The Role of Dendrites in Thalamocortical Circuitry

描述(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大脑区域之间的神经元之间的通讯中断有关。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的任何给定神经元相加。但在现实中，突触形成在长而分叉的树状树上，这可能对突触输入的正常整合产生复杂的影响。首先，树突膜本身减弱了任何突触诱发的电信号，这些电信号沿着树枝传导到细胞体。信号减弱可能不太可能导致神经元放电，并激活下游与其他神经元的突触。其次，几个相邻突触的同时激活可以在细胞膜上打开专门的电压门控通道，产生比单个突触信号总和更大的树枝状膜电位“尖峰”。这个项目的目的是了解这两种树突特性如何影响皮质活动和感觉刺激的处理，重点放在新皮质处理的初始阶段。加工被认为是从外部世界的感觉信息通过从丘脑到皮质第四层的丘脑皮质突触进入感觉皮质开始的。丘脑皮质突触被认为单独比皮质突触更强。第一个目标是测试丘脑皮质突触到皮质树突触是否更靠近细胞体，这是丘脑皮质连接更有效的潜在机制。相关的共聚焦显微镜和电子显微镜将被用来绘制跨越皮质神经元树突的突触的位置。将测量单个丘脑和皮质神经元标记对的感受野，以询问树突衰减是否有助于皮质神经元对特定感觉刺激的调谐。第二个目的是询问树突是否提高了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对电压门控通道或个别皮质层的药物阻断来测试。此外，还将使用共聚焦显微镜来测试丘脑皮质突触是否沿着皮质树突充分聚集，以与树突接合。如果这些目标表明突触的位置是重要的，那么通过功能失调的遗传或活动依赖机制对突触进行细微的错误定位将导致大脑区域之间异常的兴奋流动，可能启动或促成神经系统疾病中的癫痫或震颤样活动。 与公共健康相关：这项研究将阐述神经元的树突机制如何影响兴奋从一个大脑区域传播到下一个大脑区域。这一结果将有助于我们理解细胞机制，当细胞机制被破坏时，可能会产生癫痫、震颤和其他神经病理。这些目标与NINDS的蓝天战略规划努力相一致，通过绘制健康神经系统的解剖学和功能连接性图，并确定可能成为神经退行性疾病治疗目标的细胞机制。

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.