Neural Correlates of Sleep Homeostasis

本研究的主要目的是确定稳态睡眠背后的神经底物(S) 反应(HSR)，即长期睡眠剥夺(SD)后昏昏欲睡。SD由以下人员经历 许多是由于生活方式或职业需求，并伴随着认知障碍，冲动增加， 事故发生的可能性也增加了。此外，睡眠中断是许多疾病的共同特征 神经精神障碍。因此，了解高铁背后的机制对开发高铁至关重要 对抗可持续发展有害后果的措施。具体地说，这里我们将讨论中央 问：“是不是所有的神经唤醒系统在触发高铁中都同样重要？”我们最重要的是 假设基底前脑(BF)胆碱能神经元(ChAT+)受谷氨酸调节并发挥作用。 通过导致细胞外腺苷(ADEX)的释放而在HSR中扮演特权角色，ADEX通过以下方式增加睡眠 抑制促进觉醒的BF神经元，从而将系统的状态调整为接近其设定点。 为了实现这一目标，目标1将测试BF胆碱能神经元，但不测试脑干桥脑脚被盖 (Ppt)胆碱能神经元是HSR所必需的。目标2将检验这一假设，即在高炉内，只有那些非 胆碱能觉醒促进神经元投射和兴奋BF ChAT+神经元将诱发HSR。目标3 将测试刺激唤醒BF-vGluT2+和PPT-vGluT2+神经元是否仅在BF ChAT+神经元是完整的，即BF ChAT+神经元的完整性是触发HSR所必需的。最后，瞄准 4将测试BF ChAT+神经元在促进觉醒和睡眠动态平衡方面的双重作用。我们将使用我们的 结合对选择性神经元的光学操作的新型小鼠“光透析”探针(Zant等人，2016) 体内微透析检测局部神经化学变化和/或应用 药理制剂。这些调查的成功完成将加深我们对 诱导HSR所需的神经底物，从而有助于开发有针对性的 针对失眠有害影响的药物干预。

The broad objective of this study is to identify the neural substrate(s) underlying the homeostatic sleep response (HSR), i.e. enhanced sleepiness following prolonged sleep deprivation (SD). SD is experienced by many due to lifestyle or vocational demands and is accompanied by impaired cognition, increased impulsivity, and an increased likelihood of accidents. Furthermore, disrupted sleep is a common feature of many neuropsychiatric disorders. Thus, understanding the mechanisms underlying the HSR is critical to develop measures to combat the deleterious consequences of SD. Specifically, here we will address the central question: “Are all neural wake-promoting systems equally important in triggering the HSR?” Our overarching hypothesis is that basal forebrain (BF) cholinergic neurons (ChAT+) are modulated by glutamate and play a privileged role in the HSR by causing the release of extracellular adenosine (ADex), which increases sleep by inhibiting wake-promoting BF neurons, and thereby adjusts the state of the system towards its' set point. Towards this goal, Aim 1, will test if BF cholinergic neurons, but not the brainstem pedunculopontine tegmental (PPT) cholinergic neurons, are required for HSR. Aim 2 will test the hypothesis that within BF, only those non- cholinergic wake-promoting neurons projecting to, and exciting, BF ChAT+ neurons will induce HSR. Aim 3 will test if stimulation of wake-promoting BF-vGluT2+ and PPT-vGluT2+ neurons will only induce HSR if BF ChAT+ neurons are intact, i.e. the integrity of BF ChAT+ neurons is necessary to trigger the HSR. Finally, Aim 4 will test the dual role of BF ChAT+ neurons in promoting arousal and sleep homeostasis. We will use our novel mouse `optodialysis' probes (Zant et al., 2016) that combine optical manipulation of selective neuronal populations with in vivo microdialysis for detecting local neurochemical changes and/or application of pharmacological agents. The successful completions of these investigations will further our understanding of the neural substrates necessary for inducing the HSR, and thus will help in developing targeted pharmacological interventions against the deleterious effects of sleep loss.