Study of the entorhinal-hippocampal circuitry supporting spatial pattern separation in behaving animals

尽管几十年的研究已经明确了海马齿状回(DG)在支持记忆方面的功能，但模式分离等特定认知功能背后的神经生物学机制仍然难以捉摸。模式分离指的是分离非常相似的记忆的能力(即“我昨天把车停在哪里了”和“我今天把车停在哪里了”)？虽然这两个事件有许多相似之处(相同的汽车，相同的停车场)，但它们不重叠的编码和存储对于准确提取相关记忆是必要的。在神经网络层面，模式分离包括在整合相似输入后产生不同输出的能力。在这里，我提出了一系列实验，以加深对模式分离所涉及的神经生物学过程的理解。这一点尤其重要，因为这种认知功能已经被证明在包括阿尔茨海默病和精神分裂症在内的几种病理生理条件下会发生变化。具体地说，DG支持空间模式分离(即区分相似空间信息的能力)，其中到达DG颗粒细胞(GC)的空间信息由内侧内嗅皮层(MEC)携带，内侧内嗅皮层是已知的感知探索环境的空间线索的皮质区域。然而，DG的网络活动支持空间模式分离的潜在机制仍然难以捉摸。事实上，虽然DG的神经元活动已经被证明在接触到具有一定程度相似性的不同环境时会发生变化，但GC如何调整其网络放电来解决依赖于空间模式分离的学习任务尚不清楚。利用体内电生理学和体内钙成像等尖端工具与自由行为动物的光遗传学相结合，该项目旨在解开MEC-DG网络执行的空间模式分离所执行的电路操作。为了解决这个问题，我将首先考察在空间模式分离需求的渐变条件下，DG在空间辨别任务中的活动变化。这项初步实验将允许确定DG中哪种类型的网络活动变化与空间模式分离相关。第二组实验将利用转基因小鼠，在转基因小鼠中，投射DG的MEC星状细胞的活动将受到光遗传控制，以确定这一神经元通路在空间模式分离中的功能。因此，该项目旨在为从根本上理解MEC-DG电路在支持空间模式分离方面的功能做出重要贡献。

Although decades of investigations have pinpointed the function of the dentate gyrus (DG) of the hippocampus in supporting memory, the neurobiological mechanisms underlying specific cognitive functions, such as pattern separation, remain elusive. Pattern separation refers to the ability to dissociate very similar memories (i.e. “where did I park my car yesterday” versus “where did I park my car today”)? Although these two events share many similarities (same car, same parking lot), their non-overlapping encoding and storage is necessary for accurate retrieval of the associated memories. At the neuronal network level, pattern separation consists of the ability to generate dissimilar outputs after integration of similar inputs. Here, I propose a set of experiments to develop a deeper understanding of the neurobiological processes involved in pattern separation. This is especially important as this cognitive function has been shown to be altered in several pathophysiological conditions including Alzheimer’s disease and schizophrenia. Specifically, the DG is known to support spatial pattern separation (i.e. the ability to discriminate similar spatial information), where spatial information reaching the granule cells (GCs) of the DG are carried by the medial entorhinal cortex (MEC), a cortical area known to sense spatial cues of the explored environment. However, the underlying mechanisms by which DG’s network activity supports spatial pattern separation remain elusive. Indeed, while DG’s neuronal activity has been shown to change across exposure to different environments sharing a certain degree a similarity, how the GCs adapt their network firing to solve learning tasks relying on spatial pattern separation is unknown. Using a combination of cutting-edge tools such as in vivo electrophysiology and in vivo calcium imaging coupled with optogenetics in freely behaving animals, this project aims to unravel the circuit operations performed by the MEC-DG network that underlie spatial pattern separation. To address this question, I will first investigate the changes in DG’s activity during a spatial discrimination task in gradual conditions of spatial pattern separation demand. This initial experiment will allow to determine which type of network activity changes in DG is associated with spatial pattern separation. A second set of experiments will take advantage of transgenic mice in which the activity of DG-projecting MEC stellate cells, known to convey spatial information to the DG, will be optogenetically controlled to determine the function of this neuronal pathway in spatial pattern separation. Thus, this project is designed to bring an important contribution to the fundamental understanding of the function of the MEC-DG circuitry in supporting spatial pattern separation.