Connecting objects to places: functional investigation of projections from lateral to medial entorhinal cortex

我们的记忆能力对日常生活至关重要，对我们是谁的感觉也至关重要。大脑的有意识记忆系统被认为在早期阶段使用平行的信息流，大脑中一个名为内侧内嗅皮层(MEC)的区域处理有关我们所在位置的信息，而邻近的一个区域称为后期内嗅皮层(LEC)，处理有关我们环境中的特征的信息，如物体的位置和身份。根据这一观点，这些不同的信号然后被称为海马体的下游大脑区域整合起来，以产生完整的记忆。然而，最近的实验表明，在MEC和LEC中表示我们所在的位置和我们周围有什么物体之间的区别并不像通常假设的那样明显。与此一致，我们的初步数据显示，LEC直接连接到MEC。这种未知的神经通路可以使特征信息和空间信息在到达海马体之前被整合。我们的初步数据还表明，从LEC到MEC的这条通路来自LEC中的“扇形细胞”，LEC是一种脑细胞或神经元，对记忆形成很重要，在阿尔茨海默病中受到损害。我们在这里的目标是确定这条途径何时以及如何影响MEC的信息处理。我们的第一个目标将是描绘来自风扇单元的信号到达MEC时所遵循的路线。我们的初步数据显示，MEC中的主要神经元以复杂的方式对扇形细胞的激活做出反应。MEC是一种将信号传递到其他大脑区域的神经元类型。我们将使用分子遗传学工具来描述中间神经元在这些复杂反应中的作用，中间神经元是一种数量较少的神经元，具有广泛的局部连接，我们的初步数据表明，这是复杂反应的基础。我们的第二个目标将是确定扇形细胞投射何时活跃，以及它们对MEC中的神经元有什么影响。我们将使用成像技术来监测小鼠探索竞技场和遇到物体时粉丝细胞的活动。这些实验将告诉我们，在探索过程中，扇形细胞投射是否总体上是活跃的，或者它们的活动是否特定于物体或了解某个环境。然后，我们将记录MEC中单个神经元在类似行为和扇形细胞投射直接激活期间的电活动。通过这种方式，我们将能够将MEC中每个神经元在行为过程中代表的信息与其对扇形细胞通路激活的反应联系起来。我们的第三个目标将是评估当Fan细胞失活时，MEC中单个神经元对空间和物体相关信息的表示发生了什么变化，以及局部中间神经元在这些表示中扮演什么角色。为了做到这一点，我们将再次记录MEC中神经元在行为过程中的电活动。然后，我们将失活向MEC的扇形细胞投射，并测量这种失活如何改变MEC中神经元的表示。我们还将通过应用我们在第一个目标中验证的分子遗传学工具来描述局部中间神经元的角色。这些实验将告诉我们MEC中的空间和对象相关信息是否得到扇形细胞的支持，以及局部中间神经元在处理扇形细胞信号中的潜在作用。我们的结果将影响我们对大脑如何将告诉我们所在位置的信号与告诉我们环境特定特征的信号相结合的理解。这将促进我们对记忆是如何形成的以及我们如何使用空间信号导航的基本理解。此外，由于LEC中的Fan细胞在阿尔茨海默病中受损，我们的数据将有助于确定阿尔茨海默病的症状，如漫步行为和记忆障碍，是否可能是LEC和MEC之间直接连接受损的结果。

Our capacity for memory is critical for everyday life and is central to our sense of who we are. The brain's system for conscious memories is thought to use parallel streams of information in its early stages, with a brain region called the medial entorhinal cortex (MEC) processing information about where we are and an adjacent region called the later entorhinal cortex (LEC) processing information about features in our environment such as the location and identity of objects. According to this view, these distinct signals are then integrated by a downstream brain area called the hippocampus to generate complete memories. However, recent experiments suggest that the distinction between representations in the MEC and LEC of where we are and what objects are around us is not as clear cut as is often assumed. Consistent with this, our preliminary data show that the LEC directly connects to the MEC. This uncharted neural pathway could enable feature information and spatial information to be integrated prior to reaching the hippocampus. Our preliminary data also show that this pathway from the LEC to the MEC arises from 'fan cells' in LEC, a type of brain cell, or neuron, that is important for memory formation and is damaged in Alzheimer's disease. Our goal here is to establish when and how this pathway influences information processing in the MEC. Our first aim will be to delineate the routes that signals from fan cells follow when they arrive in the MEC. Our preliminary data show that principal neurons in the MEC, a numerous type of neuron that relays signals to other brain areas, respond in complex ways to the activation of fan cells. We will use molecular-genetic tools to delineate roles in these complex responses of interneurons, a less numerous type of neuron that has extensive local connections, which our preliminary data suggest underlie the complex responses. Our second aim will be to determine when fan cell projections are active and what effect they have on neurons in the MEC. We will use imaging technology to monitor the activity of fan cells as mice explore arenas and encounter objects. These experiments will tell us if fan cell projections are active during exploration in general or if their activity is specific to objects or to learning about an environment. We will then record the electrical activity of individual neurons in the MEC during similar behaviours and during direct activation of fan cell projections. In this way we will be able to associate the information that each neuron in the MEC represents during behaviour with its response to activation of the fan cell pathway.Our third aim will be to evaluate what happens to representations of spatial and object-related information by individual neurons in the MEC when fan cells are inactivated, and what role local interneurons play in these representations. To do this, we will again record the electrical activity of neurons in the MEC during behaviour. We will then inactivate fan cell projections to the MEC and measure how this inactivation changes the representations of neurons in MEC. We will also delineate roles for local interneurons by applying the molecular-genetic tools that we validated in our first aim. These experiments will tell us whether spatial and object-related information in the MEC is supported by fan cells, and the underlying roles of local interneurons in processing fan cell signals.Our results will impact our understanding of how the brain integrates signals that tell us where we are with signals that tell us about specific features of our environment. This will advance our fundamental understanding of how memories are formed and how we use spatial signals to navigate. Further, because fan cells in LEC are damaged in Alzheimer's disease, our data will help determine if symptoms of Alzheimer's disease, such as wandering behaviour and memory impairment, could be the result of damage to direct connections between LEC and MEC.