Multisite analysis of hippocampal neuronal ensembles

描述(申请人提供)：海马体是一种大脑结构，对正常的学习和记忆功能至关重要。例如，阿尔茨海默病最先开始恶化的大脑区域之一是内嗅皮层，这是新皮质和海马体之间的关键处理阶段。这种退化与记忆缺陷有关，记忆缺陷是这种疾病的第一个认知症状。为了了解为什么海马区的损伤会导致如此严重的记忆缺陷，有必要了解这个脑区的基本计算功能。海马加工的第一阶段是齿状回(DG)，它接受内嗅皮层的主要输入，并投射到CA3区，那里被认为存储着依赖于海马的联想记忆。长期以来，人们一直假设，DG通过执行模式分离功能来对来自内嗅觉皮质的数据进行“预处理”--创建彼此不像内嗅觉输入模式那样相似的神经活动的输出模式。当这些图案作为存储器存储在CA3中时，该操作减少了干扰。然而，对这一理论的测试一直是模棱两可的，部分原因是DG包含许多兴奋细胞类型，这使得很难确定电路的哪一部分涉及模式分离功能。这些细胞类型在解剖学和细胞生理学方面都有很好的特征，但它们在行为自由的动物身上的激发相关性尚不清楚。该项目的具体目的是鉴定自由活动动物DG中的不同细胞类型(成熟颗粒细胞、新生的成体颗粒细胞和苔藓细胞)，并利用经典的位置细胞重新映射现象测试每种类型在模式分离中的作用。高密度神经记录探针、光遗传学和细胞旁标记的新组合将被用来(A)记录大鼠探索不同环境时DG神经元的空间放电特性，并(B)将这些特性分配给特定的细胞类型。成熟的颗粒细胞被假设为执行经典计算理论赋予它们的模式分离功能，反映在它们的超稀疏放电和它们基于极端活动的识别 不同的环境。相比之下，新生的颗粒细胞和苔藓细胞也被假设参与模式分离计算，但使用了与成熟颗粒细胞不同的编码策略，在不同的环境中混杂地放电，但在每个环境中具有不同的空间活动速率和模式。这些实验的结果将为这些细胞类型中每一种的生理作用提供关键的知识，并将极大地提高未来工作的能力，以测试关于DG和成人神经发生在学习和记忆功能中的作用的许多问题。

DESCRIPTION (provided by applicant): The hippocampus is a brain structure that is critical for normal learning and memory functions. For example, one of the first brain regions to begin deterioration in Alzheimer's Disease is the entorhinal cortex, the key processing stage between the neocortex and the hippocampus proper. This degeneration correlates with the memory deficits that are the first cognitive symptoms of the disease. To understand why hippocampal damage causes such severe memory deficits, it is necessary to understand the basic computational functions of this brain region. The first stage of hippocampal processing is the dentate gyrus (DG), which receives major inputs from the entorhinal cortex and projects to the CA3 region, where hippocampus-dependent associative memories are thought to be stored. It has long been hypothesized that the DG "preprocesses" the data from the entorhinal cortex by performing a pattern separation function-creating output patterns of neural activity that are less similar to each other than the entorhinal input patterns. This operation reduces interference when these patterns are stored as memories in CA3. Tests of this theory have been equivocal, however, in part because the DG contains a number of excitatory cell types that makes it difficult to determine what part of the circuitry is involved in the pattern separation function. These cell types are well-characterized in terms of anatomy and cellular physiology, but their firing correlates in freely behaving animals are not understood. The specific aims of this project are to identify the different cell types in the DG (mature granule cells, new adult-born granule cells, and mossy cells) in freely moving animals and to test the role of each type in pattern separation using classic tests of the place-cell "remapping" phenomenon. A novel combination of high-density neural recording probes, optogenetics, and juxtacellular labeling will be used to (a) record the spatial firing properties of DG neurons as rats explore different environments and (b) assign these properties to the specific cell types. The mature granule cells are hypothesized to perform the pattern separation function ascribed to them by the classic computational theories, reflected in their ultra-sparse firing and their extreme activity-based discrimination of different environments. In contrast, the newborn granule cells and mossy cells are hypothesized also to take part in the pattern separation computation, but with the use of a different coding strategy than the mature granule cells, firing promiscuously in different environments but with different rates and patterns of spatial activity in each environment. The results of these experiments will provide crucial knowledge of the physiological roles of each of these cell types, and will greatly enhance the ability of future work to test the many questions about the roles of the DG and adult neurogenesis on learning and memory function.