Synaptic Organization of the Auditory System

描述（由申请人提供）：本项目的总体目标是了解大脑如何处理声音信息。下丘（IC）是中脑的主要听觉结构。所有关于声音的信息都必须通过IC，因为它从耳朵传播到大脑皮层。这个项目继续我们的努力，了解IC功能的细胞基础。尽管有许多研究，但对IC中听觉处理的微观解剖学、神经元特化和突触组织的了解太少。在下丘神经元上有两种非常不同的兴奋性输入。我们已经发现，专门的“花萼样”轴体突触发生在大的GABA能神经元IC。这些突触包含VGLUT 2，一种将递质谷氨酸装载到突触囊泡中的分子。这些兴奋性突触在兴奋性神经元或较小的GABA能神经元上不存在，其中树突状兴奋性突触占主导地位。提出了该集成电路中的两种基本电路。在一种情况下，大的GABA能IC神经元在细胞体和近端树突上接收密集的兴奋性突触输入。另一个回路具有较小的多巴胺能和GABA能IC神经元，仅在树突上具有多巴胺能输入。在两个实验中研究了IC中的GABA能神经元。我们将展示：（1）大的GABA能神经元只投射到丘脑;（2）有和没有花萼样输入的GABA能神经元在它们的放电模式和内在膜特性上是不同的。在实验中研究了对IC的兴奋性输入，以揭示对大GABA能IC神经元（电路1）的VGLUT 2杯状输入的结构和功能。我们将展示：（3）分离的听觉脑干神经元表达VGLUT 1或VGLUT 2投射到IC;（4）VGLUT 2轴体突触起源于听觉脑干中的单一来源，并且这种特化突触来自单一轴突;（5）GABA能神经元上的VGLUT 2轴体突触不同于IC中的其他谷氨酸突触。IC中的脑回路是值得注意的，因为IC接收来自下听觉脑干的抑制性和兴奋性输入。对IC的兴奋性输入被分离到功能区，但不清楚抑制性输入是否也遵循相同的模式。在这里，在实验6中，我们将使用听觉生理学与未麻醉的兔子准备，在IC的神经反应的抑制性输入的模式。我们将专门测试的假设，ICc域有不同的模式的抑制输入。下丘对正常听力很重要，因为它是中枢听觉通路的主要部分，从听觉皮层到耳蜗核的神经元直接连接到下丘。下丘中风或肿瘤等病理可能导致耳聋、听力损失或听源性癫痫发作。下丘现在是听觉中脑植入物的部位，用于电刺激手术切除第八神经后患者的中枢听觉通路。

DESCRIPTION (provided by applicant): The general goal of this project is to understand how information about sound is processed by the brain. The inferior colliculus (IC) is the main auditory structure in the midbrain. All information about sound must pass through the IC as it travels from the ear to the cerebral cortex. This project continues our effort to understand the cellular basis for function of the IC. Despite numerous studies, far too little is known about how microanatomy, neuronal specializations, and synaptic organization underlie auditory processing in the IC. There are two very different types of excitatory input on neurons in the IC. We have discovered that specialized "calyx-like" axosomatic synapses occur on the large GABAergic neurons in IC. These synapses contain VGLUT2, a molecule that loads the transmitter glutamate into synaptic vesicles. These excitatory synapses are absent on excitatory neurons or smaller GABAergic neurons where dendritic excitatory synapses predominate. Two basic circuits in the IC are proposed. In one, large GABAergic IC neurons receive a dense, excitatory synaptic input on the cell body and proximal dendrites. The other circuit has smaller glutamatergic and GABAergic IC neurons with glutamatergic inputs only on dendrites. GABAergic neurons in IC are studied in two experiments. We will show: (1) the large GABAergic neurons project exclusively to the thalamus; (2) the GABAergic neurons with and without calyx-like inputs will differ in their firing patterns and intrinsic membrane properties. Excitatory inputs to IC are studied in experiments to reveal the structure and function of the VGLUT2 calyx-like input to the large GABAergic IC neurons (circuit 1). We will show: (3) segregated auditory brainstem neurons expressing VGLUT1 or VGLUT2 that project to IC; (4) VGLUT2 axosomatic synapse originates from a single source in the auditory brainstem, and that this specialized synapse comes from a single axon; and (5) the VGLUT2 axosomatic synapses on GABAergic neurons differ from other glutamate synapses in IC. Brain circuitry in the IC is notable because the IC receives both inhibitory and excitatory inputs from the lower auditory brainstem. The excitatory inputs to the IC are segregated into functional zones, but it is not clear if inhibitory inputs also follow the same pattern. Here, in experiment 6, we will use auditory physiology with an unanesthetized rabbit preparation to relate the patterns of inhibitory input to neural responses in the IC. We will specifically test the hypothesis that the ICc domains have different patterns of inhibitory inputs. The inferior colliculus is important for normal hearing since it is a major part of the central auditory pathway and neurons from the auditory cortex to the cochlear nucleus send direct connections to the inferior colliculus. Pathology such as stroke or tumor in the inferior colliculus may contribute to deafness, hearing loss, or audiogenic seizures. The inferior colliculus is now the site of auditory midbrain implants to electrically stimulate the central auditory pathway in patients after surgical removal of the eighth nerve.