Development of Neuronal Circuits in the Auditory Systems

描述(申请人提供)：我们研究的长期目标是了解建立精确组织的听觉网络的细胞机制，以及这一过程如何受到正常和异常神经元活动的影响。这项拟议的项目旨在阐明听觉脑干中音调组织的抑制性声音定位通路中的这些机制。具体地说，我们的目标是阐明从斜方体内侧核(MNTB)到外侧上橄榄(LSO)的抑制性联系变得音调组织和功能微调的机制。我们最近证明，MMTB-LSO通路的紧张性组织的形成涉及特定的功能消除(沉默)和在听力开始之前加强GABA/甘氨酸能连接。我们还发现，在这一重组期间，MNTB-LSO突触可以经历活动依赖的长期抑制，这涉及到大麻素信号，除了GABA和甘氨酸之外，令人惊讶的是，它还释放谷氨酸作为第三种神经递质。在这些发现的基础上，我们建议进行实验，以阐明在电路重组过程中MNTB-LSO连接被加强或消除的基本细胞和突触机制，以及b)揭示从GABA/甘氨酸能MNTB-LSO突触释放谷氨酸的看似矛盾的现象。为了实现这些目标，我们将应用各种现代电生理学和成像技术，如全细胞和穿孔膜片钳记录，共聚焦钙成像，以及通过笼养谷氨酸的焦点光解绘制功能连接图，从新生小鼠的听觉脑干切片中提取。这项拟议的研究可能会为哺乳动物大脑中初级声音定位电路组装和功能微调的基本规则和依赖活动的机制提供新的见解。对这些机制的详细了解对于理解由早期耳蜗损伤或功能障碍引起的异常听觉回路的出现至关重要，从而有助于我们理解人类交流障碍的原因，如语言感知、特定语言障碍和阅读障碍，这些障碍是由听觉加工受损引起的，可能具有发育成分。

DESCRIPTION (provided by applicant): The long-term goal of our research is to understand the cellular mechanisms by which precisely organized auditory networks become established and how this process is influenced by normal and abnormal neuronal activity. The proposed project is aimed at elucidating these mechanisms in a tonotopically organized, inhibitory sound localization pathway in the auditory brainstem. Specifically, we aim to shed light on the mechanisms by which the inhibitory connections from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) become tonotopically organized and functionally fine-tuned. We recently demonstrated that formation of the tonotopic organization of the MMTB-LSO pathway involves specific functional elimination (silencing) and strengthening of GABA/glycinergic connections before hearing onset. We also found that during this period of reorganization, MNTB-LSO synapses can undergo activity- dependent long-term depression that involves cannabinoid signaling and, in addition to GABA and glycine, surprisingly also release glutamate as a third neurotransmitter. Building on these findings we are proposing experiments to a) illuminate the basic cellular and synaptic mechanisms by which MNTB-LSO connections become strengthened or eliminated during circuit reorganization and b) shed light on the seemingly paradoxical phenomenon of glutamate release from GABA/glycinergic MNTB-LSO synapses. To achieve these goals we will apply a variety of modern electrophysiological and imaging techniques, such as whole-cell and perforated patch clamp recordings, confocal calcium imaging, and mapping of functional connectivity with focal photolysis of caged glutamate, in auditory brainstem slices prepared from neonatal mice. The proposed research may provide new insights into the basic rules and activity-dependent mechanisms by which primary sound localization circuits in the mammalian brain become assembled and functionally fine- tuned. Detailed knowledge of these mechanisms is crucial for understanding the emergence of abnormal auditory circuits that result from early cochlea damage or malfunction and thus can help us to understand the cause of human communication disorders such as language perception, specific language impairment, and dyslexia that result from impaired auditory processing and that likely have developmental components.