Corticofugal Circuits for Active Listening

项目摘要 在主动聆听过程中，干扰、无关或完全可预测的声音特征被抑制， 不要上升到知觉觉知。相比之下，选择用于放大的输入传达行为相关的信息， 听觉信号用于指导正在进行的感知决策。神经回路机制， 选择性地抑制或放大自下而上的输入，以支持积极的倾听，在很大程度上仍然是神秘的。 从逻辑上讲，支持主动倾听的神经元会有来自认知信号的输入， 期望，注意力选择和任务要求，但也将能够调整增益和调谐 编码或计算自下而上的声音特征的低级听觉神经元。庞大的网络 下行听觉离皮质神经元符合这一要求，因为它们的细胞体嵌在高度可塑的 皮质声音处理中心，但它们的轴突支配丘脑中的皮质下听觉核， 中脑和脑干。探讨离皮质神经元参与主动倾听行为， 由于分离和操纵特定类别的听觉皮层的技术难度， 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问题的方法。 障碍和解决的假设，一个特定的子类听觉离皮质神经元，层6 皮质丘脑神经元（L 6 CT），在塑造增强的皮质和知觉中起着重要作用。 处理预期的声音。在目标1中，我们将使用尖端方法进行细胞类型特异性成像， 清醒、行为小鼠的电生理学对两类听觉进行有针对性的记录 大脑下投射神经元：第5层皮质丘神经元（L5 CCo 1）和L 6 CT。我们希望能找到斯塔克 听觉调谐的差异，对内部状态变量的敏感性，局部输出和单突触输入 L5 CCo 1和L 6 CT神经元（分别为Aim 1a-1d）。在目标2中，我们将从目标亚型中记录 听觉皮层神经元作为小鼠学习形成一个时空滤波器处理预期的声音。我们将 解决了L 6 CT神经元在预期声音开始前不久修改其活动的假设， 优化行为相关信号的皮层处理。在目标3中，我们将测试L 6的因果关系 通过光遗传学沉默预期声音的活性来增强对预期声音的处理的CT尖峰图案化 关键时间在训练有素的小鼠（测试必要性）或激活它们在幼稚小鼠（测试充分性）。 总的来说，这些实验将揭示支持自下而上选择的神经回路机制 在主动收听期间用于增强感知处理的输入。推而广之，对此的不当监管 电路可能是对不想要的或分散注意力的声音的不可抑制的意识的基础（例如，注意缺陷 多动障碍）或对环境中不存在的声音的感知（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). 