Circuits driving spatial coding deficits in epilepsy

项目总结/摘要 颞叶癫痫（TLE）是一种使人衰弱的疾病，包括广泛的记忆障碍， 严重影响生活质量。在TLE的啮齿类动物模型中，我的实验室和其他人发现， 学习和记忆以及CA 1位置细胞的精确性和稳定性。但尚不清楚 CA 1的空间编码受损是否主要是由于海马的局部加工缺陷， 受到来自上游输入的受损空间编码和同步的影响。事实上， 有证据表明，从内侧内嗅皮层（MEC）进入海马的上游输入可能会改变， 癫痫这个提议将检验一个假设，即从MECII到海马的间接输入是 特别是在癫痫小鼠中改变。为了验证这一假设，我们将首先使用钙成像与微型 显微镜来表征慢性癫痫如何改变MECII星状细胞和MECIII的空间编码 神经元，直接输入海马。接下来，我们将使用硅探针记录中间神经元的放电， LFP同时在MECII、MECIII、DG和CA 1中，并确定如何在整个 癫痫小鼠的内鼻-海马回路改变。最后，我们将使用兴奋和抑制 DREADDs调节MECII星状细胞并确定这种输入如何改变海马 海马电路和空间记忆的同步。总之，这些目标将使用最先进的 记录和操纵技术，以精确地确定空间编码和 同步在癫痫小鼠中被打破，并对认知缺陷的原因有了新的认识。

Project Summary/Abstract Temporal lobe epilepsy (TLE) is a debilitating disorder that includes pervasive memory impairments that significantly impact quality of life. In rodent models of TLE, my lab and others have found major deficits in learning and memory as well as in the precision and stability of CA1 place cells. However, it remains unclear whether impaired spatial coding in CA1 is primarily due to local processing deficits in hippocampus or rather is influenced by impaired spatial coding and synchronization from upstream inputs. In fact, there is significant evidence that upstream inputs into the hippocampus from the medial entorhinal cortex (MEC) may be altered in epilepsy. This proposal will test the hypothesis that the indirect inputs into hippocampus from MECII are specifically altered in epileptic mice. To test this hypothesis, we will first use calcium imaging with miniature microscopes to characterize how chronic epilepsy alters spatial coding in MECII stellate cells and MECIII neurons, which directly input into hippocampus. Next, we will use silicon probes to record interneuron firing and LFPs simultaneously in MECII, MECIII, DG, and CA1 and determine how synchronization throughout the entorhinal-hippocampal circuit is altered in epileptic mice. Finally, we will use excitatory and inhibitory DREADDs to modulate MECII stellate cells and determine how this input into hippocampus alters synchronization of hippocampal circuits and spatial memory. Together, these aims will use state-of-the-art recording and manipulation techniques to determine precisely where and how spatial coding and synchronization breaks down in epileptic mice and gain new insights into the cause of cognitive deficits.