Motor Modulation of Auditory Processing

项目摘要 声音交流依赖于区分我们自己的声音（声音反馈）和其他声音。 发声运动相关的必然放电（声音CD）信号，抑制对可预测的听觉反应 声音反馈有助于做出这种区分。值得注意的是，人类听觉皮层中的声音CD信号是 特别是重要的讲话和他们的功能障碍被认为是导致幻听。尽管 关键角色假定为声乐CD信号，监测和操纵他们的活动， 动物的发声阻碍了系统的分析。本申请的长期目标是 了解突触，细胞和电路分辨率如何声乐CD信号调制听觉皮层 对声音反馈的反应，详细了解这一点对于理解适应性和适应不良至关重要 试听方面。我们将获得突触，细胞和电路机制的详细知识， 这一过程通过研究小鼠，脊椎动物最适合先进的遗传，电生理， 光学工具在之前的资助期间，我们使用这些工具来推进我们对突触和 运动相关CD信号调节听觉皮层活动的电路机制。这些 研究进展包括绘制了运动到听觉皮层的回路，确定了不同的头部和身体 运动激活了这条通路，抑制了听觉皮层对声音的反应，这表明， 这条通路可以“学会”选择性地抑制那些与运动有关的声音。我们 还观察到发声雄性小鼠的听觉皮层抑制，但发声发生在雌性小鼠 求爱，总是伴随着其他运动，以及社会和性刺激。 因此，发声特异性CD信号是否调节听觉皮层并抑制可预测的 声音反馈仍然是未知的。幸运的是，我们还开发了光遗传学门控超声波的方法， 发声（USV）和扭曲的声音反馈在孤立的，头部固定的小鼠。在此，我们建议 联合收割机将这些方法与其他现有技术结合，包括体内多电极阵列 多光子成像，发声相关的听觉反馈的控制操作，以及新的 声-声分析的计算方法。在第一个目标中，我们将测试发声 抑制听觉皮层活动，并使用机器学习方法来严格量化和比较 自发和光遗传学诱发的USV。在第二个目标中，我们将分离皮质对 听觉皮层活动的声音调制。在第三个目标中，我们将扭曲声音反馈，以确定是否 听觉皮层的声音抑制是可预测的，并使用计算方法系统地 量化声音失真。总之，这些目标将提供新的见解突触，细胞和电路 声音CD信号影响听觉皮层处理的机制。

Project Summary Vocal communication depends on distinguishing our own vocal sounds (vocal feedback) from other sounds. Vocal motor-related corollary discharge (vocal CD) signals that suppress auditory responses to predictable vocal feedback help make this distinction. Notably, vocal CD signals in the human auditory cortex are especially important to speech and their dysfunction is thought to cause auditory hallucinations. Despite the key roles postulated for vocal CD signals, the challenges of monitoring and manipulating their activity in vocalizing animals has prevented systematic analyses. The long-term objective of this application is to understand with synaptic, cellular, and circuit resolution how vocal CD signals modulate auditory cortical responses to vocal feedback, detailed knowledge of which is essential to understand adaptive and maladaptive aspects of audition. We will gain detailed knowledge of synaptic, cellular, and circuit mechanisms underlying this process by studying the mouse, the vertebrate most suited to advanced genetic, electrophysiological, and optical tools. In the prior funding period, we used these tools to advance our understanding the synaptic and circuit mechanisms by which movement-related CD signals modulate auditory cortical activity. These advances included mapping a motor to auditory cortical circuit, determining that various head and body movements activate this pathway to suppress auditory cortical responses to sounds, and showing that this pathway can “learn” to selectively suppress sounds that are predictably yoked to locomotor movements. We also observed auditory cortical suppression in vocalizing male mice, but vocalization occurred during female courtship and was always accompanied by other movements, as well as by social and sexual stimuli. Therefore, whether vocalization-specific CD signals modulate the auditory cortex and suppress predictable vocal feedback remain unknown. Fortunately, we also developed methods for optogenetically gating ultrasonic vocalizations (USVs) and for distorting vocal feedback in the isolated, head-fixed mouse. Here we propose to combine these methods with other state of the art techniques, including multi-electrode arrays, in vivo multiphoton imaging, controlled manipulation of vocalization-related auditory feedback, and novel computational methods for voco-acoustic analysis. In the first Aim, we will test the idea that vocalization suppresses auditory cortical activity and use machine learning methods to rigorously quantify and compare spontaneous and optogenetically-evoked USVs. In the second Aim, we will isolate cortical contributions to the vocal modulation of auditory cortical activity. In the third Aim, we will distort vocal feedback to determine if vocal suppression of the auditory cortex is predictive, and use computational methods to systematically quantify vocal distortion. Together, these Aims will provide novel insights into the synaptic, cellular, and circuit mechanisms by which vocal CD signals influence auditory cortical processing.