Thalamic gating during sleep oscillations

背景：我对理解意识状态的生理基础很感兴趣，意识状态本质上是一种皮层现象。几乎所有到达大脑皮层的信息都要经过丘脑，这是理解皮层功能的一个关键因素。感觉丘脑和丘脑皮质系统（体感、视觉等）的形态学和生理学是已知的。然而，中线丘脑核（MTN）的作用在很大程度上仍然不清楚。来自这些核的神经元可能负责产生有意识和无意识状态以及不同程度的警觉性。我建议不仅要研究这些神经元如何与大脑状态的产生有关，还要研究它们的兴奋性的改变如何影响行为表现。***目的：(1)评估MTN抑制的主要来源；(2)评估脑激活状态（清醒、快速眼动睡眠）与慢波睡眠时MTN的活动模式；(3)操纵MTN的兴奋性，影响睡眠-清醒状态的表达和行为表现。***假设：来自MTN的丘脑皮层神经元控制皮层兴奋性并介导睡眠和觉醒等状态的产生。它们控制着警觉性水平。***方法：(1)逆行标记确定MTN的主要输入，结合光遗传刺激和电生理记录。(2) MTN神经元在脑振荡状态（主要是麻醉状态）的胞内记录。(3) MTN神经元在不同警戒状态下的神经元放电记录。(4) MTN兴奋性的药理学调控及其对睡眠-觉醒周期和行为表现的影响。***原创性和可行性：很少有研究调查MTN；在文献中没有这些细胞的细胞内记录。因此，以上提出的一切都将是新的。细胞内记录技术非常复杂，很难在小鼠身上进行。我的实验室率先在未麻醉的动物身上进行细胞内记录；它最近还发表了一些论文，其中对老鼠进行了细胞内记录，因此技术上复杂的实验似乎是可行的。***对知识进步的贡献：关于MTN神经元在脑功能中的作用的系统知识尚不存在。我们提出了一系列的实验来研究这些核在警觉性和整体警觉性状态的产生中起什么作用。

Background: I am interested in the understanding of physiological basis of conscious states, which are essentially cortical phenomena. Almost all information reaching cerebral cortex passes through the thalamus that is a key element in the understanding of cortical function. Morphology and physiology of sensory thalamus and thalamocortical system (somatosensory, visual etc) is known. However, the role of midline thalamic nuclei (MTN) remains largely obscure. Neurons from these nuclei are likely responsible for the generation of conscious vs. unconscious states and different levels of alertness. I propose to investigate not only how these neurons are implicated in the generation of brain states, but also how a modification of their excitability could affect behavioral performance. ***Objectives: (1) To evaluate the main sources of inhibition in MTN, (2) to evaluate patterns of activity of MTN during brain activated states (wake, REM sleep) vs. slow-wave sleep, (3) to manipulate MTN excitability and to affect the expression of sleep-wake states and behavioral performance.***Hypothesis: Thalamocortical neurons from MTN provide control of cortical excitability and mediate generation of states, like sleep and wake. They control levels of alertness.***Methods: (1) Retrograde labeling to determine the main inputs to MTN, combined with optogenetic stimulation and electrophysiological recordings. (2) Intracellular recordings in vivo from MTN neurons during brain oscillatory states (mainly anesthesia). (3) Neuronal firing recording from MTN neurons during different states of vigilance. (4) Pharmacogenetic modulation of MTN excitability and its effects on sleep-wake cycle as well as behavioral performance.***Originality and feasibility: Very few studies investigated MTN; no intracellular recordings from these cells are available in the literature. Therefore, everything proposed above will be new. Intracellular recording technique is very complex and difficult to do on mice. My laboratory pioneered intracellular recordings in non-anesthetized animals; it also recently published a number of papers where intracellular recordings were done on mice, therefore the technically complex experiments appear feasible.***Contribution to the advancement of knowledge: Systematic knowledge on the role of MTN neurons in brain functions does not exist. We propose series of experiments to investigate what role these nuclei play in the generation of states of vigilance and overall alertness.