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

 描述(由申请者提供)：动物必须保持方向感和位置才能有效导航。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，当大脑损伤扰乱了这些过程，让一个人处于慢性迷失方向的毁灭性状态，迷失在物理世界中，并与物理世界脱节时，他或她会痛苦地意识到空间处理对我们的生活质量做出的重要贡献。这种情况被称为地形性定向障碍，通常是由中风引起的脾后皮质(RSP)的损伤引起的，RSP是哺乳动物保守的空间处理电路的组成部分。在啮齿类动物中，RSP含有头部方向(HD)细胞；这些神经元作为动物HD的功能而激活，运作方式很像指南针。这一发现与RSP受损的人失去方向感有关。重要的是，啮齿动物RSP和空间处理回路中其他节点之间的功能和解剖关系尚不清楚；这里提出的实验将检查这些关系，阐明RSP对啮齿动物大脑空间编码的准确贡献，并为临床医生提供有价值的见解，以了解地形定向障碍的病因。RSP与多个结构相互连接，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灭活单个大脑区域-由设计药物(DREADD)专属激活的设计者受体1将确定1)RSP中的HD细胞活动是固有的还是依赖于其他HD细胞包含区域的输入，以及2)RSP是否影响下游空间信号的活动。这一目标将揭示进出可再生能源的空间信息的功能流动。特定目标2将 确定RSP是否表现出与啮齿动物病变一样的空间处理功能的功能和解剖结构，行为学研究表明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，以确定这一潜在的功能地形图是否映射到一种潜在的解剖地形图，在该解剖地形图中，RSP尾侧与其他含HD细胞的区域比吻侧RSP更紧密地相互联系。具体目标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和下丘后(POS)都将视觉信息整合到空间处理电路中；这种共同的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体是否同时投射到RSP和POS。总之，这些拟议的实验结果将为临床医生提供关于RSP损伤的系统层面的有价值的见解，帮助他们更好地诊断和治疗患有地形定向障碍的患者。

 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.