Development of Neuronal Circuits in the Auditory Systems

我们研究的长期目标是了解精确组织的细胞机制 听觉网络的建立以及正常和异常神经元对这一过程的影响 活动。拟议的项目旨在以音调组织的方式阐明这些机制， 听觉脑干中的抑制性声音定位通路。具体地说，我们的目标是阐明 斜方体内侧核(MNTB)至丘脑的抑制性联系 外侧上橄榄(LSO)变得有条不紊，功能微调。我们最近 证明了MMTB-LSO途径的紧张性组织的形成涉及特定的 听力发作前功能消除(沉默)和增强GABA/甘氨酸能连接。 我们还发现，在这一重组期间，MNTB-LSO突触可以进行活动- 依赖的长期抑郁，涉及大麻素信号，除了GABA和甘氨酸， 令人惊讶的是，它还会释放谷氨酸作为第三种神经递质。 在这些发现的基础上，我们提议进行实验，以a)阐明基本的细胞和突触 MNTB-LSO连接在电路过程中得到加强或消除的机制 重组和b)揭示了似乎自相矛盾的谷氨酸从 GABA/甘氨酸能MNTB-LSO突触。为了实现这些目标，我们将应用各种现代化的 电生理和成像技术，如全细胞和穿孔膜片钳记录， 共聚焦钙成像和笼中谷氨酸光解的功能连通性图谱 新生小鼠听性脑干切片。 拟议的研究可能通过以下方式为基本规则和活动依赖机制提供新的见解 哺乳动物大脑中的主要声音定位回路会组装在一起并在功能上很精细- 调好了。对这些机制的详细了解对于理解异常的出现至关重要 由早期耳蜗损伤或故障引起的听觉回路，因此可以帮助我们理解 人类交流障碍的原因，如语言感知、特定语言障碍和 由于听觉处理受损而导致的阅读障碍，可能有发育成分。

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.