Role of the basal forebrain in sleep loss induced attention impairments

睡眠不足和睡眠障碍(如睡眠呼吸暂停)会导致白天过度困倦和受损 注意力和认知。睡眠障碍的症状现在被认为是导致睡眠障碍的主要原因 事故率和工作场所生产率下降。注意力、注意力和认知问题也是 在美国退伍军人中普遍存在的其他疾病的一个主要特征--例如，脑外伤、创伤后应激障碍、阿尔茨海默病、 抑郁症、物质使用障碍和精神分裂症。了解控制注意力的大脑回路 将指导治疗的发展，以改善这些患者的注意力和认知障碍 条件。大量证据表明，基底前脑(BF)区含有皮质投射& 促进觉醒的神经元，对皮质激活、行为唤醒/警觉和 请注意。尽管以前的工作主要集中在BF胆碱能神经元在注意中的作用上，但在 光遗传学方法可以研究含有GABA能神经元的BF小白蛋白(PV)。工作于 我们目前的优秀奖表明，选择性兴奋小鼠的BF PV神经元可以产生皮质激活， 清醒和行为唤醒。我们新的初步数据表明，BF PV神经元的兴奋可以 提高注意力、认知力和抢救反应时间表现因睡眠不足而造成的障碍。 这些发现使我们得出了两个可检验的假说：1)BF PV神经元在 通过对有意义的或令人惊讶的感官刺激迅速激活大脑皮层来提高警觉性/注意力。 2)BF PV神经元的兴奋不会改变动机(如饥饿)，也不会有回报。 神经元可以增强注意力和认知能力，副作用有限，成瘾潜力低。我们的模特 预测：作为对有意义或令人惊讶的感觉刺激的反应，BF PV神经元短暂地激活皮质， 增强皮质处理和警觉性，促进注意力依赖反应时表现 和联想学习。这项工作将通过展示监管来解决我们知识中的一个缺口 BF PV神经元对大脑皮质的激活对注意力的控制很重要。使用的方法包括光纤 BF-PV神经元活性的比色法测定及光遗传学对这些神经元的兴奋和抑制 两者都将与行为测试和大脑皮层电活动测量相结合。这三个目标是： 目的1将证明增加和减少BF PV神经元的活动可以调节大脑皮层 对重复呈现的感官刺激的反应。这一发现将提供一种可信的机制 这些神经元如何增强目标2和3中研究的注意力依赖的行为表现。 目标2将证明BF PV兴奋增强小鼠的持续注意力和表现 反应时间测试类似于人类用来检测嗜睡和持续注意力缺陷的测试。 实验将证明，睡眠剥夺(SD)和BF PV抑制会减缓反应时间，而 高炉光伏的激发将加快反应时间，并将挽救SD产生的赤字。 目标3.注意力对于学习来说也很重要，这里使用脑电刺激来改变注意力 联想学习所需要的。我们的预测得到了初步数据的支持，即BF PV激发 通过向大脑皮层广播以高电平编码的“惊喜”信号来增强联想学习 大脑皮层伽马振荡的频率，以及BF PV的兴奋不会影响奖励通路。我们也 预测BF PV抑制和SD将损害注意力依赖型联想学习。 如果成功，这个项目将表明BF PV神经元兴奋模型增强了人们的注意力和 副作用有限，成瘾潜力低的认知能力。该模型可以方便地应用到小鼠身上 美国退伍军人群体中流行的其他疾病的模型。未来的工作也可以确定 以药物靶向BF PV神经元上的受体以激活它们的新疗法。

Sleep loss and sleep disorders (e.g., sleep apnea) lead to excessive daytime sleepiness and impaired attention & cognition. The symptoms of sleep disturbance are now recognized as major contributors to accident rates and decreased workplace productivity. Attention, concentration, and cognitive problems are also a major feature of other disorders that are prevalent in US veterans – e.g., TBI, PTSD, Alzheimer's disease, depression, substance use disorder, and schizophrenia. Understanding the brain circuitry controlling attention will guide the development of treatments to ameliorate the attention and cognitive impairments of these conditions. Abundant evidence indicates that the basal forebrain (BF) region contains cortically projecting & wakefulness promoting neurons that are important for cortical activation, behavioral arousal/alertness, and attention. Although previous work has focused on the role of BF cholinergic neurons in attention, advances in optogenetic methods allow the investigation of BF parvalbumin (PV) containing GABAergic neurons. Work on our current Merit grant indicates that selective excitation of BF PV neurons in mice produces cortical activation, wakefulness, and behavioral arousal. Our new preliminary data suggest that excitation of BF PV neurons can enhance attention, cognition, and rescue reaction time performance impairments produced by sleep loss. The findings described led us to two testable hypotheses: 1) BF PV neurons mediate rapid changes in alertness/attention by quickly activating the cortex in response to meaningful or surprising sensory stimuli. 2) Excitation of BF PV neurons does not alter motivation (e.g., hunger) and is not rewarding indicating these neurons can enhance attention and cognition with limited side effects and low addictive potential. Our model prediction: In response to meaningful or surprising sensory stimuli, BF PV neurons briefly activate the cortex, enhancing cortical processing and alertness which facilitates attention-dependent reaction time performance and associative learning. The work will address a gap in our knowledge by demonstrating that regulation of cortical activation by BF PV neurons is important for the control of attention. Methods used include fiber photometry to measure the activity of BF PV neurons and optogenetics to excite and inhibit these neurons in mice; both will be combined with behavioral tests and measures of cortical electrical activity. The 3 aims are: Aim 1 will demonstrate that increasing and decreasing the activity of BF PV neurons can modulate cortical responses to repetitive presentations of sensory stimuli. This finding will provide a plausible mechanism for how these neurons enhance the attention dependent behavioral performance studied in Aims 2 & 3. Aim 2 will demonstrate that BF PV excitation enhances sustained attention and performance in a mouse reaction time test like the test used in humans to detect sleepiness and sustained attention deficits. Experiments will demonstrate that sleep deprivation (SD) and BF PV inhibition slows reaction times, whereas BF PV excitation will quicken reaction times and will rescue deficits produced by SD. Aim 3. Attention is also important for learning and here BF PV manipulations are used to alter the attention needed for associative learning. Our predictions, supported by preliminary data, are that BF PV excitation enhances associative learning by broadcasting `surprise' signals to the cortex that are encoded in high frequency cortical gamma oscillations, and that BF PV excitation does not affect reward pathways. We also predict that BF PV inhibition and SD will impair attention-dependent associative learning. If successful, this project will show that the BF PV neuron excitation model enhances attention and cognition with limited side effects and low addictive potential. This model can be readily applied to mouse models of other conditions that are prevalent in the US Veteran population. Future work could also identify novel therapeutics to pharmacologically target receptors on BF PV neurons in order to activate them.