The Role of Dendrites in Thalamocortical Circuitry

描述（由申请人提供）：现在认为许多神经系统疾病涉及脑区域内和脑区域之间的神经元之间的通信中断。神经网络中活动流的传统模型是，在处理的一个阶段来自神经元的突触输入被下一阶段中的任何给定神经元求和。但实际上，突触是长在树枝状的树枝上，对突触输入的正常整合有复杂的影响。首先，树突状细胞膜本身会减弱任何由突触诱发的电信号，这些电信号会沿着树传导到细胞体。减弱的信号可能不太可能有助于神经元放电并激活下游突触到其他神经元上。其次，几个相邻突触的同时激活可以打开细胞膜中的专门的电压门控通道，在膜电位中产生大于单个突触信号之和的树突“尖峰”。该项目的目的是了解这两种树突特性如何影响皮层活动和感觉刺激的处理，重点是新皮层处理的初始阶段。加工被认为是开始于来自外部世界的感觉信息通过从丘脑到皮层4层的丘脑皮层突触进入感觉皮层。丘脑皮质突触被认为是单独强于皮质皮质突触。第一个目的是测试是否丘脑皮层突触到皮层树突树更接近细胞体，一个潜在的机制，更大的相对功效的丘脑皮层连接。相关的共聚焦和电子显微镜将被用来映射的位置突触在树突状树的皮层神经元。将测量标记的单个丘脑和皮质神经元对的感受野，以询问树突衰减是否有助于皮质神经元如何调谐到特定的感觉刺激。第二个目的是询问树突棘波是否增强了丘脑皮层突触直接激活皮层神经元的能力。这将通过将体内细胞内记录与电压门控通道或单个皮质层的药理学阻断相结合来进行测试。此外，共聚焦显微镜还将用于测试丘脑皮质突触是否沿沿着皮质树突充分聚集以接合树突棘。如果这些目标表明突触位置很重要，那么由功能失调的遗传或活动依赖性机制引起的突触的细微错误定位将导致大脑区域之间的兴奋异常流动，可能引发或促成神经系统疾病中的癫痫或震颤样活动。 公共卫生相关性：这项研究将解决神经元的树突机制如何影响兴奋从一个大脑区域到下一个区域的传播。这些结果将有助于我们理解细胞机制，当被破坏时，可能会产生癫痫发作，震颤和其他神经病理学。这些目标与NINDS的蓝天战略规划工作相一致，通过绘制健康神经系统的解剖学和功能连接，并确定可能用于治疗神经退行性疾病的细胞机制。

DESCRIPTION (provided by applicant): Many diseases of the nervous system are now thought to involve breakdowns in communication among neurons within and between brain regions. The conventional model for the flow of activity in neural networks is that synaptic inputs from neurons at one stage of processing are summed by any given neuron in the next stage. In reality though, synapses are made onto long, branching dendritic trees that can have complicated effects on normal integration of synaptic inputs. First, the dendritic membrane itself attenuates any synaptically-evoked electrical signal being conducted along the tree to the cell body. Diminished signals may be less likely to contribute to a neuronal discharge and to activate downstream synapses onto other neurons. Second, the coincident activation of several neighboring synapses can open specialized voltage-gated channels in the cell membrane, generating a dendritic "spike" in membrane potential larger than the sum of the individual synaptic signals. The aims of this project are to understand how each of these two dendritic properties affect cortical activity and processing of sensory stimuli, with a focus on the initial stages of processing in neocortex. Processing is thought to begin with sensory information from the outside world entering sensory cortex via thalamocortical synapses from thalamus to cortical layer 4. Thalamocortical synapses are thought to be individually stronger than corticocortical synapses. The first aim is to test whether thalamocortical synapses onto a cortical dendritic tree are closer to the cell body, a potential mechanism for the greater relative efficacy of thalamocortical connections. Correlative confocal and electron microscopy will be used to map the locations of synapses across the dendritic trees of cortical neurons. Receptive fields of labeled pairs of individual thalamic and cortical neurons will be measured to ask if dendritic attenuation contributes to how cortical neurons are tuned to particular sensory stimuli. The second aim is to ask if dendritic spikes boost the ability of thalamocortical synapses to directly activate cortical neurons. This will be tested by combining intracellular recording in vivo with pharmacological blockade of voltage-gated channels or individual cortical layers. Confocal microscopy will additionally be used to test whether thalamocortical synapses are sufficiently clustered along cortical dendrites to engage dendritic spikes. If these aims show that synaptic location is important, subtle mistargeting of synapses by dysfunctional genetic or activity-dependent mechanisms would lead to abnormal flow of excitation between brain regions, potentially initiating or contributing to seizure- or tremor-like activity in neurological diseases. PUBLIC HEALTH RELEVANCE: This study will address how dendritic mechanisms of neurons influence the propagation of excitation from one brain region to the next. The results will contribute to our understanding of cellular mechanisms that, when disrupted, may produce seizures, tremors, and other neurological pathology. These goals are compatible with NINDS' Blue Sky strategic planning efforts by mapping out the connectivity of the healthy nervous system, both anatomically and functionally, and identifying cellular mechanisms that may be targeted in the treatment of neurodegenerative disorders.