Roles of the thalamus and retinoid signaling in prefrontal cortex development

丘脑和类维生素A信号在前额皮质发育中的作用

• 批准号: 8804673
• 负责人: YASUSHI NAKAGAWA
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804673
• 关键词: Ablation; Adult; Affect; Amygdaloid structure; Applications Grants; Area; Attention; Autistic Disorder; Axon; Brain; Brain Diseases; Brain region; Cell membrane; Corpus striatum structure; Cytoplasm; Data; Decision Making; Development; Disease; Elements; Enzymes; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; Generations; Genes; Genomics; Hippocampus (Brain); Human; Knowledge; Label; LacZ Genes; Length; Light; Link; Maintenance; Medial; Mediating; Mental Depression; Mental disorders; Methods; Molecular; Molecular Genetics; Monkeys; Mus; Mutant Strains Mice; Neocortex; Neurons; Neuropsychology; Nuclear; Pathogenesis; Pattern; Pharmacogenetics; Play; Prefrontal Cortex; Primates; Public Health; Reporting; Research; Research Personnel; Retinoic Acid Receptor; Retinoids; Rodent; Role; Schizophrenia; Sensory; Short-Term Memory; Signal Transduction; Social Behavior; Staging; Testing; Tetanus Toxin; Thalamic Nuclei; Thalamic structure; Transgenes; Tretinoin; Vertebral column; base; cognitive function; density; executive function; genetic approach; hippocampal pyramidal neuron; insight; mutant; neocortical; nerve stem cell; neuropsychiatry; non-genomic; postnatal; programs; public health relevance; receptor

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.

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的功能障碍与神经精神障碍有关，包括精神分裂症、自闭症和抑郁症。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生成、特化和分化机制至关重要。尽管新皮质发育的研究取得了新的进展，但关于新皮质其他部分的研究结果有多少适用于PFC仍然是未知的。近年来，新皮层的区域特异性发育程序得到了广泛的研究。这些包括内在的图案机制，赋予神经祖细胞的位置身份，以及丘脑传入的外在影响。在这一领域的大部分研究，特别是对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，而很少有人注意到PFC。为了阐明PFC的分子遗传学方法的发展机制，我们已经确定了基因的表达模式描绘出生后早期PFC领域。然后，我们分析了这些基因在突变小鼠缺乏丘脑PFC连接的表达，并发现了一个深刻的变化，预测改变类维生素A信号在PFC。基于这些初步数据，我们建议研究丘脑和类维生素A信号在PFC发展中的作用。投射轴突到PFC的丘脑核的异常发育以及PFC中的异常类维生素A信号传导都与发育性脑障碍的发病机制有关。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。