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: 10613580
• 负责人: Hirofumi Morishita
• 金额: $ 55.15万
• 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/10613580
• 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; Fiber; Fragile X Syndrome; Frequencies; Gene Expression; Genes; Genetic; Goals; Image; Intervention; Knockout Mice; 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; attentional modulation; cingulate cortex; cognitive function; extrastriate visual cortex; improved; in vivo; insight; knock-down; neural; neuropsychiatric disorder; optogenetics; overexpression; patch clamp; response; risk variant; sensory integration; 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凝聚力活动。长程皮质-皮质 预测通过整合来自各种输入的信息然后转发它来促进此类网络活动 到其他皮质区域。特别重要的是进化上保守的自上而下的预测 前额叶皮层 (PFC) 到感觉视觉皮层 (VIS)，整合了感觉、运动和认知功能 调节感觉处理的信息。保守的 PFC->VIS 投影调节 VIS 反应 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该回路 可以增强视觉辨别灵敏度。值得注意的是，PFC 对 VIS 活动的调节存在普遍缺陷。 据报道，存在神经发育和精神疾病，并且经常在儿童期和儿童期后出现 青春期。然而，对长程皮层回路发育过程的了解有限，阻碍了 对这些情况的进一步病理生理学了解。本研究的目的是确定发育 PFC 电路的机制，介导自上而下的注意力网络和行为控制。这里我们测试一下 假设自上而下的 PFC->VIS 皮质回路需要 Lynx1，发育调节的烟碱 调节器依赖的青少年在局部/远程输入平衡中的转变以协调时间 PFC 和 VIS 之间的动态调节注意力行为，Lynx1 调节可以改善顶部- 具有神经发育障碍风险基因的小鼠的下调电路缺陷。我们将通过以下方式检验他的假设 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 在与翻译相关的触摸屏系统中测试小鼠，以评估自然自由活动期间的注意力 移动行为。