Subiculm circuits for cortical feedback regulation of spatial mapping and learning

用于空间映射和学习的皮层反馈调节的下电路

• 批准号: 10318631
• 负责人: Douglas Arthur Nitz
• 金额: $ 50.28万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318631
• 关键词: Address; Affect; Alzheimer' s Disease; Anatomy; Animal Model; Animals; Back; Behavior; Behavioral; Brain; Brain region; Calcium; Canine Adenoviruses; Cells; Cognition; Complex; Data; Decision Making; Environment; Etiology; Exhibits; Feedback; Genetic; Goals; Hippocampal Formation; Hippocampus (Brain); Image; Label; Learning; Left; Link; Location; Mammals; Maps; Medial; Mediating; Memory; Mus; Neurons; Output; Parietal Lobe; Pathway interactions; Pattern; Performance; Physiological; Play; Population; Positioning Attribute; Process; Property; Publishing; Rattus; Regulation; Reporting; Research; Resolution; Role; Route; Running; Specific qualifier value; Structure; Synapses; System; Temporal Lobe Epilepsy; Testing; Time; Travel; Viral; Visual Cortex; base; combinatorial; designer receptors exclusively activated by designer drugs; entorhinal cortex; genetic approach; genetic manipulation; hippocampal subregions; human model; in vivo; insight; microscopic imaging; neocortical; nervous system disorder; neural circuit; neural correlate; neurophysiology; novel; optogenetics; rabies viral tracing; relating to nervous system; spatial relationship; vector; virus genetics; way finding

Project Summary / Abstract Encoding of environmental location and navigational behavior in mammals involves large ensembles of specific neuron types across multiple interacting brain regions. “Place cell” and “grid cell” mapping of spatial location in the CA1 region of hippocampus and medial entorhinal cortex (EC), respectively, is thought to be fed forward to associative cortical brain regions including the posterior parietal cortex (PPC) and retrosplenial cortex (RSP) to map conjunctions of egocentric and external spatial relationships. This notion implies that the hippocampal-neocortical pathway involves a gradual transformation of spatial cognition to action along with encoding of specific route information at intermediate processing stages. While the characterization of this hippocampal feedforward output to the neocortical system has been conceptually useful for our understanding of spatial navigation processes, it is now time to consider the role of the largely unexplored “top-down” neocortical inputs from RSP to the hippocampus. The subiculum (SUB) is an under-investigated brain structure well positioned to mediate circuit interactions between the hippocampal and neocortical systems. Based on our recent discoveries, we hypothesize that specific subsets of SUB neurons receive significant direct “top-down” inputs from RSP and that these inputs yield specialized SUB encoding of multiple spatial relationships including the axis of travel, boundary vectors, and route sub-spaces. These SUB neurons are expected to overlap with the population of CA1-projecting SUB neurons that exert direct feedback regulation of hippocampus-associated spatial mapping and learning. We propose to study the synaptic circuit organization and functional implications of this “top-down” pathway from RSP cortex, to SUB, to hippocampal CA1, using recent technological advancements. To test the hypothesis, in Aim 1, we will map brain-wide circuit input connections of CA1-projecting SUB neurons and compare these to EC-projecting, and RSP-projecting SUB neurons using new viral tracing and optogenetic stimulation mapping. A combinatorial viral and genetic strategy will be used to selectively label projection-specific SUB neurons for circuit studies and physiological characterization. In Aims 2 and 3, we will link circuit connection mapping to neurophysiological function and behavior. Tetrode recordings and in vivo GCaMP6-based calcium imaging of CA1 at single-cell resolution in freely moving animals will resolve how RSP inputs and projection-specific SUB neurons modulate CA1 place cell activities and how they contribute to spatial learning and navigation. The studies will be conducted in conjunction with behavioral analyses addressing how animals learn object-place associations and routes through environments having multiple interconnected pathways. Genetically targeted neuronal inactivation will be used to establish the causality of circuit connections and function. The proposed studies are aligned with the specified goals of Targeted Brain Circuits Projects, and will contribute to a mechanistic understanding of how dynamic patterns of specific SUB neural activity are transformed into spatial navigation and cognition.

