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.

关于海马在存储新记忆中的独特作用的多年研究和理论导致了一个一般的想法 海马为每种独特体验生成了独特的输出代码，该代码投影回新皮层， 它与广泛分散在皮质上的体验的属性相结合，从而使他们的 连贯的检索。海马蜂窝射击植根于基于自运动的空间框架，所谓的“地方” 单元格是由每种体验的属性调节的（在给定位置实际发生的情况，包括感觉 输入，电动机输出和内部大脑状态，例如计划和“工作”记忆）。这些记忆如何“索引”影响 在神经种群水平上，在皮层中记忆的表示和存储尚不清楚。我们表明了这一点 海马输出可以在浅表新皮层中形成独特的，与内存相关的代码（ 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 参与稀疏的正交表示，对应于虚拟现实中的位置和经验 环境（VRE）。我们还表明，像情节记忆的行为表现及其导数一样， 广义知识，这些代码在随后对海马的损害中幸存下来，并且表现出模式的完成和误差 面对提示缺失和重排的校正。 这些以及相关的发现开辟了一个新的皮质记忆研究领域，以及许多重要的问题 出现有关PCC空间调整的起源，自上而下（海马）和自下而上（感觉）的确切作用 将输入与表面皮层的收敛，包括离线重播，以及控制创建的可塑性规则 皮质PCC的稳定及其表现出模式完成的能力 - 一种正弦的缔合记忆。 我们建议在VR范式中探索小鼠中的这些问题。我们将使用介观2-的组合 光子和宽场Ca2+成像，海马和皮质活性的光学遗传和化学遗传操纵， 海马和皮质神经合奏和LFP动力学的多神经元电生理记录以及 浅表神经元独特子集的皮质微刺激。后者可以实现人工创建新的PCC 以及他们插入正在进行的内存表示。具体实验包括：1）测试，使用光遗传学 在重播事件（锋利的波 - 纹状体）期间，海马的灭活，无论海马模式是否离线重放 有助于皮质PCC的出现。 2）定义自下而上的感觉输入在编队中的作用 随后的表达皮质PCC。 3）探索有关皮质出现的突触可塑性规则 PCC。 这些实验将更好地理解海马流向新皮层如何指导 新的皮质特征探测器和模式的出现，以及关于这种关键功能如何研究的框架 在正常衰老和退化性脑疾病期间降解。