Synaptic Organization of the Auditory System

描述(申请人提供)：本项目的总体目标是了解大脑如何处理有关声音的信息。下丘是中脑的主要听觉结构。当声音从耳朵传到大脑皮层时，所有关于声音的信息都必须通过IC。这个项目继续我们的努力，以了解IC功能的细胞基础。尽管有许多研究，但人们对显微解剖、神经元特化和突触组织如何在IC中进行听觉处理知之甚少。在IC的神经元上有两种非常不同的兴奋性输入。我们发现，在IC的大型GABA能神经元上存在特化的“花帽状”轴体突触。这些突触含有VGLUT2，一种将递质谷氨酸加载到突触小泡中的分子。这些兴奋性突触在以树突兴奋性突触为主的兴奋性神经元或较小的GABA能神经元上缺失。给出了该芯片的两个基本电路。其中，大的GABA能IC神经元在细胞体和近端的树突上接受密集的兴奋性突触输入。另一个回路有较小的谷氨酸能和GABA能IC神经元，谷氨酸能输入仅在树突上。在两个实验中，我们研究了IC内的GABA能神经元。我们将显示：(1)大的GABA能神经元仅投射到丘脑；(2)有和没有帽状输入的GABA能神经元在其放电模式和固有的膜特性方面将有所不同。在实验中研究了对IC的兴奋性输入，以揭示VGLUT2花盏样输入到大型GABA能IC神经元的结构和功能(电路1)。我们将发现：(3)表达VGLUT1或VGLUT2的分离听性脑干神经元投射到IC；(4)VGLUT2轴体突触起源于听性脑干中的单一来源，并且这种专门化突触来自单一轴突；(5)GABA能神经元上的VGLUT2轴体突触不同于IC中的其他谷氨酸突触。IC中的大脑回路是值得注意的，因为IC接受来自低级听觉脑干的抑制性和兴奋性输入。IC的兴奋性输入被分成不同的功能区，但尚不清楚抑制性输入是否也遵循同样的模式。在这里，在实验6中，我们将使用听觉生理学和未麻醉的兔子的准备，将抑制输入的模式与IC中的神经反应联系起来。我们将具体测试这一假设，即ICC结构域具有不同的抑制输入模式。下丘是中枢听觉通路的主要部分，从听皮质到耳蜗核的神经元与下丘有直接联系，因此下丘对正常听力很重要。中风或下丘肿瘤等病理改变可能导致耳聋、听力损失或听源性癫痫。在手术切除第八神经后，下丘现在是听觉中脑植入物的位置，以电刺激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.