Neural representations of external stimuli in the lateral entorhinal cortex

描述（由申请人提供）：认知神经科学的一个关键问题是大脑如何构建和存储自传式事件的长期记忆。在这个过程中，关键的大脑结构是海马体和内侧颞叶的周围区域。尽管经过数十年的深入研究，海马体的精确电路机制和计算仍然不清楚。虽然我们对海马体本身编码的表征了解很多，但主要的障碍之一是缺乏对海马体的两个主要皮层输入的特性的详细了解，即内侧内嗅皮层（MEC）和外侧内嗅皮层（LEC）。几年前，当“网格细胞”在MEC中被发现时，一个重大的突破发生了，提供了第一个对海马传入信号中编码的表征的坚实处理，并为开始理解将海马传入信号表征转化为输出表征所涉及的计算奠定了基础。与此同时，我们的实验室报告LEC神经元显示出很少的空间放电。也许在我们对海马体处理的系统级理解中，目前缺失的最关键的信息是对LEC中所代表的内容的阐明。当大鼠观察环境中的单个物体时，LEC细胞是活跃的。本研究旨在更深入地研究由LEC编码的这些外部刺激表征的性质，以及这些表征如何融入海马位置细胞表征。我们将使用多个四极阵列来记录行为大鼠的LEC、MEC、CA1和CA3神经元群，以研究LEC浅层（向海马体发送投射）和深层（从海马体接收投射）的空间和非空间处理的本质。我们将测试这样一个假设，即当大鼠从事主动关注周围环境的行为时，LEC有选择性地活跃（比如在运动暂停时进行头部扫描运动），而当动物在环境中进行探索性运动时，MEC有选择性地活跃。我们将测试CA1和CA3是否在与大鼠头部扫描行为相关的位置产生新的位置细胞，这表明来自LEC的外部信息整合到大鼠对其环境的内部空间表征中。由于人类内侧颞叶可能具有类似的位置和网格状特性，这些实验将有助于为理解人类的学习和记忆奠定基础，这对于开发治疗因阿尔茨海默病、颞叶癫痫和中风等疾病而遭受毁灭性记忆丧失的失忆患者的疗法至关重要。

DESCRIPTION (provided by applicant): One of the key questions in cognitive neuroscience is how the brain constructs and stores long-term memories of autobiographical events. The critical brain structures in this process are the hippocampus and surrounding regions of the medial temporal lobe. Despite decades of intensive research, the precise circuit mechanisms and computations performed by the hippocampus remain unclear. Although much is known about the representations encoded by the hippocampus proper, one of the major impediments has been a lack of detailed knowledge of the properties of the two major cortical inputs to the hippocampus, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). A major breakthrough occurred a few years ago when the "grid cell" was discovered in the MEC, providing the first firm handle on the representations encoded in this hippocampal afferent and a basis for beginning to understand the computations involved in transforming hippocampal afferent representations into its output representations. At the same time, our laboratory reported that LEC neurons displayed little spatial firing. Perhaps the most critical piece of information presently missing in our systems-level understanding of hippocampal processing is an elucidation of what is represented in the LEC. LEC cells are active when the rat investigates individual objects in an environment. The present proposal seeks to investigate in greater depth the nature of the representations of such external stimuli encoded by the LEC and how these representations become incorporated into the hippocampal place cell representation. We will use multiple tetrode arrays to record from populations of LEC, MEC, and CA1, and CA3 neurons in behaving rats to investigate the nature of spatial and nonspatial processing in the superficial layers of the LEC (which send projections into the hippocampus) and the deep layers (which receive projections from the hippocampus). We will test the hypothesis that the LEC is selectively active when the rat is engaged in behaviors denoting active attention to its surroundings (such as head- scanning movements during pauses in locomotion) and the MEC is selectively active when the animal is engaged in exploratory movements through its environment. We will test whether CA1 and CA3 create new place cells at locations associated with the rat's head-scanning behavior, suggesting the incorporation of external information from LEC into the rat's internal spatial representation of its environment. Because the human medial temporal lobe is likely to have similar place and grid-like properties, these experiments will help lay the foundation for understanding human learning and memory, which is critical for developing therapies for amnesic individuals that suffer from the devastating memory loss associated with such disorders as Alzheimer's Disease, temporal lobe epilepsy, and stroke. PUBLIC HEALTH RELEVANCE: Profound memory loss is a hallmark of such degenerative brain disorders as Alzheimer's Disease, which originates in an area called the entorhinal cortex, progresses into the hippocampus, and eventually progresses throughout the brain's cortical regions. The experiments in this proposal will address fundamental issues regarding the nature of information processing and functions in the entorhinal cortex and hippocampus, generating insight into how these brain regions work normally and how they may go awry when the regions are damaged by Alzheimer's disease, epilepsy, stroke, or traumatic injury.