From synapses to neural representations: The role of neuromodulatory circuits in shaping contextual memories in the hippocampus

从突触到神经表征：神经调节回路在塑造海马情境记忆中的作用

• 批准号: 10447353
• 负责人: Mark E J Sheffield
• 金额: $ 194.73万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447353
• 关键词: Affect; Anatomy; Animals; Arousal; Attention; Axon; Behavior; Brain; Brain region; Calcium; Caliber; Cells; Chemosensitization; Cognitive; Dendrites; Development; Electron Microscopy; Environment; Episodic memory; Fire - disasters; Functional Imaging; Head; Hippocampus (Brain); Image; Knowledge; Learning; Location; Maps; Measures; Memory; Memory Disorders; Mus; Neurons; Patients; Population; Positioning Attribute; Problem Solving; Property; Pupil; Regulation; Resolution; Rewards; Role; Running; Shapes; Signal Transduction; Slice; Synapses; Synaptic plasticity; Time; Ventral Tegmental Area; Work; antagonist; design; expectation; experience; experimental study; innovation; insight; locus ceruleus structure; memory encoding; memory process; memory recall; nanoscale; neural circuit; neuromechanism; neuroregulation; novel; optogenetics; postsynaptic; receptor; relating to nervous system; response; two-photon; virtual

Project Summary: Memory enables animals to acquire, store, and recall knowledge of the world through experience and use this knowledge to maximize reward and avoid danger. Understanding the circuit mechanisms within and between brain regions that underlie the formation and recall of memories is considered one of the great scientific challenges of our time, and has the potential to drastically influence the treatment of memory disorders. The hippocampus is both necessary and sufficient for the formation and recall of episodic memories—memories of experiences placed in time and space. These memories are encoded in the hippocampus by the firing activity of populations of neurons called place cells, which fire at specific locations as animals move around their environment, creating a cognitive map. Synaptic plasticity in the hippocampus is critical for forming cognitive maps, and in brain slices norepinergic and dopaminergic inputs from the Locus Coeruleus (LC) and the ventral tegmental area (VTA) to the hippocampus modulate synaptic plasticity, suggesting LC and VTA inputs to the hippocampus may influence cognitive map formation and plasticity. However, the activity of VTA and LC inputs to the hippocampus during learning, their synaptic connectivity, and their effect on hippocampal cognitive maps are unknown. Currently, a major technical obstacle in the field is measuring and manipulating the activity of LC and VTA axons during learning, and determining their synaptic connectivity, directly in the hippocampus. To solve this problem, we will implement an innovative approach to directly measure and manipulate the spiking activity of LC and VTA axons, and the spiking activity of large populations of place cells, in the hippocampus of mice during hippocampal-dependent learning tasks—changes in environment context and novel environment exposure. Optogenetic manipulation of LC and VTA axons in hippocampus and locally applied receptor antagonists will reveal the necessity, sufficiency, and mechanism of action of these hippocampal inputs on cognitive map formation and plasticity. Ex-vivo electron microscopy of the axons imaged during behavior will reveal their synaptic connectivity in the hippocampus. We hypothesize that LC and VTA axons in hippocampus will signal environment novelty and changes in context, respectively, with LC signals influencing cognitive map formation during novel environment exposure, and VTA signals reshaping cognitive maps during contextual changes. This will provide the first insight into the information being carried by these neuromodulatory circuits directly in the hippocampus during hippocampal-dependent learning, and will reveal how these signals form and alter memory representations and the synaptic circuitry through which this occurs.

项目摘要：记忆使动物能够获取，存储和回忆世界知识 通过经验并利用这些知识来最大化奖励并避免危险。了解 构成和回忆记忆的大脑区域内和大脑区域之间的电路机制 被认为是我们这个时代的巨大科学挑战之一，并且有可能急剧 影响记忆障碍的治疗。海马既需要 情节记忆的形成和回忆 - 时空的经验记忆。这些 记忆是通过称为位置的神经元人群的发射活动在海马中编码的 当动物在环境周围移动时，在特定位置发射的细胞会产生认知图。 海马中的突触可塑性对于形成认知图和脑切片至关重要 来自基因座（LC）和腹侧对段区域（VTA）的去甲肾上腺素能和多巴胺能输入 到海马调节突触可塑性，建议对海马的LC和VTA输入 影响认知图的形成和可塑性。但是，VTA和LC输入的活动 在学习过程中海马，其突触连通性及其对海马认知图的影响 是未知的。目前，该领域的主要技术障碍是测量和操纵活动 LC和VTA轴突在学习过程中，并确定其突触连通性直接在 海马。 为了解决这个问题，我们将采用一种创新的方法来直接衡量和操纵 LC和VTA轴突的尖峰活性，以及​​大量位置细胞种群的峰值活性， 海马依赖性学习任务期间小鼠的海马 - 在环境环境中变化 和新颖的环境暴露。海马和 局部应用的受体拮抗剂将揭示必要，充分性和作用机理 这些海马在认知图形成和可塑性上的输入。前体电子显微镜 行为过程中成像的轴突将揭示其在海马中的突触连通性。我们假设 海马中的LC和VTA轴突会向环境新颖性发出新颖性，并在上下文中变化 分别使用LC信号会影响新的环境暴露期间的认知图形成，并影响 VTA信号在上下文更改中重塑认知图。这将为您提供第一个洞察力 这些神经调节电路直接在海马中携带的信息 海马依赖于学习，并将揭示这些信号如何形成和改变记忆 表示发生的表示和突触电路。