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 将指导治疗方法的开发，以改善这些疾病的认知障碍。富饶 有证据表明，基底前脑(BF)区含有皮层投射和觉醒促进作用。 对皮质激活、行为觉醒/警觉和注意力很重要的神经元。虽然之前 研究的重点是BF胆碱能神经元在注意中的作用，光遗传学方法的进步允许 含GABA能神经元的BF小白蛋白(PV)的研究 我目前对奖金的研究表明，选择性兴奋小鼠的BF PV神经元产生 大脑皮层激活、清醒和行为唤醒。我们的新数据显示，BF-PV神经元的兴奋 提高对因睡眠不足而导致的救援反应时间不足的警惕，并提高 注意力依赖的联想学习，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最重要的假设是BF PV神经元 通过快速激活大脑皮质来调节警觉性/注意力的快速变化 对、有意义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 测量BF PV神经元活性的光度法，以及，II)激发或抑制光遗传学的方法 这两种方法都结合了行为学测试和皮层电信号的测量 活动。这个基础科学项目的翻译相关性是，BF光伏激发可能用于 增强认知，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。 对皮质活动和认知的调节，这可能导致治疗各种影响 我们退伍军人。例如，上述BF PV模型的先验认知属性可以容易地 应用于在美国退伍军人群体中流行的其他小鼠疾病模型，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和研究 费利佩·希菲诺博士和合作者(杰伊·麦克纳利博士和李·戈尔茨坦博士)正在测试高炉光伏的励磁 对阿尔茨海默病和脑外伤小鼠模型的益处。 1