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

项目说明 拟议项目的中心目标是制定一个概念框架，以了解 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 大脑皮层含有乙酰胆碱，这是运动学习和相关突触可塑性所必需的神经调节剂。 尽管选择性胆碱能消融术后观察到严重的运动学习缺陷，但令人惊讶的是， 已知在顺序运动行为过程中胆碱能神经元的活动。我们所知道的大部分 来自动物执行简单刺激反应任务的录音，以获得 外部奖励，如食物或水。大多数人的行为，比如说话或演奏乐器，都不是后天习得的 追求外部奖励，而不是通过将表现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中尚不清楚。和人类一样，鸣禽也学会发声 通过反复尝试和错误的过程-将声乐表演与他们导师的听觉记忆相匹配 没有明确需要外部加固的歌曲。重要的是，鸣禽有胆碱能投射 从基底前脑到初级运动皮质回路，是声乐学习和发声所必需的。该功能 这一预测的具体内容尚不清楚。在目前的方案中，我研究了胆碱能输入对皮层SING的作用。 声乐学习过程中的运动回路。我假设胆碱能神经元传递预期的表现 在皮质马达电路中实现可塑性的不确定信号。原则上，预期的性能不确定性 可能是在电机序列的特定部分期间重复错误的结果。我假设这是 不确定信号是运动序列学习所必需的。在目标1中，我建议测试以下要求 鸣禽发声学习的胆碱能信号。我会在声带运动皮质使用反向微透析 在幼鸟学习唱歌时，慢性阻断它们的乙酰胆碱受体。在目标2中，我建议确定 突触传入投射到歌声运动皮质的胆碱能神经元，目前尚不清楚。在……里面 为了构建预期的性能不确定信号，需要两条信息--SONG 计时和性能错误。我们将使用已建立的来确定这些信号的神经底物 麻醉鸟类的解剖示踪技术和电生理标测。Aim 3将直接测试 投射到SONG运动的基底前脑神经元预期操作不确定性的神经特征 歌唱时的大脑皮层。我将从逆行识别的、运动皮质投射的基底前脑神经元记录 同时用失真的听觉实验控制歌曲中特定时间的表现不确定性 反馈。预计声音序列的失真部分的结果不确定性比 未变形的部分。我假设预期的不确定性信号将被表示为时间上的精确 在歌曲中扭曲时间之前的神经活动增加，并提供了初步结果 来支持这一假设。综合起来，这项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，这是一个更大的努力的一部分 了解不同神经调节系统在学习中的作用。

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.