Mechanisms regulating developmental critical period for establishing attention

 描述(由申请人提供)：在易感性增加的关键时期，大脑发育异常会导致许多精神疾病的终身认知障碍。驱动关键期电路发育的机制在感觉系统中得到了很好的描述，但在复杂的认知行为中却没有得到很好的描述。识别认知回路和行为的关键时期和潜在机制最终将改善精神障碍的诊断、预防和治疗。这项研究将测试调节视皮层发育关键期的关键机制是否也调节额叶皮质依赖的注意功能的成熟。Lynx1是一种内源性烟碱型乙酰胆碱受体(NAchR)抑制剂，通过其在青春期表达的增加来调节视皮层可塑性的关键期。除了它在以下方面的作用 视觉皮质，我们的初步数据显示，具有高nAChR信号的Lynx1基因敲除小鼠在成年后出人意料地出现注意力缺陷。值得注意的是，这种缺陷只在青春期早期通过短暂抑制nAChR信号来预防，而在成年时并不明显。这项研究将检验最重要的假设，即青春期过多的nAChR信号，通常受到青春期期间Lynx1表达增加的限制，会导致额叶皮质回路和支持注意力的行为的长期损害。了解过量的nAChR信号如何扰乱正常的电路发育，可以为以nAChR信号中断为特征的发育性神经精神疾病提供机械性的洞察，如自闭症、ADHD和精神分裂症。在Aim1中，我们将检验这一假设，即青春期前扣带回皮质中Lynx1的表达是成年人正常注意功能所必需的。我们将准确界定关键时期 以及关键的大脑区域，通过将体内的药物、病毒和遗传基因操作与使用翻译触摸屏系统的5项选择系列反应时间任务(5-CCRTT)相结合，介导过量的nAChR信号对成人注意功能的长期影响。在AIM2中，我们将测试这一假设，即额叶-后部皮质回路需要在青春期被Lynx1抑制的nAChR信号，以在成人中建立注意力。通过引入一种新的病毒系统，允许在感兴趣的时间点进行电路特异性标记和基因操作，将确定Lynx1缺失对从前扣带皮质投射到视觉皮质的神经元的影响，以及Lynx1在这些电路中的细胞自主贡献。在这项研究完成时，我们将定义正常注意功能所需的最佳nAChR信号的发育时间窗口、解剖区域和回路，这被NIMH研究领域标准(RDoC)项目确定为许多精神疾病中认知系统受损的主要结构之一。

 DESCRIPTION (provided by applicant): Aberrant brain development during critical periods of heightened vulnerability contributes to lifelong cognitive impairments underlying many psychiatric disorders. Mechanisms driving critical period circuit development are well described in sensory systems-but poorly characterized for complex cognitive behaviors. Identification of a critical period and underlying mechanisms for cognitive circuits and behavior would eventually improve diagnosis, prevention and treatment of psychiatric disorders. This study will test whether a mechanism critical for regulating the critical period for visual cortex development also modulates maturation of frontal cortex- dependent attentional functions. Lynx1 is an endogenous nicotinic acetylcholine receptor (nAchR) inhibitor and regulates the critical period of visual cortex plasticity by its increased expression across adolescence. In addition to its role in visual cortex, our preliminary data show that the Lynx1 knock-out mice with high nAChR signaling unexpectedly present with attention-deficits in adulthood. Strikingly, this deficit was prevented by transient suppression of nAChR signaling only during early adolescence but not acutely in adulthood. This study will test the overarching hypothesis that the excessive nAChR signaling during adolescence, normally limited by peri-adolescent increase in Lynx1 expression, causes long-lasting impairment in frontal cortical circuits and behaviors that support attention. Understanding how excess nAChR signaling disrupts normal circuit development could provide mechanistic insight into developmental neuropsychiatric disorders characterized by disrupted nAChR signaling, such as Autism, ADHD and schizophrenia. In Aim1, we will test the hypothesis that Lynx1 expression in anterior cingulate cortex during peri-adolescence is required for normal attentional function in the adult. We will precisely define the critical period and key brain regions mediating the long-lasting impact of excess nAChR signaling on adult attentional function by combining pharmacological, viral and genetic gene manipulations in vivo with 5-choice serial reaction time task (5- CCRTT) employing a translational touchscreen system. In Aim2, we will test the hypothesis that the fronto- posterior cortical circuits require nAChR signaling to be suppressed by Lynx1 during adolescence to establish attention in the adult. By introducing a novel viral system that allows circuit-specific labeling and gene manipulations at time points of interest, the impact of Lynx1 deletion to neurons projecting from anterior cingulate cortex to visual cortex, and the cell-autonomous contribution of Lynx1 in these circuits will be determined. At the completion of this study, we will have defined the developmental time window, anatomical region, and circuit that require optimal nAChR signaling for normal attentional function, which is identified by the NIMH Research Domain Criteria (RDoC) project as one major construct of cognitive systems impaired in a number of psychiatric conditions.