CRCNS: Input/Output Relationship in CA3 Pyramidal Cells

描述（由申请人提供）：CA3锥体细胞（CA3pcs）构成海马中突触整合的中心十字路口，并且在空间映射和记忆存储中起关键作用。CA3pcs由内嗅皮层、齿状颗粒细胞和其他CA3pcs单突触兴奋。CA3pcs的电生理学功能包括单个尖峰和爆发，跨越广泛的频率范围。尽管对CA3pcs的解剖学和生理学有一般性的了解，但对给定的突触输入模式和由此产生的放电输出之间的对应关系知之甚少。这些信息，这是必不可少的海马活动和功能，构成了这个项目的主要目标。首先，我们将研究CA3pc树突生物物理学（被动特性，通道分布和动力学），以及来自每个通路的单一突触输入。这将通过电压和电流钳记录、钙成像以及创建详细的数据驱动计算模型来实现。接下来，将检查CA3pcs的放电模式，以响应兴奋性输入的系统组合。将以各种强度和频率在细胞外刺激手术和电生理分离的通路，同时从单个CA 3pcs记录。相应的房室模拟，实施和验证的实验，将广泛的计算特性的CA3pcs的非线性求和，通路特异性，突触输入的重合检测。该项目的公共卫生相关性直接关系到NIA的使命。海马体的功能障碍与老年痴呆症等与年龄有关的疾病有关。最先进的实验技术与不断增长的生物物理建模计算能力相结合，将加速研究进展，并有助于培养训练有素的神经科学家。除了在会议和同行评审的出版物中传播成果外，所有模型都将通过互联网档案公开分发。

DESCRIPTION (provided by applicant): CA3 pyramidal cells (CA3pcs) constitute a central crossroad of synaptic integration in the hippocampus, and play a key role in spatial mapping and memory storage. CA3pcs are monosynaptically excited by the entorhinal cortex, dentate granule cells, and other CA3pcs. The electrophysiological repertoire of CA3pcs includes single spiking and bursting, spanning a broad range of frequencies. Despite a general understanding of the anatomy and physiology of CA3pcs, little is known about the correspondence between a given pattern of synaptic inputs and the resulting firing output. This information, which is essential to relate hippocampal activity and function, constitutes the main goal of this project. First, we will investigate CA3pc dendrite biophysics (passive properties, channel distributions and kinetics), and the unitary synaptic inputs from each pathway. This will be achieved with voltage- and current-clamp recordings, calcium imaging, and the creation of a detailed, data-driven computational model. Next, the firing patterns of CA3pcs will be examined in response to systematic combinations of excitatory inputs. Surgically and pharmacologically isolated pathways will be stimulated extracellularly at various intensities and frequencies, while recording from individual CA3pcs. Corresponding compartmental simulations, implemented and validated against the experiments, will extensively characterize the computational properties of CA3pcs with respect to non-linear summation, pathway specificity, and coincidence detection of synaptic input. The public health relevance of this project directly relates to the mission of the NIA. Malfunction of the hippocampus is linked to devastating age-related conditions such as Alzheimer's disease. The combination of state-of-the-art experimental techniques with the ever-increasing computational power of biophysical modeling will accelerate research progress and help develop highly trained neuroscientists. In addition to the dissemination of results in conferences and peer-reviewed publications, all models will be publicly distributed through internet archives.