Limbic modulation of stress-induced alterations in sleep

描述（由申请人提供）：恐惧记忆和恐惧消退（减少恐惧的新学习）问题是各种精神疾病的核心要素。与恐惧相关的学习被认为在情绪障碍的发展中发挥着重要作用，而恐惧条件反射（通常采用脚电击作为恐惧诱发刺激）是这项工作中使用的关键研究模型。在条件反射之后，对恐惧经历的记忆产生了与电击脚引起的记忆几乎相同的行为和生理反应。恐惧对睡眠也有很大的影响。恐惧对睡眠的一个突出影响是在某些恐惧经历后发生的快速眼动（REM）睡眠减少。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。与无法控制的压力相关的恐惧学习在清醒时产生明显的恐惧行为（啮齿动物的冻结）并减少REM睡眠，而与可控压力相关的恐惧学习在清醒时产生类似的恐惧行为，但可以增加REM睡眠。睡眠障碍基本上发生在所有精神疾病中;因此，了解压力和恐惧事件可以改变情绪记忆对睡眠的影响的神经生物学过程可以提供改善睡眠受到影响的疾病治疗所需的见解。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。在这个项目中，我们将通过确定BLA在恐惧学习、恐惧记忆巩固和恐惧消退中的作用，来确定BLA在介导恐惧对睡眠的影响中的作用。我们将确定BLA的整体失活对睡眠、恐惧行为以及恐惧学习、恐惧记忆巩固和恐惧消退过程中的应激反应的影响。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促代谢谷氨酸盐）改变恐惧学习、恐惧记忆巩固和恐惧消退，以及它们对睡眠、恐惧行为和应激反应的影响。我们将使用生物传感器来评估在接近真实的时间内，BLA中谷氨酸的变化如何与恐惧学习、恐惧记忆巩固和恐惧消退以及唤醒状态的自发变化相关联。最后，我们将使用光遗传学来激活和抑制BLA中的谷氨酸神经元，以描述BLA调节哪些特定的恐惧过程（恐惧学习，恐惧记忆和恐惧消退）。这些研究将通过增加我们对恐惧、睡眠和压力之间的联系以及恐惧记忆影响睡眠的神经生物学过程的理解，填补一个重大的知识空白。

DESCRIPTION (provided by applicant): 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 o 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.