MECHANISMS OF MAMMALIAN NEURONAL INTEGRATION

长期的目标是提高对突触的理解， 哺乳动物运动控制回路的整合机制 脊髓这些机制在中央政府的所有部门发挥着至关重要的作用。 神经系统，当不受调节或受损时，可能涉及 某些病理生理状态，如痉挛，癫痫， 神经退行性疾病突触的位置是一个主要因素， 确定突触功效，因为作为无源电缆的结果， 树突的（电紧张性）特性， 远端树突位置处的突触严重衰减， 当它们向细胞体传播时会被扭曲。但也可能 存在补偿这种衰减的机制，包括 可能有更多的受体存在于远端突触 与靠近索马的突触相比。了解结构和 因此，突触整合的分子基础需要精确的知识 不同种类的突触的分布和它们的 在单个识别的神经元上对应的神经递质受体 in vivo.我们的工作假设是， 神经元和突触连接的功效与 受体表达和突触输入的神经元特异性模式。到 测试这一假设，这项建议的具体目标是回答 以下问题：l）受体的确切模式是什么？ 在不同的细胞类型中的分布以及受体是否存在差异 不同隔室中的簇大小和/或密度（例如，近端与 远端树突）？2）不同种类的突触输入 在单个神经元的表面上组织起来？这些问题将 通过两种方式回答：1）通过使用免疫细胞化学结合 细胞内染色，以确定受体表达模式， 个体，生理学上鉴定的，体内神经元和2）通过 确定化学上确定的 突触前终末与单个胞内染色的 体内神经元每项研究还将使用电子显微镜检查 已识别突触的超微结构特征。本研究将重点 对已识别的α和γ运动神经元、Renshaw细胞和Ia 抑制性中间神经元在即将被发现的递质/受体家族中， 研究的是那些涉及甘氨酸能，GABA能，谷氨酸能， 单胺能和胆碱能神经传递， 在节段性运动控制中的重要作用。这种高度融合的 方法将产生具有普遍意义的结果， 了解突触和整合机制以及新的 节段性运动系统的细节。

The long term objective is to improve understanding of the synaptic and integrative mechanisms involved in motor control circuits in the mammalian spinal cord. These mechanisms play vital roles in all parts of the central nervous system and may, when unregulated or damaged, be involved in certain pathophysiological states such as spasticity, epilepsy, and neurodegenerative disorders. Synaptic location is a major factor in determining synaptic efficacy because, as a result of the passive cable (electrotonic) properties of dendrites, synaptic potentials generated by synapses at distal dendritic locations are severely attenuated and distorted as they propagate towards the cell body. But there may also exist mechanisms to compensate for this attenuation, including the possibility that there are more receptors present at distal synapses compared to synapses close to the soma. Understanding the structural and molecular basis of synaptic integration thus requires a precise knowledge of the distribution of different classes of synapses and their corresponding neurotransmitter receptors on individual identified neurons in vivo. Our working hypothesis is that the integrative properties of neurons and the efficacy of synaptic connections are intimately linked to neuron-specific patterns of receptor expression and synaptic input. To test this hypothesis the specific aims of this proposal are to answer the following questions: l) what are the precise patterns of receptor distribution in different cell types and are there differences in receptor cluster size and/or density in different compartments (e.g. proximal vs distal dendrites)? and 2) how are different classes of synaptic inputs organized over the surface of single neurons? These questions will be answered in two ways: l) by using immunocytochemistry combined with intracellular staining to determine receptor expression patterns in individual, physiologically identified, neurons in vivo and 2) by determining the precise distribution of immunohistochemically defined presynaptic terminals in contact with single intracellularly stained neurons in vivo. Each study will also use electronmicroscopy to examine the ultrastructural features of identified synapses. This study will focus on identified alpha- and gamma-motoneurons, Renshaw cells and Ia inhibitory interneurons. Among the transmitter/receptor families to be studied are those involved in glycinergic, GABA-ergic, glutamatergic, monoaminergic and cholinergic neurotransmission, all of which play important roles in segmental motor control. This highly integrative approach will produce results of general significance for advancing understanding of synaptic and integrative mechanisms as well as novel details on the segmental motor system.