Understanding neural circuits for associative memory in the lateral entorhinal cortex

摘要 内嗅皮层（EC）和海马是关键参与形成的脑区 以及陈述性记忆的提取，而对这一回路的损伤会导致记忆障碍。为了治好 痴呆症，包括阿尔茨海默病，目前影响着美国500万人，这是至关重要的 促进对参与编码和检索的细胞和电路机制的理解， 记忆在这个内鼻-海马回路中。EC在解剖学上被分成两半， 内嗅皮层（LEC）和内侧内嗅皮层（MEC）。虽然以前的研究有很大的 推进了我们对MEC在空间记忆和导航中的功能作用的理解， 对LEC的功能的理解在很大程度上仍然不清楚。在这里，我们建议研究调查 LEC在联想记忆中的功能，以解决知识的这一关键差距。我们的方法包括 多方面的分析方法，包括体内电生理学，联想学习任务，光遗传学 电路分析方法、光学成像和在启动子下表达Cre小鼠的转基因小鼠品系 细胞类型特异性标记。研究有三个具体目标：（目标1）确定 LEC层II细胞类型在联想学习中的作用;（目的2）确定LEC多巴胺输入在联想学习中的作用 （3）确定LEC 20- 40 Hz振荡在联想学习中的因果作用。如果成功， 我们的研究将确定LEC中联想记忆形成的电路机制， 建立新的框架来理解内鼻-海马回路如何形成 陈述性记忆通过整合多个维度的感觉信息。

Abstract The entorhinal cortex (EC) and the hippocampus are the brain areas which are critically involved in the formation and retrieval of declarative memory, and damage to this circuit results in memory impairment. In order to cure dementias, including Alzheimer’s disease, which currently affects 5 million people in the United States, it is critical to forward an understanding of the cellular and circuit mechanisms involved in the encoding and retrieval of memory in this entorhinal-hippocampal circuit. The EC is anatomically segregated into two halves, the lateral entorhinal cortex (LEC), and the medial entorhinal cortex (MEC). Although previous studies have significantly advanced our understanding of the functional role of the MEC in spatial memory and navigation, our understanding of the functions of the LEC remain largely unclear. Here we propose studies to investigate the function of the LEC in the associative memory to address this critical gap in knowledge. Our approach involves multi-faceted analytical methods including in vivo electrophysiology, associative learning tasks, optogenetic circuit analysis methods, optical imaging and transgenic mouse lines that express Cre mice under the promoter of cell-type-specific markers. There are three Specific Aims to the studies: (Aim 1) identify functional roles of LEC layer II cell types in associative learning; (Aim 2) identify the role of LEC dopamine input in associative learning; and (Aim 3) determine the causal role of LEC 20-40Hz oscillations in associative learning. If successful, our studies will identify the circuit mechanisms for associative memory formation in the LEC and will help establish new frameworks for understanding how the entorhinal-hippocampal circuit enables the formation of declarative memory via the integration of multiple dimensions of sensory information.