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衔接活动。远程皮质-皮质 投影通过整合来自各种输入的信息，然后将其转发，从而促进了这种网络活动 转移到其他皮质区域。特别重要的是进化上守恒的自上而下的投影 前额叶皮质(PFC)到感觉视觉皮质(VIS)，它整合了感觉、运动和认知 调节感觉加工的信息。保守的PFC-&>VIS投射调节VIS反应 猕猴基于注意的任务中的视觉刺激，以及小鼠的光遗传操作表明，这一回路 可以提高视觉辨别灵敏度。值得注意的是，在调节VIS活性的PFC方面的缺陷是普遍存在的 有神经发育和精神障碍的报道，通常出现在儿童和 青春期。然而，对控制远程大脑皮层回路发育的过程的有限知识阻碍了 进一步了解这些病症的病理生理学特征。本研究的目的是找出发展中的 调节注意网络和行为自上而下控制的PFC电路的机制。我们在这里测试 假设自上而下的PFC-VIS皮层环路需要发育调节的尼古丁 调节器，依赖于青少年在局部/远程输入平衡中的变化，以协调时间 PFC和VIS之间的动力学调节注意行为，而Lynx1调制可以改善TOP- 携带神经发育障碍风险基因的小鼠出现回路缺陷。我们将通过以下方式验证他的假设 集成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，以评估自然自由期间的注意力- 移动的行为。