Mechanisms regulating the maturation of prefrontal top-down circuitry in control of attentional behavior

控制注意力行为的前额叶自上而下电路成熟的调节机制

• 批准号: 9973170
• 负责人: Hirofumi Morishita
• 金额: $ 58.05万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973170
• 关键词: Adolescence; Adolescent; Adult; Animals; Anterior; Area; Attention; Attentional deficit; Behavior; Behavioral; Brain; Calcium; Childhood; Cognitive; Data; Development; Diagnosis; Discrimination; Disease; Distal; Equilibrium; FMR1; FMRP; Fiber; Fragile X Syndrome; Frequencies; Gene Expression; Genes; Goals; Image; Intervention; Knowledge; Macaca; Maps; Measures; Mediating; Mental disorders; Methods; Molecular; Motor; Mus; Neurodevelopmental Disorder; Neurons; Photometry; Prefrontal Cortex; Process; Rabies; Reaction Time; Reporting; Role; Sensory; Slice; System; Techniques; Testing; Viral; Visual; Visual Cortex; Visual attention; attentional control; base; cingulate cortex; cognitive function; cohesion; extrastriate visual cortex; improved; in vivo; insight; knock-down; neuropsychiatric disorder; optogenetics; overexpression; patch clamp; relating to nervous system; response; risk variant; touchscreen; transcriptome; visual stimulus

Cognitive function relies on the cohesive activity of large-scale networks. Long-range cortico-cortical projections facilitate such network activities by integrating information from various inputs and then relaying it to other cortical regions. Of particular significance is the evolutionarily conserved top-down projection from prefrontal cortex (PFC) to sensory visual cortex (VIS) which integrates sensory, motor, and cognitive information to modulate sensory processing. Conserved PFC->VIS projections regulate VIS responses to visual stimuli in attention based tasks in macaque, and optogenetic manipulation in mice shows that this circuit can enhance visual discrimination sensitivity. Notably, deficits in PFC modulation of VIS activity are pervasively reported in neurodevelopmental and psychiatric disorders, and often emerge following childhood and adolescence. Yet limited knowledge of processes governing long-range cortical circuit development hinders further pathophysiological insight into these conditions. The goal of this study is to identify the developmental mechanisms of PFC circuitry that mediate top-down control of attentional network and behavior. Here we test the hypothesis that top-down PFC->VIS cortical circuits require a Lynx1, developmentally regulated nicotinic modulator,-dependent adolescent shift in the balance of local/long-range inputs to coordinate temporal dynamics between PFC and VIS modulate attentional behavior, and that Lynx1 modulation can ameliorate top- down circuit deficits in mice with a risk gene of neurodevelopmental disorders. We will test his hypothesis by integrating techniques to measure and manipulate neural activity and gene expression within specific circuits of mice tested in a translationally-relevant touchscreen system to assess attention during naturalistic freely- moving behavior.

认知功能依赖于大规模网络的内聚活动。长程皮质-皮质 预测通过综合来自各种投入的信息并加以传播，促进了这种网络活动 到其他皮层区域。特别重要的是进化上保守的自上而下的投影， 前额叶皮层（PFC）到感觉视觉皮层（维斯），其整合感觉、运动和认知 信息来调节感觉处理。保留PFC->维斯预测调节维斯响应， 猕猴注意力任务中的视觉刺激和小鼠的光遗传学操作表明， 可增强视觉辨别灵敏度。值得注意的是，维斯活性的PFC调节缺陷普遍存在于 据报道，在神经发育和精神疾病，并经常出现以下儿童和 青春期然而，对控制长程皮层回路发育的过程的有限知识阻碍了 进一步的病理生理学洞察这些条件。这项研究的目的是确定发展的 PFC电路介导注意力网络和行为的自上而下控制的机制。在这里我们测试 自上而下的PFC->维斯皮层回路需要Lynx 1、发育调节的烟碱神经元， 调制器，依赖性青少年在局部/长程输入平衡中的转变，以协调时间 PFC和维斯之间的动力学调节注意行为，Lynx 1调节可以改善顶部- 在具有神经发育障碍风险基因的小鼠中，我们将测试他的假设， 整合技术来测量和操纵特定回路内的神经活动和基因表达， 在实验相关的触摸屏系统中测试小鼠，以评估在自然的自由状态下的注意力， 移动的行为。