Examining the integration of inputs by the subiculum during virtual navigation

描述(申请人提供)：啮齿类动物的空间导航是研究哺乳动物大脑中认知、学习和记忆的一个广泛使用的范例。下丘是构成导航基础的回路的重要输出结构，但很少有研究通过动物的行为来检验它的生理学。这项建议旨在确定单个下丘脑神经元如何在导航过程中整合其在海马区CA1区的突触前输入的信息。CA1神经元形成了对微小变化敏感的环境空间地图；例如，从圆形房间移动到方形房间可以极大地改变CA1的表示。另一方面，尽管接受了CA1的主要输入，但下丘似乎形成了稳定的图谱，在不同的环境中不会发生实质性的变化。下丘如何保持稳定的代表仍然是一个悬而未决的问题。为了在导航环境中研究这些机制，坦克实验室最近开发了一项新技术，用于在虚拟环境中导航时在清醒小鼠的大脑中进行钙成像和电生理记录。这项技术包括一台允许二维运动的球形跑步机，一个由动物在球形跑步机上的运动控制的虚拟现实环境，以及允许电生理记录或光学成像的可互换设备。与研究导航的传统方法相比，这种实验装置的主要优势是动物头部固定，但允许在虚拟环境中导航，为钙成像或全细胞记录提供了稳定性。这也是有利的，因为虚拟环境可以在导航任务期间动态改变，提供对动物体验的完全控制。这项提案利用了这些新技术，以了解下丘如何形成环境地图。在目标1中，钙活性的光学成像将被用来表征什么样的环境变化改变了CA1的表示，但保留了下丘脑中的MAP。目标2将通过追踪单个下丘脑神经元的单突触输入来解决下丘脑回路的解剖学组织。这些神经元包括来自CA1的输入和下丘体内的经常性联系。在目标3中，这些技术将被结合在一只动物身上。将单个下丘脑神经元的空间表征与CA1和下丘脑单突触输入的表征进行比较。这一比较将揭示下丘脑神经元如何整合传入信号以形成稳定的表征。解开这一计算将有助于更全面地理解海马体结构的作用。 公共卫生相关性： 下丘脑在哺乳动物大脑的认知、学习和记忆中起着重要的作用。许多健康问题都与下丘脑的破坏有关，如阿尔茨海默病、精神分裂症、癫痫和药物成瘾。了解下丘脑微电路是如何运作的，将为分析它何时被疾病状态改变提供一个模板。

DESCRIPTION (provided by applicant): Spatial navigation in rodents is a widely used paradigm for studies of cognition, learning, and memory in the mammalian brain. The subiculum is an important output structure for circuits that underlie navigation, yet few studies have examined its physiology in behaving animals. This proposal aims to identify how an individual subiculum neuron integrates information during navigation from its pre-synaptic inputs in the CA1 region of the hippocampus. CA1 neurons form a spatial map of the environment that is sensitive to small changes; for example, moving from a circular chamber to a square chamber can drastically alter the representation in CA1. The subiculum, on the other hand, seems to form stable maps that do not undergo substantial changes in different environments, despite receiving a major input from CA1. How the subiculum maintains a stable representation remains an open question. To investigate these mechanisms in the context of navigation, the Tank lab has recently developed new technology for calcium imaging and electrophysiological recordings to be performed in the brain of awake mice during navigation in a virtual environment. This technology consists of a spherical treadmill that allows for motion in two dimensions, a virtual reality environment controlled by the motion of the animal on the spherical treadmill, and interchangeable equipment allowing for either electrophysiological recordings or optical imaging. A major advantage of this experimental setup over conventional methods for studying navigation is that the animal is head-fixed, yet allowed to navigate within a virtual environment, providing stability for calcium imaging or whole cell recordings. It is also advantageous because the virtual environment can be dynamically altered during navigation tasks, providing complete control over the animal's experience. This proposal takes advantage of these new technologies in order to understand how the subiculum forms a map of the environment. In aim 1, optical imaging of calcium activity will be used to characterize what kinds of environmental alterations change the CA1 representation but preserve the map in the subiculum. Aim 2 will address the anatomical organization of subiculum circuitry by tracing mono-synaptic inputs to a single subiculum neuron. These neurons include inputs from CA1 and recurrent connections within the subiculum. In aim 3, these techniques will be combined in a single animal. The spatial representation in individual subiculum neurons will be compared to the representation of mono-synaptic inputs in CA1 and subiculum. This comparison will shed light on how subiculum neurons integrate incoming signals to form a stable representation. Unraveling this computation will help to understand the role of the hippocampal formation more generally. PUBLIC HEALTH RELEVANCE: The subiculum plays an important role in cognition, learning, and memory in the mammalian brain. Many health problems are associated with disruption of the subiculum, such as Alzheimer's disease, schizophrenia, epilepsy, and drug addiction. Understanding how microcircuits in the subiculum operate will provide a template for assaying when it is altered by disease states.