Molecular Control of Long-Range Fronto-Posterior Cortical Projection Maturation Mediating Attention

项目摘要 发育性神经精神障碍影响美国超过15%的儿童， 构成了一个重大的公共卫生问题，每年需要350亿美元来解决，这在很大程度上是由于 残疾。临床上诊断、治疗和监测疾病的努力一直受到阻碍，因为他们依赖于 对非特定症状群的观察，从而将当前的药物治疗局限于症状 管理层。初步研究报告说，在这些疾病中，远侧皮质区域无法连接，然而， 开发更有效的药理学干预措施需要更好地了解正常 成熟和牵连的病理生理学。这些过程可以在小鼠身上进行检测。在我们实验室做这样的工作 已经确定了成熟的必要驱动因素-Lynx1-对于通常从额叶受损的投射 大脑皮层到视觉皮质，负责调节视觉注意的加工。这项建议旨在更全面地审查 Lynx1如何在这一关键的皮质连接中促进正常的神经发育，并将研究 以及在缺乏这种重要分子的情况下异常发育的结构后果。我假设 内源性尼古丁受体抑制物Lynx1调节这一投射整合到形成 产生视觉注意力的神经网络。这种病理生理学的洞察力将促进 对神经发育障碍进行更有效的诊断和靶向治疗。

Project Summary Neuropsychiatric disorders with developmental origins affect more than 15% of children in the United States and poses a major public health concern requiring $35 billion a year to address in large part due to secondary disability. Clinical efforts to diagnose, treat, and monitor disease have been hindered because they rely on observations of non-specific clusters of symptoms, thus limiting current pharmacologic therapeutics to symptom management. Initial studies report that distal cortical areas fail to connect in these disorders, however, the development of more effective pharmacological interventions requires a better basic understanding of normal maturation and implicated pathophysiology. These processes can be examined in mice. Such work in our lab has identified a necessary driver of maturation—Lynx1— for a projection commonly impaired from the frontal cortex to the visual cortex that mediates visual attention processing. This proposal seeks to more fully examine how Lynx1 promotes normal neural development in this key cortical connection and will investigate the functional and structural consequences of aberrant development in the absence of this important molecule. I hypothesize that Lynx1, an endogenous nicotinic receptor inhibitor, regulates the integration of this projection into forming neural networks that enact visual attention. This pathophysiological insight will promote the development of more effective diagnosis and targeted therapies for neurodevelopmental disorders.