The Role of Dendrites in Thalamocortical Circuitry

描述（由申请人提供）：许多神经系统疾病现在被认为与大脑区域内和区域间神经元之间的交流中断有关。传统的神经网络活动流模型是神经元在一个处理阶段的突触输入由下一阶段的任何给定神经元求和。但在现实中，突触是在长而分支的树突树上形成的，这对突触输入的正常整合有复杂的影响。首先，树突膜本身会减弱沿树突传导到细胞体的突触诱发的电信号。减弱的信号可能不太可能导致神经元放电，也不太可能激活下游连接其他神经元的突触。其次，几个相邻突触的同时激活可以打开细胞膜上专门的电压门控通道，在膜电位中产生树突“尖峰”，比单个突触信号的总和还要大。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，重点关注新皮层处理的初始阶段。加工被认为是从外部世界的感觉信息通过丘脑皮层突触进入感觉皮层开始的，从丘脑到皮层第4层。丘脑皮质突触被认为单独强于皮质皮质突触。第一个目的是测试皮质树突树上的丘脑皮质突触是否更靠近细胞体，这是丘脑皮质连接相对更有效的潜在机制。相关共聚焦显微镜和电子显微镜将用于绘制皮层神经元树突树上突触的位置。将测量标记成对的单个丘脑和皮层神经元的接受野，以询问树突衰减是否有助于皮层神经元如何调谐到特定的感觉刺激。第二个目标是探究树突突是否能增强丘脑皮质突触直接激活皮质神经元的能力。这将通过结合体内细胞内记录和药物阻断电压门控通道或单个皮质层来进行测试。共聚焦显微镜还将用于测试丘脑皮质突触是否充分聚集在皮层树突上以参与树突刺。如果这些目标表明突触位置是重要的，那么通过功能失调的遗传或活动依赖机制对突触的微妙错误定位将导致大脑区域之间的异常兴奋流动，可能引发或促成神经系统疾病中的癫痫或震颤样活动。

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.