Artificially modulating memories to alleviate psychiatric disease-like states

项目总结/摘要 慢性压力会影响许多与记忆、情绪和动机有关的大脑区域，例如 海马体、杏仁核和前额皮质;它异常地改变各种细胞事件，包括 树突状形态和基因表达模式;并且，它可以沉淀几种适应不良状态，如 类似抑郁和焦虑的行为。然而，神经回路足以减轻甚至防止这种情况的发生。 表型尚不清楚。在老鼠和人类中，海马体都与储存和 恢复积极的记忆和调节与压力有关的状态。令人鼓舞的是，PI最近的工作 证明了人工刺激海马体中的细胞，这些细胞以前在阳性反应期间是活跃的， 记忆的形成足以增加奖励行为和动机。为此，在这款DP 5中 这项提议将在人工激活的积极记忆和动物记忆之间建立一座新的实验桥梁。 精神疾病的模型。将利用PI最近开发的病毒系统， 即早基因c-Fos的启动子驱动光敏离子通道的表达 channelrhodopsin-2在抗生素强力霉素的控制下。在没有 多西环素，学习诱导的神经元活动选择性标记活性c-Fos表达神经元， 通道视紫红质-2，从而赋予活性依赖性和诱导标记的，除了光学控制 海马细胞及其相应的轴突终末。本项目的实验目标是 三重和联合收割机体内光遗传学、体外免疫组织化学和一系列行为测定。 首先，假设将被测试，光学调制一组确定的积极或消极的记忆， 携带海马体细胞足以改善或模拟慢性应激对细胞和 行为水平。下一步，目标是测试是否激活记忆轴承海马轴突 终末--将不同的记忆信息传递到杏仁核、前额叶皮层和核团 它可以不同地调节精神疾病样状态的独立特征，如社会性， 损伤、焦虑样和与快感缺失相关的行为。最后，我们的目标是测试长期刺激 在压力之前，海马体细胞的积极记忆可以防止这种适应不良的行为， 沉淀，同时随后进行全脑解剖学和组织学分析，以确定关键的 调节记忆预防能力的细胞位点。

PROJECT SUMMARY / ABSTRACT Chronic stress affects numerous brain areas involved in memory, emotion, and motivation, such as the hippocampus, amygdala, and prefrontal cortex; it abnormally alters a variety of cellular events, including dendritic morphology and gene expression patterns; and, it can precipitate several maladaptive states, such as depression- and anxiety-like behaviors. Yet, the neural circuitry sufficient to mitigate or even prevent such phenotypes is unclear. In both mice and humans, the hippocampus has been implicated in storing and retrieving positive memories and in modulating stress-related states. Promisingly, the recent work of the PI has demonstrated that artificially stimulating cells in the hippocampus that previously were active during positive memory formation are sufficient to increase reward-like behavior and motivation. To that end, in this DP5 proposal, a novel experimental bridge will be built between artificially activated positive memories and animal models of psychiatric disorders. The recently developed virus system by the PI will be utilized in which the promoter of the immediate early gene c-Fos drives the expression of the light-sensitive ion channel channelrhodopsin-2 in a manner that is under the control of the antibiotic Doxycycline. In the absence of Doxycycline, learning-induced neuronal activity selectively labels active c-Fos-expressing neurons with channelrhodopsin-2, thus conferring activity-dependent and inducible labeling of, in addition to optical control over, hippocampus cells and their corresponding axon terminals. The experimental goals of this project are threefold and combine in vivo optogenetics, in vitro immunohistochemistry, and a battery of behavioral assays. First, the hypothesis will be tested that optically modulating a defined set of positive or negative memory bearing hippocampus cells is sufficient to ameliorate or mimic the effects of chronic stress at the cellular and behavioral levels. Next, the goal is to test whether or not activating memory bearing hippocampus axon terminals—which route distinct mnemonic information to the amygdala, prefrontal cortex, and nucleus accumbens—can differentially modulate independent features of psychiatric disease-like states, such as social impairments, anxiety-like, and anhedonic-related behavior. Finally, the goal is to test if chronically stimulating positive memory bearing hippocampus cells prior to stress can prevent such maladaptive behaviors from precipitating, while subsequently performing a brain-wide anatomical and histological analysis to identify key cellular loci mediating memory's putative prophylactic capacity.