Enabling precise cell-type-specific dissection of orientation and memory circuits in retrosplenial cortex

实现压后皮层定向和记忆电路的精确细胞类型特异性解剖

• 批准号: 10446099
• 负责人: Omar Jamil Ahmed
• 金额: $ 67.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446099
• 关键词: Behavior; Behavioral; Blood Vessels; Brain; Brain region; Cells; Communities; Computer Models; Custom; Databases; Disorientation; Dissection; Dorsal; Electrodes; Electrophysiology (science); Future; Goals; Head; Hippocampus (Brain); Human; Institutes; Label; Lead; Lesion; Link; Maps; Memory; Memory impairment; Morphology; Names; Neurons; Neurosciences; Output; Physiological; Physiology; Play; Positioning Attribute; Production; Property; Reporting; Rodent; Role; Rotation; Rupture; Sentinel; Sleep; Source; Space Perception; Speed; Synapses; Testing; Thalamic structure; Transgenic Mice; cell cortex; cell type; design; entorhinal cortex; hippocampal pyramidal neuron; in vivo; inhaled nitric oxide; memory consolidation; memory process; neuronal excitability; next generation sequencing; non rapid eye movement; novel; optogenetics; patch sequencing; prevent; recruit; spatial memory; transcriptomics

PROJECT SUMMARY/ABSTRACT In humans, damage to a brain region called the retrosplenial cortex leads to pronounced spatial disorientation and severe retrograde and anterograde memory deficits. Similar navigational and memory impairments are also seen in rodents with either lesions or chemogenetic inactivation of the retrosplenial cortex. Despite its critically important functions, the cells, circuits, and computations of the retrosplenial cortex remain understudied, especially when compared to those of the hippocampus and entorhinal cortex. We have recently shown that a small, excitable, pyramidal neuron – only found in layers 2/3 (L2/3) of the granular retrosplenial cortex (RSG) – has properties that are very different from its more standard (regular-spiking; RS) neighbors and is uniquely suited to computing compass-like directional information over long durations. We have named this neuron the Low Rheobase (LR) cell. Using optogenetic ex vivo circuit mapping, we have subsequently found that inputs from the thalamus (source of directional information) and from the dorsal subiculum (source of spatial information) converge selectively onto these small LR cells, while avoiding nearby RS cells. Thus, LR neurons are ideally positioned to support the RSG’s spatial orientation computations. During non-REM sleep, hippocampal ripples (known to be important for memory consolidation) are propagated, via the dorsal subiculum, to L2/3 of the RSG. Since these dorsal subicular outputs selectively recruit LR but not neighboring RS cells, LR neurons are also ideally positioned to play a central role in the consolidation of memories from the hippocampus to the RSG. Despite this strong rationale to dissect the behavioral role of LR cells in vivo, two critical hurdles remain to enable a TargetedBCP R01 submission in the near future. First, it is technically challenging to electrophysiologically record from large numbers of simultaneous LR cells in vivo. This is because they are located within a narrow ~120 um band of RSG tucked away close to the midline, with vertical access prevented by blood vessels. Second, the transcriptomic signature of LR neurons remains unknown, preventing the rational selection or production of transgenic mouse lines that selectively and specifically label LR neurons. To overcome these hurdles, in Aim 1, we will develop and test custom-designed probes optimized to record large numbers of L2/3 RSG neurons. In Aim 2, we will utilize Allen Brain Institute databases, 10x Next-Gen sequencing, and Patch-seq to identify the transcriptomic class corresponding to the morphophysiological class of LR neurons. The completion of these Aims will set the stage for a subsequent TargetedBCP R01 submission that will utilize large-scale recordings and causal opto/chemogenetics to carefully decipher the importance of LR neurons in the representation and consolidation of spatial information.

项目摘要/摘要 在人类中，对称为泛胞浮是肾上腺皮质的大脑区域的损害会导致明显的空间迷失方向 严重的逆行和顺行记忆定义。类似的导航和记忆障碍也是 在患有病变或化学遗传灭活后皮质的啮齿动物中可见。尽管有批判性 重要的功能，细胞，圆和计算的重复皮质的计算仍然可以理解， 特别是与海马和内嗅皮层相比。 我们最近表明，一个小的，令人兴奋的锥体神经元 - 仅在颗粒的2/3（L2/3）中发现 后泛皮层（RSG） - 具有与其标准更为标准的特性（常规尖峰； RS）非常不同 邻居，非常适合在长时间计算指南针的方向信息。我们有 将此神经元命名为低风湿病酶（LR）细胞。使用光遗传学的离体电路映射，我们有 随后发现来自丘脑的输入（方向信息来源）和背面 下调（空间信息的来源）选择性地收敛到这些小的LR单元上，同时避免接近 RS细胞。这是LR神经元的理想位置，可以支持RSG的空间取向计算。 在非REM睡眠期间，海马纹波（已知对于记忆巩固很重要）被传播， 通过背部下调，到RSG的L2/3。由于这些背部下输出有选择地招募LR，但不招募LR 相邻的RS细胞，LR神经元也有理想的位置，可以在整合中发挥核心作用 从海马到RSG的回忆。尽管有很强的理由来剖析 LR细胞在体内，仍然有两个关键障碍在不久的将来可以提交目标BCP R01。首先，它 技术在技术上具有挑战性，可从体内从大量的简单LR细胞中记录电生理学。 这是因为它们位于狭窄的〜120 um的RSG范围内，靠近中线， 血管阻止了垂直通道。其次，LR神经元的转录组特征保留 未知，防止有选择地和 特异性标记LR神经元。为了克服这些障碍，在AIM 1中，我们将开发和测试定制设计的 优化可记录大量L2/3 RSG神经元的探针。在AIM 2中，我们将利用Allen Brain Institute 数据库，10倍的下一代测序和补丁序列，以识别对应于该的转录组类 LR神经元的形态生理类。这些目标的完成将为后续 目标BCP R01提交将利用大规模记录和因果OPT/Chemogeonics仔细 破译LR神经元在空间信息的表示和巩固中的重要性。