Basal forebrain parvalbumin neurons regulate attention by controlling cortical oscillations

基底前脑小清蛋白神经元通过控制皮质振荡来调节注意力

• 批准号: 9905923
• 负责人: Felipe Lopes Schiffino
• 金额: $ 7.19万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905923
• 关键词: Address; Alzheimer' s Disease; Arousal; Attention; Attentional deficit; Award; Behavioral; Behavioral Paradigm; Cognition; Communication; Cues; Data; Dementia; Detection; Disease; Electrophysiology (science); Etiology; Event; Fatigue; Frequencies; Functional disorder; Goals; Impairment; Knowledge; Learning; Light; Maintenance; Measures; Medial; Mediating; Mental disorders; Mentorship; Motivation; Mus; Neurodegenerative Disorders; Neurons; Parietal Lobe; Parvalbumins; Pattern; Performance; Prefrontal Cortex; Procedures; Psychological reinforcement; Reaction Time; Regulation; Research; Rodent; Role; Self Stimulation; Sensory; Signal Transduction; Site; Sleep Deprivation; Source; Stimulus; Subgroup; System; Task Performances; Techniques; Testing; Time; Training; Visual Cortex; Work; alertness; basal forebrain; basal forebrain cholinergic neurons; behavior test; brain circuitry; career; classical conditioning; design; experimental study; improved; medical schools; multimodality; neuromechanism; neuropsychiatric disorder; new therapeutic target; novel; optogenetics; prevent; professor; reinforcer; response; sensory stimulus; signal processing; sustained attention; vigilance

Deficits in attention are a major feature of many neurodegenerative and neuropsychiatric diseases. Thus, understanding the brain circuitry underlying attention is important to develop novel treatments. Dysfunction and degeneration of basal forebrain (BF) neurons are early features of these diseases. Previous studies have suggested that cholinergic BF neurons are important in attention and their loss contributes to attention deficits. However, the majority of BF neurons are non-cholinergic and little is known about their role in cognition. Here, we use state-of-the-art optogenetic techniques in combination with cortical local field potential (LFP) recordings and behavioral paradigms in mice to test the role of one non-cholinergic subtype, basal forebrain parvalbumin neurons (BF PV), in attention for the first time. Our group and others have shown that BF PV neurons control fast cortical oscillations. These oscillations are associated with increased levels of arousal, alertness, and attention, but direct behavioral tests implicating BF PV for functions in attention are lacking. This proposal will address that gap in our knowledge by demonstrating that regulation of cortical oscillations by BF PV neurons is important for two domains of attention (Aim 1. Attention for Action; Aim 2. Attention for Learning). The first aim will assess the role of BF PV neurons in promoting levels of sustained attention needed for optimal performance in signal detection tasks. We predict that BF PV optogenetic excitation with specific parameters (tonic vs patterned frequency) and during specific task epochs (prior to vs coincident with signals) will entrain cortical oscillations to enhance performance in attentional challenges and ameliorate vigilance decrements incurred either by sleep deprivation or time-on- task. Furthermore, we predict that BF PV optogenetic inhibition will impair maintenance of attention and mimic the effects of sleep deprivation. The second aim will show that BF PV neurons modulate learning by altering the attentional salience of sensory stimuli. Research under this aim will use classical conditioning procedures to show that BF PV activity underlies cortical processing of prediction error, the discrepancy between predicted events and actual events, and that bidirectional optogenetic modulation of BF PV activity can promote with excitation or disrupt with inhibition the allocation of attention to cues for the purposes of learning. The training plan for this award includes mentorship from an expert team of Harvard Medical School professors specializing in BF mechanisms in arousal, attention, and cortical oscillations. Indeed, the proposed training on advanced signal processing and electrophysiological analysis techniques will prove invaluable for an independent research career studying systems level neural mechanisms of attention.

注意力缺陷是许多神经退行性疾病和神经精神疾病的主要特征。因此， 了解注意力背后的大脑回路对于开发新的治疗方法非常重要。功能障碍和 基底前脑（BF）神经元的退化是这些疾病的早期特征。之前的研究有 表明胆碱能 BF 神经元对注意力很重要，它们的损失会导致注意力缺陷。 然而，大多数 BF 神经元是非胆碱能的，人们对它们在认知中的作用知之甚少。这里， 我们使用最先进的光遗传学技术与皮质局部场电位 (LFP) 记录相结合 和小鼠行为范例，以测试一种非胆碱能亚型——基底前脑小白蛋白的作用 神经元（BF PV），首次受到关注。 我们的小组和其他人已经证明 BF PV 神经元控制快速的皮质振荡。这些振荡 与觉醒、警觉性和注意力水平的提高有关，但直接行为测试表明 缺乏注意力功能的 BF PV。该提案将通过以下方式解决我们的知识差距： 证明 BF PV 神经元对皮质振荡的调节对于两个注意力领域很重要 （目标 1. 关注行动；目标 2. 关注学习）。第一个目标是评估 BF PV 神经元的作用 提高信号检测任务最佳性能所需的持续注意力水平。我们预测 BF PV 光遗传学激发具有特定参数（强直与图案频率）并且在特定期间 任务时期（在与信号同时发生之前或同时）将引发皮质振荡，以增强以下方面的表现： 注意力挑战并改善因睡眠不足或长时间睡眠而导致的警惕性下降 任务。此外，我们预测 BF PV 光遗传学抑制将损害注意力和模仿的维持 睡眠不足的影响。第二个目标将表明 BF PV 神经元通过改变 感官刺激的注意力显着性。该目标下的研究将使用经典调节程序 表明 BF PV 活动是预测误差的皮层处理的基础，预测之间的差异 事件和实际事件，并且 BF PV 活动的双向光遗传学调节可以促进 为了学习的目的，激发或抑制对线索的注意力分配。培训内容 该奖项的计划包括由哈佛医学院教授组成的专家团队提供指导 BF 机制中的唤醒、注意力和皮质振荡。事实上，拟议的高级培训 信号处理和电生理分析技术对于独立的研究将被证明是无价的。 研究生涯研究注意力的系统级神经机制。