BLRD Research Career Scientist Award Application

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，以改善这些条件的认知障碍。丰富 有证据表明，基底前脑（BF）区域含有皮质投射和觉醒促进功能， 这些神经元对于皮层激活、行为唤醒/警觉和注意力是重要的。尽管先前 工作集中在BF胆碱能神经元在注意力中的作用，光遗传学方法的进展允许 BF小清蛋白（PV）GABA能神经元的研究。 我目前的优异奖研究表明，选择性激发小鼠BF PV神经元， 皮层激活、清醒和行为唤醒。我们的新数据表明，BF PV神经元的兴奋 提高警惕注意力，以挽救睡眠不足产生的反应时间不足， 注意力依赖的联想学习，而不影响动机（即饥饿，潜在的副作用），或 奖励（即滥用潜力）。我们解释这些发现的首要假设是，BF PV神经元 通过预期或响应快速激活皮层来调节警觉性/注意力的快速变化 有意义的或令人惊讶的感官刺激。用于评估这一假设的研究方法包括i）纤维 光度法来测量BF PV神经元的活性，和，ii）光遗传学方法来激发或抑制 这两种方法都结合了行为测试和皮层电测量， 活动这个基础科学项目的翻译相关性是，BF PV激发可用于 增强认知能力，副作用有限，滥用可能性低。 这项研究计划的首要目标是了解基底前脑的机制， 调节皮质活动和认知，这可能导致治疗各种疾病，影响 美国退伍军人。例如，上述BF PV模型的促认知特性可以容易地被解释为： 适用于美国退伍军人群体中流行的疾病的其他小鼠模型，包括 阿尔茨海默病（AD）和创伤性脑损伤（TBI）。事实上，其他正在进行的研究 研究员（Felipe Schiffino博士）和合作者（Jay McNally博士和Lee Goldstein博士）正在测试BF PV激发 AD和TBI小鼠模型的益处。 1

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 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 my current Merit grant indicates that selective excitation of BF PV neurons in mice produces cortical activation, wakefulness, and behavioral arousal. Our new data show that excitation of BF PV neurons enhances vigilant attention to rescue reaction time deficits produced by sleep loss and also enhances attention-dependent associative learning without affecting motivation (i.e. hunger, a potential side effect) or reward (i.e. abuse potential). Our overarching hypothesis to explain these findings is that BF PV neurons mediate rapid changes in alertness/attention by quickly activating the cortex in anticipation of, or in response to, meaningful or surprising sensory stimuli. Research methods used to evaluate this hypothesis include i) fiber photometry to measure the activity of BF PV neurons, and, ii) optogenetic methods to either excite or inhibit these neurons in mice; both approaches are combined with behavioral tests and measures of cortical electrical activity. The translational relevance of this basic science project is that BF PV excitation may be used to enhance cognition with limited side effects and low abuse potential. The overarching goal of this research program is to understand the mechanisms of basal forebrain regulation of cortical activity and cognition which could lead to treatments for a variety of disorders that impact US Veterans. For example, the pro-cognitive properties of the BF PV model described above can be readily applied to additional mouse models of diseases that are prevalent in the US Veteran population including Alzheimer’s disease (AD) and traumatic brain injury (TBI). Indeed, other ongoing studies with research fellow (Dr. Felipe Schiffino) and collaborators (Drs. Jay McNally & Lee Goldstein) are testing BF PV excitation benefits in mouse models of AD and TBI. 1