Circuit Mechanisms for the Cancellation of Self-Generated Sounds in the Dorsal Cochlear Nucleus

项目摘要/摘要 大脑如何区分行为相关的感觉输入和动物的 自己的行为？长期以来，人们一直认为与行为有关的信号可以用来预测和抵消 对动物自身运动的感官反应。然而，这一过程背后的神经机制 一直难以捉摸。最近发现的证据表明，自我产生的声音在一开始就被取消了 哺乳动物听觉处理的阶段--耳蜗背核(DCN)--但其回路机制 都是未知的。洞察力可能来自DCN的独特电路，它与 小脑，包括浦肯野样车轮细胞(CWCs)，它大量整合了非听觉、行为- 受突触可塑性影响的相关输入。已知在电鱼中类似小脑的环路 使用与行为相关的信号来预测行为的感官后果。这些 预测以高度具体的“负面图像”的形式出现，这些图像抵消了对自身产生的反应 感官输入。目标1将通过测试DCN在听觉系统中的作用来探索感觉预测的作用 使用负片图像来消除自己产生的声音。目标2将阐明CWCS在感觉中的作用 通过有选择地监测和光遗传操作它们在清醒、行为正常的小鼠中的活动来取消。 CWCs是DCN中数量最多的抑制性中间神经元，但有证据表明，它们并不参与 对外部听觉刺激的处理。这些实验将是第一次测试CWCS是否有助于 到处理自己产生的声音。这项工作有助于治疗和理解耳鸣，一种 一种常见的、有时会使人衰弱的疾病，在这种疾病中，声音总是被感知到而实际上并不是 现在时。耳鸣与异常的突触可塑性、躯体感觉整合和 DCN中的神经元过度活动。探索DCN可塑性和躯体感觉统合的正常功能， 此外，CWCS的作用--它有效地抑制耳鸣中过度活跃的DCN细胞--可能会产生 对耳鸣病理的重要见解。

PROJECT SUMMARY / ABSTRACT How does the brain distinguish between behaviorally relevant sensory input and that caused by an animal's own behavior? It has long been thought that signals related to behavior may be used to predict and cancel out sensory responses to animals' own movements. However, the neural mechanisms underlying this process have been elusive. Evidence was recently uncovered that self-generated sounds are cancelled at the first stage of auditory processing in mammals – the dorsal cochlear nucleus (DCN) – but the circuit mechanisms are unknown. Insights may come from the distinctive circuitry of DCN, which has striking similarities to the cerebellum, including Purkinje-like cartwheel cells (CWCs) that massively integrate non-auditory, behavior- related inputs that are subject to synaptic plasticity. Similar cerebellum-like circuits in electric fish are known to use behavior-related signals to generate predictions of the sensory consequences of behavior. These predictions take the form of highly specific “negative images” that cancel out responses to self-generated sensory input. Aim 1 will explore the role of sensory prediction in the auditory system by testing whether DCN uses negative images to cancel self-generated sounds. Aim 2 will elucidate the role of CWCs in sensory cancellation by selectively monitoring and optogenetically manipulating their activity in awake, behaving mice. CWCs are the most numerous inhibitory interneuron in DCN, but evidence suggests they do not contribute to the processing of external auditory stimuli. These experiments will be the first to test whether CWCs contribute to processing self-generated sounds. This work can contribute to the treatment and understanding of tinnitus, a common and sometimes debilitating disorder in which sound is persistently perceived that is not actually present. Tinnitus has been associated with aberrant synaptic plasticity, somatosensory integration, and neuronal hyperactivity in DCN. Exploring the normal function of DCN plasticity and somatosensory integration, as well as the role of CWCs – which potently inhibit DCN cells that are hyperactive in tinnitus – could yield important insights into the pathology of tinnitus.