Synaptic processing in the basal ganglia

描述（由申请人提供）：鸣禽的声音学习是人类声音学习的一个独特的、实验上可访问的模型，也证实了复杂社会行为的获得。一只雄性鸣禽学习求偶歌的方法是先记住父亲的歌，然后利用听觉反馈将自己的歌与记忆中的父亲的歌相匹配。这个模型系统的一个主要优点是，存在独立的前脑回路，它们分别参与了歌曲的产生和学习。学习歌曲所需的通路涉及基底神经节，这是哺乳动物中已知的一组大脑区域，对运动控制、运动学习和各种认知功能都很重要。由于相对简单的电路的歌曲学习，我们假设，了解鸣禽的声乐学习将提供一般的见解，在哺乳动物的学习机制，包括人类。具体而言，我们建议探索通过学习回路的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了解这一途径的布线的结构，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的细胞特化;（2）测试“抑制性”突触是否可以在体内驱动突触后神经元的活动;（3）确定对学习至关重要的一个基底神经节结构中的关键神经元中的多巴胺受体和神经肽;（4）测试一种新的解剖学特征通路中的功能连接，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;以及（5）测量多巴胺何时在学习回路中释放，作为多巴胺是否可能在歌曲学习中起作用的第一个测试。这些实验将提供有关鸟类学习回路如何实现其正常功能的必要基本信息。由于我们和其他人已经建立了坚实的基础，比较鸟类的歌曲学习回路与哺乳动物的基底神经节回路，结果将产生更广泛的见解，了解基底神经节回路如何有助于学习复杂的行为。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。虽然这项工作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障碍都涉及基底神经节，因此这项研究也有可能对那些障碍产生长期影响。 公共卫生相关性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基底神经节回路之间的强烈相似性。他们共同探讨了基底神经节中信息处理的细胞机制，这些机制是青少年学习复杂社会行为和成年人修改此类行为的基础。研究结果将指导对基底神经节在认知过程（如学习）中的作用的理解，并最终可能揭示基底神经节相关的疾病，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.