Thalamic gating during sleep oscillations

背景：我对了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质现象。几乎所有到达大脑皮层的信息都通过丘脑传递，丘脑是了解皮质功能的关键因素。感觉丘脑和丘脑皮质系统(体感、视觉等)的形态和生理学是已知的。然而，丘脑中线核(MTN)的作用在很大程度上仍不清楚。来自这些核团的神经元可能负责产生意识状态和无意识状态以及不同程度的警觉。我建议不仅研究这些神经元如何参与大脑状态的产生，而且研究它们兴奋性的改变如何影响行为表现。目的：(1)评估MTN的主要抑制来源；(2)比较MTN在脑激活状态(觉醒、REM睡眠)和慢波睡眠时的活动模式；(3)控制MTN的兴奋性，影响睡眠-觉醒状态的表达和行为表现。方法：(1)逆行标记确定MTN的主要输入，结合光发生刺激和电生理记录。(2)脑振荡状态(主要是麻醉状态)下MTN神经元的细胞内记录。(3)记录不同警戒状态下MTN神经元的放电。(4)MTN兴奋性的药物遗传调节及其对睡眠-觉醒周期和行为表现的影响。来源和可行性：很少有研究MTN；文献中没有这些细胞的细胞内记录。因此，上面提出的一切都将是新的。细胞内记录技术非常复杂，在小鼠身上很难做到。我的实验室率先在非麻醉动物身上进行了细胞内记录；最近还发表了一些论文，其中细胞内记录是在小鼠身上进行的，因此技术上复杂的实验似乎是可行的。知识的进步：关于MTN神经元在脑功能中的作用的系统知识尚不存在。我们提出了一系列实验来研究这些核团在警觉状态和整体警觉状态的产生中所起的作用。

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.