Contributions of the retrosplenial cortex to spatial processing in the rodent brain

 描述（由申请人提供）：动物必须保持方向感和位置感，以有效导航。人类几乎毫不费力地做到了这一点，没有意识到产生我们空间知识的复杂神经机制。然而，当大脑损伤破坏了这些过程，使一个人处于慢性定向障碍的毁灭性状态，迷失在物理世界中并与之断开联系时，他或她会痛苦地意识到空间处理对我们生活质量的重要贡献。这种情况，被称为地形定向障碍，通常是由中风引起的损伤压后皮质（RSP），一个保守的哺乳动物空间处理电路的组成部分。在啮齿类动物中，RSP包含头部方向（HD）细胞;这些神经元根据动物的HD功能进行放电，操作起来很像指南针。这一发现与患有RSP损伤的人失去方向感的事实有关。重要的是，啮齿动物RSP和空间处理电路中的其他节点之间的功能和解剖关系仍然未知;这里提出的实验将检查这些关系，阐明RSP对啮齿动物大脑中空间编码的精确贡献，并为临床医生提供对地形定向障碍病因学的有价值的见解。RSP与多个结构相连，这些结构也包含HD细胞以及其他类型的空间调谐神经元。使用一种创新的方法可逆地激活单个大脑区域-设计师药物专门激活的设计师受体（DREADD）-特异性目标1将确定1）RSP中的HD细胞活性是固有地产生还是依赖于来自其他含HD细胞区域的输入，以及2）RSP是否影响下游空间信号的活性。这一目标将揭示空间信息的功能流和从RSP。具体目标2将 确定RSP在其空间处理功能方面是否显示功能和解剖学拓扑结构，因为啮齿动物病变和行为研究表明HD细胞主要局限于RSP的尾部。将进行顺行和逆行神经元追踪实验，以确定这种潜在的功能性地形图是否映射到基础解剖学地形图上，其中与吻侧RSP相比，尾侧RSP与其他含HD细胞的区域更紧密地相互连接。特定目标3将检查先前证明的RSP在处理环境中的视觉地标中的作用的解剖学基础。RSP和后下托（Postsubiculum，PoS）都将视觉信息整合到空间处理回路中;这一共享功能可能来自这两个区域的共同视觉输入。为了验证这一假设，将进行逆行追踪实验，以确定视觉系统中的单个细胞群是否投射到RSP和PoS。总之，这些拟议实验的结果将为临床医生提供有价值的见解，RSP损伤的系统水平的影响，帮助他们更好地诊断和治疗患者患有地形定向障碍。

 DESCRIPTION (provided by applicant): Animals must maintain a sense of direction and location to efficiently navigate. Humans do this almost effortlessly, unaware of the complex neural mechanisms that generate our spatial knowledge. However, when brain damage disrupts these processes and leaves an individual in a devastating state of chronic disorientation, lost in and disconnected from the physical world, he or she becomes painfully aware of the vital contribution spatial processing makes to our quality of life. This condition, known as topographic disorientation, is commonly caused by stroke-induced damage to retrosplenial cortex (RSP), a component of a conserved mammalian spatial processing circuit. In rodents, the RSP contains head direction (HD) cells; these neurons fire as a function of the animal's HD, operating much like a compass. This finding has been linked to the fact that humans with RSP damage lose their sense of direction. Importantly, the functional and anatomical relationships between the rodent RSP and other nodes in the spatial processing circuit remain unknown; the experiments proposed here will examine these relationships, elucidating the precise contributions of the RSP to spatial coding in the rodent brain and providing clinicians with valuable insights into the etiology of topographic disorientation. The RSP is reciprocally connected with multiple structures that also contain HD cells as well as other types of spatially-tuned neurons. Using an innovative method to reversibly inactivate individual brain regions - Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) - Specific Aim 1 will determine 1) if HD cell activity in the RSP is generated intrinsically or dependent upon input from other HD cell-containing regions and 2) if the RSP influences that activity of downstream spatial signals. This aim will reveal the functional flow of spatial information to and from the RSP. Specific Aim 2 will determine if the RSP displays a functional and anatomical topographic organization in regard to its spatial processing functions as rodent lesion and behavioral studies suggest that HD cells are largely confined to the caudal portion of the RSP. Anterograde and retrograde neuronal tracing experiments will be performed to determine if this potential functional topography maps on to an underlying anatomical topography in which the caudal RSP is more heavily interconnected with other HD cell-containing regions compared to the rostral RSP. Specific Aim 3 will examine the anatomical basis for the previously demonstrated role of the RSP in processing visual landmarks in the environment. Both the RSP and the postsubiculum (PoS) integrate visual information into the spatial processing circuit; this shared function might arise from common visual inputs into these two regions. To test this hypothesis, retrograde tracing experiments will be performed to determine if a single population of cells in the visual system projects to both the RSP and PoS. Together, the results of these proposed experiments will provide clinicians with valuable insights into the systems-level implications of RSP damage, helping them to better diagnose and treat patients suffering from topographic disorientation.