Corticofugal Circuits for Active Listening

项目摘要 在主动倾听期间，分散注意力、不相关或完全可预测的声音特征会被抑制，并 不要上升到知觉。相比之下，选择用于放大的输入传达行为相关的信息 用于指导正在进行的知觉决策的听觉信号。神经回路机制 有选择地抑制或放大自下而上的输入以支持主动倾听在很大程度上仍然是个谜。 从逻辑上讲，支持主动倾听的神经元将有来自编码的认知信号的输入 期望、注意力选择和任务要求，但也能够调整获得和调整 低级听觉神经元，编码或计算自下而上的声音特征。庞大的网络 下行的听觉皮质分离神经元符合这一要求，因为它们的细胞体嵌入了高度可塑性的 皮质声音处理中心，但它们的轴突支配丘脑的皮质下听觉核团， 中脑和脑干。解决皮质分离神经元参与主动倾听行为的问题 由于分离和操作特定类别的听觉皮质的技术困难，一直具有挑战性 清醒的、积极倾听的动物的神经元。在这里，我们描述了一种克服这些技术 并提出了一种假设，即听觉皮质疏松神经元的一个特定亚类，第6层 皮质丘脑神经元(L6CT)在塑造增强的皮质和知觉方面起着至关重要的作用 处理预期的声音。在目标1中，我们将使用尖端方法进行特定细胞类型的成像和 清醒小鼠的电生理学行为对两类听觉的靶向记录 脑下投射神经元：第5层皮质小丘神经元(L5CCol)和L6CTs。我们希望找到史塔克 听觉调谐、对内部状态变量的敏感性、局部输出和单突触输入的差异 L5CCol和L6CT神经元(目标分别为1a-1d)。在目标2中，我们将从目标子类型记录 随着老鼠学习形成时空过滤器来处理预期的声音，听觉皮质神经元也开始学习。我们会 解决了L6 CT神经元在预期声音开始之前不久修改其活动的假设 优化行为相关信号的皮质处理。在目标3中，我们将测试L6的因果牵连 CT棘波模式通过光基因沉默预期声音的活动来增强对预期声音的处理 在训练有素的小鼠(测试必要性)或在幼稚的小鼠(测试充分性)中激活它们的关键时刻。 总的来说，这些实验将揭示支持自下而上选择的神经电路机制 在积极倾听过程中增强感知处理的输入。推而广之，对这一点的不当监管 电路可能是对不想要的或令人分心的声音(例如，注意力缺陷)的不可抑制的意识的基础 多动症)或感觉到环境中不存在的声音(例如，耳鸣和 精神分裂症)。

Project Summary During active listening, sound features that are distracting, irrelevant, or totally predictable are suppressed and do not rise to perceptual awareness. By contrast, inputs selected for amplification convey behaviorally relevant auditory signals used to guide ongoing perceptual decision making. The neural circuit mechanisms that selectively suppress or amplify bottom-up inputs to support active listening remain largely mysterious. Logically, neurons that support active listening would have inputs from cognitive signals that encode expectation, attentional selection and task demands, yet would also be able to adjust the gain and tuning of low-level auditory neurons that encode or compute bottom-up sound features. The massive network of descending auditory corticofugal neurons fit the bill because their cell bodies are embedded in highly plastic centers for cortical sound processing, yet their axons innervate subcortical auditory nuclei in the thalamus, midbrain and brainstem. Addressing the involvement of corticofugal neurons in active listening behaviors has been challenging due to the technical difficulty of isolating and manipulating specific classes of auditory cortex neurons in awake, actively listening animals. Here, we describe an approach to overcome these technical obstacles and address the hypothesis that a specific sub-class of auditory corticofugal neuron, the layer 6 corticothalamic neuron (L6 CT), plays an essential role in sculpting enhanced cortical and perceptual processing of expected sounds. In Aim 1, we will use cutting-edge methods for cell type-specific imaging and electrophysiology in awake, behaving mice to make targeted recordings from two classes of auditory subcerebral projection neurons: layer 5 corticocollicular neurons (L5 CCol) and L6 CTs. We expect to find stark differences in the auditory tuning, sensitivity to internal state variables, local outputs and monosynaptic inputs of L5 CCol and L6 CT neurons (Aim 1a-1d, respectively). In Aim 2, we will record from targeted subtypes of auditory cortex neurons as mice learn to form a spatiotemporal filter for processing expected sounds. We will address the hypothesis that L6 CT neurons modify their activity shortly before the onset of expected sounds to optimize cortical processing of behaviorally relevant signals. In Aim 3, we will test the causal involvement of L6 CT spike patterning for enhanced processing of expected sounds by optogenetically silencing their activity at key times in well-trained mice (to test necessity) or activating them in naïve mice (to test sufficiency). Collectively, these experiments will reveal neural circuit mechanisms that support the selection of bottom-up inputs for enhanced perceptual processing during active listening. By extension, improper regulation of this circuit could underlie the irrepressible awareness of unwanted or distracting sounds (e.g., attention deficit hyperactivity disorder) or the perception of sounds that do not exist in the environment (e.g., tinnitus and schizophrenia). 