Roles of the thalamus and retinoid signaling in prefrontal cortex development

描述（由申请人提供）：人类神经心理学和猴子消融研究表明，前额叶皮层（PFC）参与情感，社会行为以及执行功能，如工作记忆和决策。PFC功能障碍与包括精神分裂症、自闭症和抑郁症在内的神经精神疾病有关。鉴于许多这些疾病的发育起源，了解PFC神经元在正常发育过程中的产生、规范和分化机制至关重要。尽管最近在新皮层发育的研究中取得了进展，但关于新皮层其他部分的发现有多少适用于PFC仍然未知。近年来，人们对大脑皮层的区域特异性发育机制进行了广泛的研究。这些包括赋予神经祖细胞位置身份的内在模式机制，以及丘脑传入事件的外在影响。该领域的大多数研究，特别是关于丘脑在新皮层区域发育中的外在作用的研究，都集中在初级感觉区，而对PFC的关注很少。为了用分子遗传学的方法阐明PFC的发育机制，我们已经确定了表达模式描绘出生后早期PFC区域的基因。然后，我们分析了这些基因在缺乏丘脑-PFC连接的突变小鼠中的表达，并发现了一个深刻的变化，可以预测PFC中维甲酸信号的改变。基于这些初步数据，我们建议研究丘脑和维甲酸信号在PFC发育中的作用。向PFC投射轴突的丘脑核的异常发育以及PFC中异常的类视黄醇信号都与发育性脑疾病的发病机制有关。然而，这种相关性的分子和细胞基础在很大程度上仍然难以捉摸。我们提出的研究将是更好地理解这些重要问题的第一步。

DESCRIPTION (provided by applicant): Human neuropsychology and monkey ablation studies show that the prefrontal cortex (PFC) is involved in affect, social behavior as well as executive functions such as working memory and decision-making. Dysfunction of the PFC is associated with neuropsychiatric disorders including schizophrenia, autism and depression. Given the developmental origin of many of these disorders, it is crucial to understand the mechanisms of generation, specification and differentiation of PFC neurons during normal development. Despite the recent advances in the studies of neocortical development, how much of the findings on other parts of the neocortex is applicable to the PFC has remained unknown. Region-specific developmental programs of the neocortex have been studied extensively in recent years. These include intrinsic patterning mechanisms that confer positional identity to neural progenitor cells, as well as the extrinsic influences by thalamic afferents. A majority of research in this field, especially the studies on the extrinsic roles of the thalamus in regional development of the neocortex, has focused on primary sensory areas, while little attention has been paid to the PFC. In order to elucidate the developmental mechanisms of the PFC with molecular genetic approaches, we have identified genes whose expression patterns delineate early postnatal PFC areas. We then analyzed the expression of these genes in mutant mice that lack thalamus-PFC connections, and found a profound change that predicts an altered retinoid signaling in the PFC. Based on these preliminary data, we propose to study the roles of the thalamus and retinoid signaling in PFC development. Abnormal development of the thalamic nuclei that project axons to the PFC as well as abnormal retinoid signaling in the PFC are both implicated in the pathogenesis of developmental brain disorders. However, molecular and cellular basis of such correlations have remained largely elusive. Our proposed research will be a first step to a better understanding of these important questions.