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（例如睡眠呼吸暂停）会导致白天过度嗜睡并受损 注意力和认知障碍的症状现在被认为是导致注意力和认知障碍的主要原因。 事故率和工作效率下降也是注意力、注意力和认知问题。 美国退伍军人中常见的其他疾病的一个主要特征——例如创伤性脑损伤、创伤后应激障碍、阿尔茨海默氏病、 了解控制注意力的大脑回路。 将指导改善这些疾病的认知障碍的治疗方法的开发。 有证据表明基底前脑 (BF) 区域包含皮质突出和促进觉醒的区域 对于皮质激活、行为唤醒/警觉性和注意力很重要的神经元。 工作重点是 BF 胆碱能神经元在注意力中的作用，光遗传学方法的进步使得 含 GABA 神经元的 BF 小白蛋白 (PV) 的研究。 我目前的优异资助工作表明，选择性激发小鼠 BF PV 神经元会产生 我们的新数据表明 BF PV 神经元的兴奋。 提高警惕性，以挽救因睡眠不足而导致的反应时间缺陷，并增强 依赖注意力的联想学习而不影响动机（即饥饿，潜在的副作用）或 我们解释这些发现的首要假设是 BF PV 神经元。 通过快速激活皮层来预测或响应，从而介导警觉性/注意力的快速变化 用于评估这一假设的有意义或令人惊讶的感官刺激的研究方法包括 i) 纤维。 光度测定法测量 BF PV 神经元的活性，ii) 光遗传学方法激发或抑制 小鼠的这些神经元；这两种方法都与行为测试和皮层电测量相结合 该基础科学项目的转化意义在于 BF PV 激励可用于 增强认知，副作用有限且滥用可能性低。 该研究计划的总体目标是了解基底前脑的机制 皮质活动和认知的调节可能导致治疗影响大脑功能的各种疾病 例如，上述 BF PV 模型的促认知特性很容易被理解。 应用于美国退伍军人群体中流行的其他疾病小鼠模型，包括 事实上，其他正在进行的研究还包括阿尔茨海默病（AD）和创伤性脑损伤（TBI）。 研究员（Felipe Schiffino 博士）和合作者（Jay McNally 和 Lee Goldstein 博士）正在测试 BF PV 激励 AD 和 TBI 小鼠模型的益处。 1