Identifying the roles of the basal forebrain cholinergic system in motor sequence learning

项目描述 拟议项目的中心目标是制定一个概念框架， 基底前脑胆碱能神经元在运动序列学习中的作用这些神经元为马达提供动力 皮质与乙酰胆碱，一个神经调质必不可少的运动学习和相关的突触可塑性。 尽管在选择性胆碱能消融后观察到运动学习的严重缺陷， 已知胆碱能神经元在有序运动行为中的活动。我们所知道的大部分 关于这个系统的信息来自于动物执行简单刺激反应任务的记录， 外部奖励，如食物或水。人类的大多数行为，如说话或演奏乐器，都不是后天习得的 追求外部奖励，而是通过将绩效与内部目标相匹配来学习。的作用 基底前脑胆碱能神经元在这种形式的学习是未知的。像人类一样，鸣禽也学习发声 通过反复的试错过程--将声乐表演与他们导师的听觉记忆相匹配， 没有明确需要外部强化的歌曲。重要的是，鸣禽有一个胆碱能投射 从基底前脑到初级运动皮层回路，这些回路是声音学习和产生所必需的。功能 这个预测是未知的。在目前的建议中，我调查的作用，胆碱能输入皮层歌曲 运动神经回路在发声学习中的作用我假设胆碱能神经元传递预期的表现 不确定性信号，使可塑性皮层运动电路。原则上，预期业绩不确定性 可能由于在电机序列的特定部分期间重复的错误而出现。我假设 不确定性信号是电机序列学习所必需的。在目标1中，我建议测试 鸣禽发声学习的胆碱能信号。我将在发声运动皮层中使用反向微透析， 在幼鸟学唱时，长期阻断其乙酰胆碱受体。在目标2中，我建议确定 突触输入到胆碱能神经元投射到歌曲运动皮层，这是目前未知的。在 为了构建预期的性能不确定性信号，需要两条信息： 时间和性能错误。我们将确定这些信号的神经基板使用既定的 解剖追踪技术和电生理映射在麻醉鸟类。目标3将直接测试 基底前脑投射到鸣唱运动神经元中预期表现不确定性的神经信号 唱歌时的大脑皮层我将记录下从逆行识别的，运动皮质投射的基底前脑神经元 同时实验性地控制歌曲中特定时间的表现不确定性 反馈声音序列的失真部分预期具有比声音序列更高的结果不确定性。 不扭曲的部分。我假设预期的不确定性信号将被表示为时间上精确的 在歌曲中扭曲时间之前神经活动的增加，并提供初步结果 来支持这一假设。结合在一起，拟议的研究旨在建立精确的计算 基底前脑胆碱能神经元在运动序列学习中的作用，是更大努力的一部分， 了解不同的神经调节系统在学习中的功能。

PROJECT DESCRIPTION The central goal of the proposed project is to develop a conceptual framework for understanding the function of basal forebrain cholinergic neurons in motor sequence learning. These neurons supply the motor cortex with acetylcholine, a neuromodulator indispensable for motor learning and associated synaptic plasticity. Despite the profound deficits in motor learning observed following selective cholinergic ablation, surprisingly little is known about the activity of cholinergic neurons during sequenced motor behavior. Much of what we know about this system comes from recordings in animals performing simple stimulus-response tasks to obtain external rewards like food or water. Most human behaviors, like speech or playing an instrument, are not learned in pursuit of external rewards, but instead are learned by matching performance to internal goals. The role of basal forebrain cholinergic neurons in this form of learning is not known. Like humans, songbirds learn to vocalize through an iterant process of trial and error – matching vocal performance to an auditory memory of their tutor’s song without an explicit need for external reinforcement. Importantly, songbirds have a cholinergic projection from the basal forebrain to primary motor cortical circuits required for vocal learning and production. The function of this projection is unknown. In the present proposal, I investigate the role of cholinergic inputs to cortical song motor circuits during vocal learning. I hypothesize that cholinergic neurons transmit an expected performance uncertainty signal that enables plasticity in cortical motor circuits. In principle, expected performance uncertainty could arise as a result of repeated errors during specific parts of a motor sequence. I hypothesize that this uncertainty signal is necessary for motor sequence learning. In Aim 1, I propose to test the requirement of cholinergic signaling for vocal learning in songbirds. I will use reverse microdialysis in vocal motor cortex to chronically block acetylcholine receptors in young birds as they learn to sing. In Aim 2, I propose to identify the synaptic inputs onto cholinergic neurons projecting to the song motor cortex, which are presently unknown. In order to construct an expected performance uncertainty signal, two pieces of information are required – song timing and performance error. We will determine the neural substrates for these signals using established anatomical tracing techniques and electrophysiological mapping in anesthetized birds. Aim 3 will directly test for neural signature of expected performance uncertainty in basal forebrain neurons projecting to the song motor cortex during singing. I will record from antidromically-identified, motor cortex-projecting basal forebrain neurons while experimentally controlling performance uncertainty at specific times in the song with distorted auditory feedback. Distorted parts of the vocal sequence are expected to have higher outcome uncertainty compared to undistorted parts. I hypothesize that expected uncertainty signals would be expressed as temporally precise increases in neural activity immediately preceding the distorted time in the song and provide preliminary results in support of this hypothesis. Combined together, the proposed research aims to establish precise computational roles for basal forebrain cholinergic neurons during motor sequence learning and is part of a larger endeavor to understand the function of different neuromodulatory systems in learning.