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

确定基底前脑胆碱能系统在运动序列学习中的作用

• 批准号: 9191443
• 负责人: Pavel Anatolyevich Puzerey
• 金额: $ 5.61万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9191443
• 关键词: Ablation; Acetylcholine; Age-associated memory impairment; Alzheimer' s Disease; Amnesia; Animals; Area; Auditory; Basal Ganglia; Behavior; Biological Models; Birds; Cell Nucleus; Cells; Cholinergic Receptors; Cognitive; Dystonia; Electric Stimulation; Electrophysiology (science); Exhibits; Food; Foundations; Goals; Human; Juice; Learning; Maps; Memory; Microdialysis; Modeling; Motor; Motor Cortex; Neuromodulator; Neurons; Outcome; Output; Parkinson Disease; Performance; Play; Process; Production; Psychological reinforcement; Research; Response to stimulus physiology; Rewards; Role; Schizophrenia; Sensory; Signal Transduction; Songbirds; Speech; Structure; Synapses; Synaptic plasticity; System; Techniques; Testing; Thalamic structure; Time; Uncertainty; Water; Work; anatomical tracing; auditory feedback; basal forebrain; basal forebrain cholinergic neurons; cholinergic; cholinergic neuron; innovation; instrument; motor learning; neural circuit; neuroregulation; neurotransmission; relating to nervous system; research study; response; sequence learning; tutoring; vocal learning

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.

项目描述 拟议项目的中心目标是开发一个概念框架来理解 基底前脑胆碱能神经元在运动序列学习中的功能。这些神经元提供运动 大脑皮层含有乙酰胆碱，乙酰胆碱是运动学习和相关突触可塑性不可或缺的神经调节剂。 尽管选择性胆碱能消融后观察到运动学习方面存在严重缺陷，但令人惊讶的是，这种缺陷很少 已知胆碱能神经元在有序运动行为期间的活动。很多我们所知道的 关于这个系统的信息来自于动物执行简单的刺激反应任务以获得 外部奖励，如食物或水。大多数人类行为，例如言语或演奏乐器，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的这种学习形式尚不清楚。像人类一样，鸣禽学习发声 通过反复试验和犯错的过程——将声音表演与导师的听觉记忆相匹配 歌曲不需要明确的外部强化。重要的是，鸣禽具有胆碱能投射 从基底前脑到声音学习和产生所需的初级运动皮质回路。功能 该预测的具体情况未知。在目前的提案中，我研究了胆碱能输入对皮质歌曲的作用 声音学习期间的运动电路。我假设胆碱能神经元传递预期的性能 不确定性信号使皮质运动电路具有可塑性。原则上，预期绩效的不确定性 可能是由于运动序列的特定部分重复出现错误而导致的。我假设这 不确定性信号对于运动序列学习是必要的。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。我将在发声运动皮层使用反向微透析 当幼鸟学习唱歌时，长期阻断乙酰胆碱受体。在目标 2 中，我建议确定 胆碱能神经元的突触输入投射到歌曲运动皮层，目前尚不清楚。在 为了构建预期的性能不确定性信号，需要两条信息 – 歌曲 时序和性能错误。我们将使用已建立的方法确定这些信号的神经基质 麻醉鸟类的解剖追踪技术和电生理图。目标 3 将直接测试 投射到歌曲运动的基底前脑神经元预期表现不确定性的神经特征 唱歌时的皮质。我将从逆向识别的运动皮层投射基底前脑神经元进行记录 同时通过实验控制听觉扭曲的歌曲中特定时间的表演不确定性 反馈。与相比，声音序列的扭曲部分预计具有更高的结果不确定性 不变形的部分。我假设预期的不确定性信号将表示为时间精确的 歌曲中扭曲时间之前的神经活动增加并提供初步结果 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过程中的作用，是更大努力的一部分 了解不同神经调节系统在学习中的功能。