Development of Neuronal Circuits in the Auditory Systems

我们研究的长期目标是了解细胞机制， 听觉网络的建立，以及这个过程如何受到正常和异常神经元的影响。 活动拟议的项目旨在阐明这些机制， 听觉脑干中的抑制性声音定位通路。具体来说，我们的目标是阐明 机制，通过它的抑制性连接从内侧核的斜方体（MNTB）， 外侧上级橄榄（LSO）在音调上被组织并在功能上被微调。我们最近 证明了MMTB-LSO通路的音调组织的形成涉及特定的 功能性消除（沉默）和加强GABA/甘氨酸能连接听力发作前。 我们还发现，在重组期间，MNTB-LSO突触可以进行活动- 依赖性长期抑郁症，涉及大麻素信号传导，除了GABA和甘氨酸， 令人惊讶地还释放谷氨酸作为第三种神经递质。 在这些发现的基础上，我们提出实验，a）阐明基本的细胞和突触 MNTB-LSO连接在电路期间被加强或消除的机制 重组和B）揭示了谷氨酸释放的看似矛盾的现象， GABA/甘氨酸能MNTB-LSO突触。为了实现这些目标，我们将采用各种现代 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，以及与笼状谷氨酸的局灶性光解的功能连接的映射， 从新生小鼠制备的听觉脑干切片。 这项研究可能会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电路变得组装和功能良好， 即将呈现这些机制的详细知识对于理解异常的出现是至关重要的。 早期耳蜗损伤或故障导致的听觉回路，因此可以帮助我们了解 人类沟通障碍的原因，如语言感知，特定的语言障碍， 由听觉处理受损引起的阅读障碍，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.