Optogenetic analysis of circuits for vocal recognition

描述（由申请人提供）：检测和解释交际发声的能力是人类互动的基础。识别支持声音感知的大脑回路和机制对于治疗影响语言理解的一系列疾病至关重要，例如失语症中风、自闭症和发展性阅读障碍。大多数这些情况涉及听觉皮层的损伤或功能障碍，表明该结构在声音感知中起着至关重要的作用。令人失望的是，作为交流发声感知基础的皮层回路机制，以及听觉皮层在选择适当行为反应中的作用，仍然是一个谜。本研究的目标是整合光遗传学、电生理学和行为学方法，以解决使声音识别的皮层回路的突触特性，并测试听觉皮层在介导听觉引导行为中的作用。这一目标需要一种模型动物，它依赖于声音交流，适合于神经回路的高分辨率电生理分析，并且能够适应基因工具来操纵大脑活动。老鼠是高度群居的哺乳动物，它们使用发声来进行交流，并且可以使用尖端技术来精确解剖听觉皮层的突触组织和功能。雌性小鼠被选择性地吸引到孤立的幼崽的叫声中，简化了对声音感知及其与神经活动的关系的评估。此外，小鼠听觉皮层包含一个区域（UF），专门用于检测幼犬叫声的声学频率范围内的声音，从而缩小了对声音感知电路的搜索范围。尽管有这些关键的优势，但对小鼠听觉皮层的功能性突触特性以及这些特性如何服务于声音识别知之甚少。我们的建议利用了新创建的转基因小鼠系，这些小鼠在皮质神经元的有限亚群中表达光敏离子通道。这种通道蛋白的表达可以精确地操纵神经活动，从而确定UF和周围听觉皮层区域之间的详细突触连接，我们假设这可能支持声音识别。此外，我们将从功能上评估UF回路的活动对于释放雌性小鼠发声诱发的运动行为是否必要和充分。这种在小鼠模型中检查声音感知机制的方法提供了几个关键的好处，这些好处远远超出了小鼠声音交流的生物学范围，并且与R21机制的概念直接相关，特别是与NIH的健康使命直接相关。首先，该提案的特点是开发创新的方法来探测皮层电路，这将很容易适用于广泛的系统。其次，由于小鼠皮层的细胞类型多样性和基本突触微电路与人类皮层相似，我们的研究结果几乎肯定会揭示听觉频谱整合的一般原理，这将直接丰富我们对人类听觉皮层功能的理解。最后，开发小鼠社会声音交流模型将为我们的团队以及许多其他人开辟新的研究途径，允许分析改变皮质突触结构的遗传疾病如何干扰社会认知和交流。识别支持声音感知的神经机制与治疗影响语言理解的病理有关，如失语症中风、自闭症和发展性阅读障碍。听觉皮层在声音感知中起着至关重要的作用，但声音识别背后的皮层机制以及皮层回路在听觉引导行为中的作用仍未得到解决。因此，本提案的目标是在小鼠身上发展和整合遗传、电生理和行为方法，以评估听觉皮层中的突触回路如何使声音识别，并测试它们在介导听觉引导行为中的作用。

DESCRIPTION (provided by applicant): The ability to detect and interpret communicative vocalizations is fundamental to human interaction. Identifying brain circuits and mechanisms that support vocal perception is essential for treatment of the broad array of pathologies that affect speech comprehension, such as aphasic stroke, autism and developmental dyslexia. Most of these conditions involve damage or dysfunction in the auditory cortex, indicating that this structure plays an essential role in vocal perception. Disappointingly, the cortical circuit mechanisms that underlie the perception of communicative vocalizations and the role of auditory cortex in selecting appropriate behavioral responses remain enigmatic. The goal of this proposal is to integrate optogenetic, electrophysiological and behavioral methods to resolve the synaptic properties of cortical circuits that enable vocal recognition and to test the role of the auditory cortex in mediating auditory-guided behavior. This goal requires a model animal that relies on vocal communication, is suitable for high-resolution electrophysiological analysis of neural circuitry, and is amenable to genetic tools for manipulating brain activity. Mice are highly social mammals that use vocalizations to communicate, and are accessible to cutting edge techniques for precisely dissecting the synaptic organization and function of the auditory cortex. Female mice are selectively drawn towards cries of isolated pups, simplifying assessment of vocal perception and its relation to neural activity. Moreover, the mouse auditory cortex contains a region (UF) specialized for the detection of sounds in the acoustic frequency range of pup cries, thus narrowing the search for vocal perception circuitry. Despite these critical advantages, little is known about the functional synaptic properties of the mouse auditory cortex and how these properties serve vocal recognition. Our proposal takes advantage of newly created lines of genetically modified mice that express a light-sensitive ion channel in restricted subsets of cortical neurons. Expression of this channel protein allows one to precisely manipulate neural activity, and thus to ascertain detailed synaptic connections between UF and surrounding auditory cortical regions that we hypothesize may support vocal recognition. Furthermore, we will functionally assess whether activity in the UF circuit is necessary and sufficient for releasing vocalization-evoked locomotor behavior in female mice. This approach to examining the mechanisms of vocal perception in the mouse model offers several crucial benefits that extend well beyond the scope of the biology of vocal communication in mice, and are directly relevant to the concept of the R21 mechanism specifically and NIH's health mission generally. First, the proposal features the development of innovative approaches to probing cortical circuitry that will be readily applicable to a wide range of systems. Second, because the mouse cortex shares much of its cell type diversity and basic synaptic microcircuitry with the human cortex, our results are almost certain to reveal general principles of auditory spectral integration that will directly enrich our understanding of human auditory cortical function. Finally, development of a mouse model of social vocal communication will open new avenues of research for our group as well as many others, allowing analysis of how genetic disorders that alter cortical synaptic architecture interfere with social cognition and communication. Identifying the neural mechanisms that support vocal perception is germane to treatment of pathologies that affect speech comprehension, such as aphasic stroke, autism and developmental dyslexia. The auditory cortex plays an essential role in vocal perception, but the cortical mechanisms that underlie vocal recognition and the role of cortical circuits in auditory-guided behavior remain unresolved. Therefore, this proposal's goal is to develop and integrate genetic, electrophysiological and behavioral approaches in mice to assess how synaptic circuits in auditory cortex enable vocal recognition and to test their role in mediating auditory-guided behavior.