Regulation of Neuronal Mitosis

正确数量和类型的神经细胞（包括神经元和星形胶质细胞）的产生是 是大脑正常发育和功能的基础。相反，脑细胞组成的改变， 特别是前脑，被认为是具有发育起源的成熟精神障碍的基质， 精神分裂症、抑郁症和自闭症谱系障碍。之前我们定义了积极和消极 细胞外信号，包括FGF，IGF 1和PACAP，以及调节细胞周期的内在细胞周期机制。 大脑皮层的神经发生使用这个模型，我们正在定义机制， 神经治疗性丙戊酸（VPA），常规给予育龄妇女，影响 神经/神经胶质生成，因为它是一种致畸剂，可导致畸形并导致神经精神疾病。 紊乱我们假设VPA通过不同的调节方式破坏正常的大脑发育， 神经元和神经胶质的产生，改变BDNF信号传导和干扰随后的行为功能。我们 发现VPA通过细胞周期机制刺激培养物和胚胎中的神经发生， 调节胶质细胞生成并改变BDNF信号传导。我们的目标是：1。确定VPA对产前皮质的影响 神经发生和细胞周期机制; 2.定义VPA对细胞增殖和分化的影响 星形胶质细胞; 3.确定母体VPA治疗对发育期间后代行为的影响， 成熟研究将检查DNA合成，增殖，分化，细胞死亡，细胞周期western/RT- PCR和激酶分析，体视学细胞组成，培养和/或产前和产后发育 动物，以及探索行为，社交和焦虑措施和学习的评估， 记忆过程通过定义VPA对细胞内信号传导和细胞周期的细胞类型特异性影响， 机械，并表征脑细胞组成和动物行为的后果， 开发，我们可以提供基础知识，以有效地评估药物的益处和风险 治疗，并确定干预措施可能抵消药物暴露的有害影响的途径。

Generation of the correct numbers and types of neural cells, including neurons and astrocytes, is fundamental to normal brain development and function. Conversely, alterations in brain cell composition, especially forebrain, are considered substrate of mature mental disorders with developmental origins, such as schizophrenia, depression and autism spectrum disorder. Previously we defined positive and negative extracellular signals, including FGF, IGF1 and PACAP, and intrinsic cell cycle mechanisms that regulate neurogenesis in cerebral cortex. Using this model, we are defining mechanisms by which the neurotherapeutic valproic acid (VPA), routinely administered to women of childbearing age, affects neuro/gliogenesis, because it is a teratogen that causes malformations and contributes to neuropsychiatric disorders. We hypothesize that VPA disrupts normal brain development by differentially regulating generation of neurons and glia, altering BDNF signaling and disturbing subsequent behavioral function. We find that VPA stimulates neurogenesis in culture and in embryos via cell cycle machinery, differentially regulates gliogenesis and alters BDNF signaling. Our Aims are: 1. Define effects of VPA on prenatal cortical neurogenesis and cell cycle machinery; 2. Define VPA effects on proliferation and differentiation of astrocytes; 3. Define effects of maternal VPA treatment on behavior of offspring during development and maturity. Studies will examine DNA synthesis, proliferation, differentiation, cell death, cell cycle western/RT- PCR and kinase analyses, cell composition by stereology, in culture and/or in developing pre- and postnatal animals, as well as assessments of exploratory behavior, social and anxiety measures and learning and memory processes. By defining cell type specific effects of VPA on intracellular signaling and cell cycle machinery, and characterizing consequences for brain cell composition and animal behavior during development, we may provide fundamental knowledge to effectively evaluate the benefits and risks of drug therapy, and identify pathways where intervention may counter detrimental effects of drug exposure.