wiring of this pathway. We will: (1) determine the cellular specializations underlying an unusually powerful inhibitory synapse in the learning circuit; (2) test whether that "inhibitory" synapse can drive activity in postsynaptic neurons in vivo; (3) determine the dopamine receptors and neuropeptides in key neurons in one basal ganglia structure essential for learning; (4) test for functional connections in a novel anatomically characterized pathway that could provide song-related information to neurons of the dopamine system; and (5) measure when dopamine is released in the learning circuit, as a first test of whether dopamine may play a role in song learning. These experiments will provide necessary fundamental information about how the avian learning circuit accomplishes its normal function. Because of the strong foundation that we and others have built comparing avian song learning circuits with basal ganglia circuits in mammals, the results will yield insights more broadly into how basal ganglia circuits can contribute to learning of complex behavior. They will lay the foundation for higher-level experiments aimed at manipulating information processing in the learning circuit to alter learning in a predictable fashion. Although this work is focused on the basic mechanisms underlying cognitive function, because a variety of disorders such as autism spectrum disorder, schizophrenia, Parkinson disease and Huntington disease involve the basal ganglia, this research also has the potential to have long- term impact on those disorders. PUBLIC HEALTH RELEVANCE These experiments take advantage of the strong parallels that we have demonstrated between songbird basal ganglia circuits and those of mammals. Together, they address cellular mechanisms of information processing in the basal ganglia that underlie learning of a complex social behavior in juveniles and modification of such behavior in adults. The results will guide understanding of the role of the basal ganglia in cognitive processes such as learning and ultimately may shed light on disorders in which the basal ganglia are implicated, such as autism and schizophrenia.