CRCNS: Input/Output Relationship in CA3 Pyramidal Cells

描述(申请人提供)：CA3锥体细胞(CA3PCs)构成了海马区突触整合的中心十字路口，并在空间映射和记忆存储中发挥关键作用。CA3pcs由内嗅皮层、齿状颗粒细胞和其他CA3pcs单频兴奋。CA3PCs的电生理谱系包括单峰和猝发，跨越广泛的频率范围。尽管对CA3PCs的解剖学和生理学有了大致的了解，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。这些信息对联系海马区的活动和功能是必不可少的，构成了这个项目的主要目标。首先，我们将研究CA3PC树突的生物物理学(被动特性、通道分布和动力学)，以及来自每条通路的单一突触输入。这将通过电压和电流钳位记录、钙成像和创建详细的、数据驱动的计算模型来实现。接下来，我们将研究CA3PCs的放电模式，以响应兴奋性输入的系统组合。手术和药物隔离的通路将以不同的强度和频率被细胞外刺激，同时从单个CA3PC记录。相应的隔室模拟，根据实验实施和验证，将广泛表征CA3PCs在非线性求和、路径特异性和突触输入的符合检测方面的计算特性。该项目的公共卫生相关性直接关系到国家臭氧机构的任务。海马体功能障碍与阿尔茨海默病等与年龄相关的破坏性疾病有关。将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，将加快研究进程，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议的出版物中传播成果外，所有模式都将通过互联网档案公开传播。

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.