Neural circuitry in stress-induced insomnia

描述(由候选人提供)：原发性失眠是普通人群中最普遍的睡眠障碍。应激生活事件被认为是主要因素，因为失眠症患者表现出应激激素水平的变化，相反，应激神经肽可以诱导实验性失眠。然而，人们对压力对睡眠-觉醒周期的影响的中枢通路知之甚少。腹外侧视前核(VLPO)的激活是产生正常睡眠所必需的，而在清醒时，VLPO受到来自觉醒促进区的输入的强烈抑制。已经提出睡眠-觉醒周期的稳定性取决于VLPO和觉醒促进区之间的相互抑制作用。睡眠结构的改变，例如在失眠中观察到的变化，很可能涉及睡眠-唤醒回路的神经元活动的变化。动物模型对于研究失眠时应激和睡眠-觉醒回路之间的解剖和功能关系可能非常有用。我们建议使用急性暴露于导致一过性失眠的心理应激源作为一个简单的模型来研究压力对睡眠-觉醒回路所引起的基本功能变化。我们的假设是，失眠是由应激敏感的特定抑制性VLPO传入激活引起的VLPO活性降低引起的。本研究的目的是确定：(1)特定的VLPO传入是否在应激性失眠时被激活；(2)它们是否为VLPO提供抑制性输入；(3)选择性地破坏这些传入是否能减轻一过性失眠。了解应激诱导的短暂性失眠的生物学机制将为未来的慢性失眠研究提供一个基本的框架，并将有助于确定更具体的药物治疗的靶点。

DESCRIPTION (provided by candidate): Primary insomnia is the most prevalent sleep disorder in the general population. Stressful life events have been proposed as major factors since insomniacs show alterations in stress hormone levels and, conversely, experimental insomnia can be induced by stress neuropeptides. Nevertheless, little is known about the central pathways underlying the effects of stress on the sleep-wake cycle. Activation of the ventrolateral preoptic nucleus (VLPO) is necessary to produce normal sleep, whereas during wakefulness the VLPO is strongly inhibited by inputs from wake-promoting areas. It has been proposed that the stability of the sleep-wake cycle depends on reciprocal inhibitory interactions between the VLPO and wake-promoting areas. Alterations of sleep architecture, such as those observed in insomnia, most likely involve changes in the neuronal activity of the sleep-wake circuitry. Animal models may be very useful to study the anatomical and functional relation between stress and sleep-wake circuits during insomnia. We propose to use acute exposure to a psychological stressor that causes transient insomnia as a simple model to study the basic functional changes elicited by stress on the sleep-wake circuitry. Our hypothesis is that insomnia is caused by decreased VLPO activity evoked by activation of specific inhibitory VLPO afferents that are stress-sensitive. The aims of this proposal are to determine whether: (1) specific VLPO afferents are activated during stress-induced insomnia, (2) they provide inhibitory inputs to VLPO, and (3), selective destruction of these afferents attenuates transient insomnia. Understanding the biological mechanisms underlying stress-induced transient insomnia will provide an essential framework for future studies of chronic insomnia and will help to identify targets for more specific pharmacological treatments.