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.

关于海马体在存储新记忆中的独特作用，多年的研究和理论得出了一个普遍的观点 海马体为每一次独特的经历产生一个独特的输出代码，并投射回新皮层， 在那里，它与广泛分布在大脑皮层上的体验属性相耦合，从而使他们能够在大脑皮层上进行认知活动。 相干检索海马细胞放电，这是植根于自我运动为基础的空间框架，所谓的，“地方 细胞的，是由每一个经验的属性（实际上发生了什么，在一个给定的位置，包括感官 输入、运动输出和内部大脑状态，如计划和“工作”记忆）。这些记忆“索引”如何影响 在神经群体水平上，大脑皮层中记忆的表示和存储还不清楚。我们发现 海马体的输出使得能够在表层新皮层（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）。与海马的位置细胞类似，这些编码以位置相关细胞（PCC）的形式出现 它们参与稀疏的正交表示，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， 一般的知识，这些代码在海马体随后的损伤中幸存下来，并表现出模式完成和错误 在面对线索删除和重排时的纠正。 这些以及相关的发现为大脑皮层记忆研究开辟了一个新的领域， 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， 输入到表层皮层的会聚，包括离线重放，以及控制创建和 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范例中在小鼠中探索这些问题。我们将应用介观2- 光子和宽场Ca 2+成像，海马和皮质活动的光遗传学和化学遗传学操纵， 海马和皮质神经集合和LFP动力学的多神经元电生理记录，以及 皮层微刺激的独特子集的表面神经元。后者可以人工创建新的PCC 并将其插入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 在重放事件（锐波波纹）期间海马失活，无论海马模式的离线重放 导致皮质PCCs的出现2)定义自下而上的感觉输入在形成中的作用， 随后表达皮质PCC。3)皮层神经元出现的突触可塑性规律探讨 PCC。 这些实验将提供一个更好的理解如何海马流出到新皮层引导 新的皮层特征检测器和图式的出现，以及未来研究这一关键功能的框架 在正常衰老和退行性脑部疾病期间会降解。