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

项目概述：记忆使动物能够获得、储存和回忆世界知识 通过经验和使用这些知识，以最大限度地提高回报和避免危险。了解 大脑区域内部和之间的回路机制，是记忆形成和回忆的基础 被认为是我们这个时代最大的科学挑战之一，并有可能彻底改变 影响记忆障碍的治疗海马体对于大脑的活动来说， 情景记忆的形成和回忆--将经历置于时间和空间中的记忆。这些 记忆在海马体中由称为位置的神经元群体的放电活动编码 细胞，当动物在周围环境中移动时，这些细胞在特定位置放电，形成认知地图。 海马体中的突触可塑性对于形成认知地图至关重要， 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 调节突触可塑性，表明LC和VTA输入海马可能 影响认知地图形成和可塑性。然而，VTA和LC输入的活动， 学习期间的海马体、其突触连接性及其对海马认知地图的影响 是未知的。目前，该领域的一个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，并确定其突触连接，直接在 海马体。 为了解决这个问题，我们将采用一种创新的方法，直接测量和操纵 LC和VTA轴突的尖峰活动，以及大量定位细胞的尖峰活动，在 环境背景下小鼠海马在海马依赖性学习任务中变化 和新环境暴露。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的必要性，充分性，和作用机制， 这些海马体的输入对认知地图的形成和可塑性的影响。离体电子显微镜观察 在行为过程中成像的轴突将揭示它们在海马体中的突触连接。我们假设 海马体中的LC和VTA轴突将发出环境新奇性和背景变化的信号， LC信号在新环境暴露期间影响认知地图的形成， VTA信号在上下文变化期间重塑认知地图。这将提供第一个洞察到 这些神经调节回路直接在海马体中传递信息， 依赖于记忆的学习，并将揭示这些信号如何形成和改变记忆 这一现象的发生是通过神经元的表达和突触回路来实现的。

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.