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。 记忆形成和回忆的大脑区域内部和之间的电路机制 被认为是我们这个时代最大的科学挑战之一，并且有可能产生戏剧性的影响 海马体对于记忆障碍的治疗既是必要的也是充分的。 情景记忆的形成和回忆——放置在时间和空间中的经历的记忆。 记忆在海马体中通过称为位置的神经元群的放电活动进行编码 当动物在其环境中移动时，细胞会在特定位置放电，从而创建认知地图。 海马体的突触可塑性对于形成认知图和大脑切片至关重要 来自蓝斑 (LC) 和腹侧被盖区 (VTA) 的去甲肾上腺素能和多巴胺能输入 海马体调节突触可塑性，表明海马体的 LC 和 VTA 输入可能 然而，VTA 和 LC 的活动会影响认知图的形成和可塑性。 学习过程中的海马体、突触连接及其对海马认知图的影响 目前，该领域的一个主要技术障碍是测量和操纵该活动。 LC 和 VTA 轴突在学习过程中的变化，并直接在 海马体。 为了解决这个问题，我们将实施一种创新方法来直接测量和操纵 LC 和 VTA 轴突的尖峰活动，以及大量位置细胞的尖峰活动， 海马依赖性学习任务期间小鼠的海马——环境背景的变化 以及海马 LC 和 VTA 轴突的光遗传学操作 局部应用受体拮抗剂将揭示其作用的必要性、充分性和机制 这些海马输入对认知图的形成和可塑性的离体电子显微镜观察。 行为过程中轴突成像将揭示它们在海马体中的突触连接。 海马体中的 LC 和 VTA 轴突将发出环境新颖性和背景变化的信号， LC 信号分别影响新环境暴露期间认知图的形成，以及 VTA 信号在情境变化期间重塑认知图，这将提供对认知图谱的首次洞察。 这些神经调节回路直接在海马体中携带信息 海马依赖性学习，并将揭示这些信号如何形成和改变记忆 表征以及发生这种情况的突触电路。