Bottom-Up, Top-Down, and Local Interactions in the Generation and Consolidation of Cortical Representations of Sequential Experience

顺序经验的皮层表征的生成和巩固中的自下而上、自上而下和局部交互

• 批准号: 10658227
• 负责人: BRUCE L MCNAUGHTON
• 金额: $ 195.45万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658227
• 关键词: Age; Animals; Area; Back; Behavioral; Biological Process; Brain; Brain Diseases; Brain region; Cell Shape; Cells; Code; Coin; Coupled; Coupling; Cues; Data; Development; Disease; Dissociation; Dorsal; Electrophysiology (science); Episodic memory; Event; Exhibits; Future; Generations; Genetic; Hippocampus; Image; Knowledge; Lateral; Learning; Lesion; Link; Location; Maps; Memory; Memory impairment; Methods; Modeling; Motion; Motor; Motor output; Mus; Neocortex; Neurobiology; Neurons; Organism; Output; Pattern; Population; Positioning Attribute; Predisposition; Pyramidal Cells; Randomized; Research; Resistance; Retrieval; Role; Sensory; Shapes; Short-Term Memory; Signal Transduction; Stimulus; Synapses; Synaptic plasticity; Testing; Thalamic structure; Time; Work; detector; experience; experimental study; frontier; genetic manipulation; high risk; indexing; memory consolidation; memory encoding; microstimulation; neocortical; neural; normal aging; novel; optogenetics; sensory input; sensory system; somatosensory; theories; two-photon; virtual reality environment; visual control

Years of study and theory about the unique role of the hippocampus in storing new memories has led to a general idea that the hippocampus generates a unique output code for every unique experience, that is projected back to the neocortex, where it becomes coupled to attributes of the experience that are widely dispersed over the cortex, thus enabling their coherent retrieval. Hippocampal cellular firing, which is rooted in a self-motion based spatial framework, so-called, 'place cells', is modulated by the attributes of each experience (what actually happens at a given location, including sensory input, motor output, and internal brain states such as plans, and 'working' memory). How these memory 'indexes' impact the representation and storage of memory in cortex, at the neural population level, is not understood. We showed that hippocampal output enables the formation of unique, memory-related codes in superficial neocortex (the main target of hippocampal output). Similar to hippocampal 'place' cells, these codes take the form of position correlated cells (PCCs) that participate in sparse, orthogonal representations, corresponding to position and experience in a virtual reality environment (VRE). We have also shown that, like the behavioral manifestations of episodic memory and its derivative, generalized knowledge, these codes survive subsequent damage to hippocampus, and exhibit pattern completion and error correction in the face of cue deletions and rearrangements. These, and related, findings open up a new domain of cortical memory research, and many important questions arise concerning the origins of PCC spatial tuning, the exact role of top-down (hippocampal) and bottom-up (sensory) convergence of inputs to superficial cortex, including off-line replay, and the plasticity rules governing the creation and stabilization of cortical PCCs and their ability to exhibit pattern completion - a sine qua non of associative memory. We propose to explore these questions in mice in a VR paradigm. We will apply a combination of mesoscopic 2- photon and wide-field Ca2+ imaging, optogenetic and chemogenetic manipulation of hippocampal and cortical activity, multi-neuron electrophysiological recording of hippocampal and cortical neural ensembles and LFP dynamics, and cortical microstimulation of unique subsets of superficial neurons. The latter may enable artificial creation of new PCCs and their insertion into ongoing memory representations. Specific experiments include: 1) Testing, using optogenetic inactivation of hippocampus during replay events (Sharp-Wave-Ripples), whether off-line replay of hippocampal patterns contributes to the emergence of cortical PCCs. 2) Defining the role of bottom-up sensory inputs in the formation and subsequent expression cortical PCCs. 3) Exploration of the synaptic plasticity rules governing emergence of cortical PCCs. These experiments will provide a better understanding how hippocampal outflow to neocortex guides the emergence of new cortical feature detectors and schemas, and a framework for future studies on how this crucial function is degraded during normal aging and degenerative brain disorders.

多年关于海马体在存储新记忆方面的独特作用的研究和理论得出了一个总体想法 海马体为每一次独特的体验生成独特的输出代码，并将其投射回新皮质， 它与广泛分散在皮层上的经验属性相结合，从而使他们能够 连贯检索。海马细胞放电，植根于基于自我运动的空间框架，即所谓的“位置” 细胞'，受到每种体验的属性的调节（在给定位置实际发生的事情，包括感官 输入、运动输出和内部大脑状态（例如计划和“工作”记忆）。这些内存“索引”如何影响 在神经群体水平上，皮层中记忆的表示和存储尚不清楚。我们证明了 海马输出能够在浅层新皮质（大脑皮层的主要目标）中形成独特的、与记忆相关的代码。 海马输出）。与海马“位置”细胞类似，这些代码采用位置相关细胞 (PCC) 的形式 参与稀疏、正交的表示，对应于虚拟现实中的位置和体验 环境（VRE）。我们还表明，就像情景记忆及其衍生物的行为表现一样， 根据一般知识，这些代码在随后的海马体损伤中幸存下来，并表现出模式完成和错误 面对提示删除和重新排列的纠正。 这些以及相关的发现开辟了皮质记忆研究的新领域，并解决了许多重要问题 出现关于 PCC 空间调谐的起源、自上而下（海马）和自下而上（感觉）的确切作用 将输入汇聚到浅表皮层，包括离线重放，以及管理创建和生成的可塑性规则 皮质 PCC 的稳定性及其表现出模式完成的能力——联想记忆的必要条件。 我们建议在 VR 范式中用小鼠来探索这些问题。我们将应用介观 2- 光子和广域 Ca2+ 成像、海马和皮质活动的光遗传学和化学遗传学操纵， 海马和皮质神经群的多神经元电生理记录和 LFP 动力学，以及 表面神经元独特子集的皮质微刺激。后者可能能够人工创建新的 PCC 并将它们插入到正在进行的记忆表征中。具体实验包括：1）测试，利用光遗传学 重放事件期间海马失活（锐波波纹），是否离线重放海马模式 有助于皮质 PCC 的出现。 2) 定义自下而上的感觉输入在形成和 随后表达皮质 PCC。 3）探索控制皮质出现的突触可塑性规则 PCC。 这些实验将有助于更好地理解海马向新皮质的流出如何引导 新的皮质特征检测器和模式的出现，以及未来研究这一关键功能如何发挥作用的框架 在正常衰老和退行性脑部疾病期间会降解。