Role of the basal forebrain in sleep loss induced attention impairments

睡眠丧失和睡眠障碍（例如，睡眠呼吸暂停）导致白天过度嗜睡 注意力和认知。睡眠障碍的症状现在被认为是睡眠障碍的主要原因。 事故率和工作场所生产力下降。注意力、集中力和认知问题也是 在美国退伍军人中流行的其他疾病的主要特征-例如，创伤性脑损伤创伤后应激障碍老年痴呆症 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，以改善这些人的注意力和认知障碍， 条件大量的证据表明基底前脑（BF）区域包含皮质投射& 促进觉醒的神经元，对皮层激活、行为唤醒/警觉性和 关注虽然以前的工作主要集中在BF胆碱能神经元在注意力中的作用， 光遗传学方法允许研究含有GABA能神经元的BF小清蛋白（PV）。工作 我们目前的优异奖助金表明小鼠中BF PV神经元的选择性激发产生皮质激活， 清醒和行为唤起我们新的初步数据表明，BF PV神经元的兴奋可以 增强注意力、认知能力，并挽救因睡眠不足而造成的反应时间表现障碍。 所描述的发现使我们得出两个可检验的假设：1）BF PV神经元介导了BPV的快速变化。 通过对有意义或令人惊讶的感官刺激做出反应而快速激活皮层来提高警觉性/注意力。 2)BF PV神经元的兴奋不会改变动机（例如，饥饿），而不是奖励表明这些 神经元可以增强注意力和认知，副作用有限，成瘾潜力低。我们的模型 预测：为了响应有意义或令人惊讶的感觉刺激，BF PV神经元短暂激活皮层， 增强皮层处理和警觉性，促进注意力依赖的反应时间表现 和联想学习。这项工作将解决我们知识上的一个空白， BF PV神经元的皮质激活对于注意力的控制是重要的。使用的方法包括纤维 光度法测量BF PV神经元的活性，光遗传学激发和抑制这些神经元， 小鼠;两者都将与行为测试和皮质电活动的测量相结合。这三个目标是： 目的1：通过观察BF PV神经元活动的变化，证实BF PV神经元活动的增加和减少可以调节皮层神经元的活动 对重复出现的感觉刺激的反应。这一发现将提供一个合理的机制， 这些神经元如何增强目标2和3中研究的注意力依赖行为表现。 目的2将证明BF PV激发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于检测困倦和持续注意力缺陷的测试。 实验将证明，睡眠剥夺（SD）和BF PV抑制减慢反应时间，而 BF PV激发将加快反应时间，并将挽救SD产生的缺陷。 目标3。注意力对学习也很重要，这里BF PV操作用于改变注意力 这是联想学习所需要的。我们的预测，初步数据支持，是BF PV激发 通过向大脑皮层发送“惊喜”信号来增强联想学习， 频率皮层伽马振荡，BF PV兴奋不影响奖励途径。我们也 预测BF PV抑制和SD会损害注意依赖性联想学习。 如果成功，该项目将表明BF PV神经元激发模型增强了注意力， 副作用有限，成瘾潜力低。该模型可以很容易地应用于小鼠 美国退伍军人群体中普遍存在的其他条件的模型。未来的工作还可以确定 新的治疗剂可将BF PV神经元上的受体靶向以激活它们。

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.