BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10618193
• 负责人: ROBERT E STRECKER
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618193
• 关键词: Accidents; Adenosine; Adopted; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Area; Arousal; Association Learning; Attention; Award; Basic Science; Behavior; Behavioral; Binding Proteins; Caffeine; Cardiovascular Diseases; Chronic Insomnia; Clinical; Cognition; Cognitive; Data; Diabetes Mellitus; Disease; Disease model; Drowsiness; Electroencephalography; Excessive Daytime Sleepiness; Fiber; Frequencies; Funding; Goals; Grant; Health; Healthcare; Hunger; Hypercapnia; Impaired cognition; Impairment; In Vitro; Incidence; Instruction; Investigation; Ketamine; Lead; Measures; Mediating; Mental Depression; Methods; Microdialysis; Modeling; Motivation; Mus; Neurodevelopmental Disorder; Neuromodulator; Neurons; Paper; Parkinson Disease; Parvalbumins; Pharmaceutical Preparations; Photometry; Physiological; Physiology; Population; Post-Traumatic Stress Disorders; Productivity; Property; Psychotic Disorders; Publishing; Purinergic P1 Receptors; Reaction Time; Regulation; Research; Research Methodology; Research Personnel; Rewards; Role; Schizophrenia; Science; Scientist; Seminal; Senile Plaques; Short-Term Memory; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Substance Use Disorder; Symptoms; Techniques; Technology; Testing; Therapeutic; Time; Traumatic Brain Injury; Veterans; Wakefulness; Work; Workplace; abuse liability; alertness; antagonist; attentional control; auditory stimulus; basal forebrain; basal forebrain cholinergic neurons; behavior measurement; behavior test; biochemical tools; brain circuitry; career; cell type; cholinergic; cholinergic neuron; cognitive performance; in vivo; military veteran; mouse model; neuropsychiatric disorder; optogenetics; pharmacologic; programs; receptor; response; sensory stimulus; side effect; therapeutic target; therapy development

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

睡眠丧失和睡眠障碍（例如睡眠呼吸暂停）会导致白天嗜睡和障碍 注意与认知。现在，睡眠障碍的症状被认为是 事故率和提高工作场所生产率。注意，集中和认知问题也是 美国退伍军人普遍存在的其他疾病的主要特征 - 例如TBI，PTSD，阿尔茨海默氏病， 抑郁症，药物使用障碍和精神分裂症。了解控制注意力的大脑电路 将指导治疗的发展，以减轻这些疾病的认知障碍。丰富 证据表明，基本前脑（BF）区域包含皮质突出和清醒促进 对于皮质激活，行为唤醒/警觉性和注意力很重要的神经元。虽然以前 工作的重点是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 含有GABA能神经元的BF白蛋白（PV）的投资。 在我当前的功绩赠款上的工作表明，小鼠生产中BF PV神经元的选择性兴奋 皮质激活，清醒和行为唤醒。我们的新数据表明，BF PV神经元的兴奋 增强对救援反应时间的注意力定义，这是由睡眠丧失产生的，也可以增强 依赖注意力的社会学习而不会影响动机（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总体假设是BF PV神经元 通过预期或回应快速激活皮质来介导警报/注意力的快速变化 为了有意义或令人惊讶的感觉刺激。评估该假设的研究方法包括i）光纤 测量BF PV神经元活性的光度法，以及II）刺激或抑制的光遗传学方法 这些神经元在小鼠中；两种方法都与行为测试和皮质电气测量结合 活动。这个基础科学项目的转化相关性是，BF PV兴奋可用于 增强认知能力有限，副作用有限，滥用潜力低。 该研究计划的总体目标是了解基本前脑的机制 对皮质活动和认知的调节，这可能导致对影响各种疾病的治疗 美国退伍军人。例如，上述BF PV模型的亲认知特性可以很容易地 适用于在美国退伍军人人口中普遍存在的其他疾病的老鼠模型 阿尔茨海默氏病（AD）和创伤性脑损伤（TBI）。确实，其他正在进行的研究 研究员（Felipe Schiffino博士）和合作者（Jay McNally和Lee Goldstein博士）正在测试BF PV兴奋 在AD和TBI的小鼠模型中受益。 1