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)问题是各种精神障碍的核心要素。与恐惧相关的学习被认为在情绪障碍的发展中扮演着重要的角色，而恐惧条件反射(通常使用脚电作为恐惧诱导刺激)是这项工作中使用的一个关键研究模型。经过条件反射后，对恐惧经历的记忆产生的行为和生理反应几乎与脚击引发的反应相同。恐惧对睡眠也有很大影响。恐惧对睡眠的一个显著影响是减少了快速眼动(REM)睡眠，这种睡眠发生在某些恐惧经历之后的时期。然而，恐惧行为和随后的睡眠可能会分离，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会在清醒状态下产生明显的恐惧行为(啮齿动物中的冰冻)，并减少快速眼动睡眠，而与可控压力相关的恐惧学习在清醒时会产生类似的恐惧行为，但会增加快速眼动睡眠。睡眠障碍基本上发生在所有精神障碍中；因此，了解应激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，可以提供改善睡眠障碍治疗所需的洞察力。我们最近发现，杏仁基底外侧核(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在调节恐惧对睡眠的影响方面的作用。我们将确定BLA的全球失活对睡眠、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代谢性谷氨酸)如何改变恐惧学习、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近乎实时地评估血乳酸中谷氨酸的变化与恐惧学习、恐惧记忆巩固和恐惧消退以及唤醒状态的自发变化有关的情况。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，以描绘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，来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.