Limbic modulation of stress-induced alterations in sleep

项目总结/摘要 恐惧记忆和恐惧消退（减少恐惧的新学习）的问题是各种恐惧的核心要素。 精神疾病的症状恐惧相关学习被认为在情绪发展中起着重要作用 障碍和恐惧条件反射（通常采用脚震作为恐惧诱导刺激）是一个关键的研究 在这项工作中使用的模型。在条件反射之后，恐惧经历的记忆产生了几乎相同的 行为和生理反应，这些引发的脚电击。恐惧也会对 睡吧恐惧对睡眠的一个突出影响是减少了快速眼动（REM）睡眠，这种睡眠发生在 在某些可怕的经历之后。然而，恐惧行为和随后的睡眠可以分离 这取决于恐惧发生的条件。恐惧学习与无法控制的压力有关， 在清醒状态下的明显恐惧行为（啮齿动物的冻结），并减少REM睡眠，而恐惧学习 与可控压力相关的神经刺激在清醒时产生类似的恐惧行为，但可以增加REM睡眠。 睡眠障碍发生在基本上所有的精神疾病;因此，了解神经生物学 压力和恐惧事件可以改变情绪记忆对睡眠的影响， 需要洞察力来改善睡眠受到影响的疾病的治疗。我们最近发现， 基底外侧杏仁核（BLA）在决定恐惧记忆是否改变睡眠方面起着关键作用。在这 项目中，我们将通过确定BLA在恐惧中的作用来确定BLA在介导恐惧对睡眠的影响中的作用 学习、恐惧记忆巩固和恐惧消退。我们将确定全球失活的影响， BLA对睡眠、恐惧行为以及恐惧学习、恐惧记忆巩固和恐惧过程中的应激反应的影响 灭绝我们将确定临床相关系统（即，促肾上腺皮质激素释放因子和 代谢型谷氨酸）改变恐惧学习，恐惧记忆巩固和恐惧消退，以及它们对 睡眠、恐惧行为和压力反应。我们将使用生物传感器在接近真实的时间内评估 BLA中谷氨酸的变化与恐惧学习、恐惧记忆巩固和恐惧消退相关， 唤醒状态的自发变化最后，我们将使用光遗传学来激活和抑制谷氨酸 BLA中的神经元来描述哪些特定的恐惧过程（恐惧学习，恐惧记忆和恐惧消退）， BLA规范。这些研究将填补一个重大的知识空白，增加我们对 恐惧，睡眠和压力之间的联系，以及恐惧记忆的神经生物学过程 来影响睡眠。

Project Summary/Abstract Problems with fear memory and fear extinction (new learning that reduces fear) are core elements of a variety of psychiatric disorders. Fear-related learning is thought to play a significant role in the development of emotional disorders and fear conditioning (usually employing footshock as the fear-inducing stimulus) is a key research model used in this work. After conditioning, memories of the fearful experience produce virtually identical behavioral and physiological responses to those elicited by footshock. Fear also has a significant impact on sleep. One prominent effect of fear on sleep is reduced rapid eye movement (REM) sleep that occurs in the period after certain fearful experiences. However, fear behavior and subsequent sleep can dissociate depending on the conditions in which fear occurs. Fear learning associated with uncontrollable stress produces overt fear behavior in wakefulness (freezing in rodents) and decreases REM sleep whereas fear learning associated with controllable stress produces similar fear behavior in wakefulness but can increase REM sleep. Sleep disturbances occur in essentially all psychiatric disorders; therefore, understanding the neurobiological processes by which stressful and fearful events can alter the impact of emotional memory on sleep can provide insight needed to improve treatments in disorders in which sleep is impacted. We recently found that the basolateral amygdala (BLA) plays a critical role in determining whether fear memory alters sleep. In this project, we will establish the role of BLA in mediating the impact of fear on sleep by determining its role in fear learning, fear memory consolidation and fear extinction. We will determine the effects of global inactivation of BLA on sleep, fear behavior and the stress response during fear learning, fear memory consolidation and fear extinction. We will determine how clinically relevant systems (i.e., corticotropin releasing factor and metabotropic glutamate) alter fear learning, fear memory consolidation and fear extinction, and their effects on sleep, fear behavior and the stress response. We will use biosensors to assess in near real time how glutamate changes in BLA in association with fear learning, fear memory consolidation and fear extinction and with spontaneous changes in arousal state. Lastly, we will use optogenetics to activate and inhibit glutamate neurons in BLA to delineate which specific fear processes (fear learning, fear memory and fear extinction) the BLA regulates. These studies will fill in a significant knowledge gap by increasing our understanding of the association between fear, sleep, and stress, and the neurobiological processes by which fearful memories come to affect sleep.