项目摘要 /摘要 哺乳动物中环境位置和导航行为的编码涉及大型合奏 多个相互作用大脑区域的特定神经元类型。空间的“位置单元格”和“网格单元”映射 认为分别在海马和内侧内嗅皮层（EC）的CA1区域中被认为是喂养的 前向包括后顶皮层（PPC）和肾后腺的联想皮层脑区域 皮质（RSP）以绘制以自我为中心和外部空间关系的组合。这个观念意味着 海马 - 皮层途径涉及将空间认知与行动的年级转化以及 在中间处理阶段编码特定路由信息。而这个特征 新皮层系统的海马进食输出对我们的理解很有用 在空间导航过程中，现在该考虑在很大程度上出乎意料的“自上而下”的作用 从RSP到海马的新皮质输入。下部（子）是一个不足的大脑 结构很好地介导海马和新皮质系统之间的电路相互作用。 根据我们最近的发现，我们假设子神经元的特定子集获得了重要的 来自RSP的直接“自上而下”输入，这些输入产生了多个空间的专门子编码 关系，包括行进轴，边界向量和路线子空间。这些子神经元是 预计将与CA1预测的子神经元的种群重叠，该神经元直接对反馈调节 海马相关的空间映射和学习。我们建议研究突触电路组织 从RSP皮层到子，再到海马CA1的这种“自上而下”途径的功能含义 最近的技术进步。为了测试假设，在AIM 1中，我们将绘制脑范围的电路输入 CA1射击子神经元的连接，并将其与EC项目进行比较，并将RSP投影子标记进行比较 神经元使用新的病毒痕迹和光遗传学刺激映射。组合病毒和遗传 策略将用于选择性标记投影特异性的子神经元进行电路研究和生理 表征。在AIMS 2和3中，我们将将电路连接映射链接到神经生理功能和 行为。 Tetrode记录和基于体内GCAMP6的基于CA1的基于单细胞分辨率的钙成像 自由移动的动物将解决RSP输入和特异性子神经元如何调节CA1位置 细胞活动及其如何促进空间学习和导航。研究将在 与行为分析的联系，解决动物如何学习对象的关联和路线 通过具有多个互连途径的环境。遗传靶向神经元失活 用于建立电路连接和功能的因果关系。提出的研究与 有针对性的大脑电路项目的指定目标，并将有助于对机械理解 特定的亚神经元活性的动态模式如何转化为空间导航和认知。

项目成果

Beyond t test and ANOVA: applications of mixed-effects models for more rigorous statistical analysis in neuroscience research.

• DOI: 10.1016/j.neuron.2021.10.030
• 发表时间: 2022-01-05
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Yu Z;Guindani M;Grieco SF;Chen L;Holmes TC;Xu X
• 通讯作者: Xu X

Adaptive integration of self-motion and goals in posterior parietal cortex.

• DOI: 10.1016/j.celrep.2022.110504
• 发表时间: 2022-03-08
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Alexander, Andrew S.;Tung, Janet C.;Chapman, G. William;Conner, Allison M.;Shelley, Laura E.;Hasselmo, Michael E.;Nitz, Douglas A.
• 通讯作者: Nitz, Douglas A.

Longitudinal dynamics of microvascular recovery after acquired cortical injury.

• DOI: 10.1186/s40478-022-01361-4
• 发表时间: 2022-04-25
• 期刊: ACTA NEUROPATHOLOGICA COMMUNICATIONS
• 影响因子: 7.1
• 作者: Lin, Xiaoxiao;Chen, Lujia;Jullienne, Amandine;Zhang, Hai;Salehi, Arjang;Hamer, Mary;C. Holmes, Todd;Obenaus, Andre;Xu, Xiangmin
• 通讯作者: Xu, Xiangmin

Hippocampal neural circuit connectivity alterations in an Alzheimer's disease mouse model revealed by monosynaptic rabies virus tracing.

• DOI: 10.1016/j.nbd.2022.105820
• 发表时间: 2022-10-01
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Ye, Qiao;Gast, Gocylen;Su, Xilin;Saito, Takashi;Saido, Takaomi C.;Holmes, Todd C.;Xu, Xiangmin
• 通讯作者: Xu, Xiangmin

Inferring neuron-neuron communications from single-cell transcriptomics through NeuronChat.

通过 NeuronChat 从单细胞转录组学推断神经元间通讯。

• DOI: 10.1038/s41467-023-36800-w
• 发表时间: 2023-02-28
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Zhao, Wei;Johnston, Kevin G.;Ren, Honglei;Xu, Xiangmin;Nie, Qing
• 通讯作者: Nie, Qing