Roles of Primary Cilia in the Developing Cortex Exposed to Alcohol

项目摘要/摘要 出生前接触酒精会对发育中的大脑皮层造成毁灭性的影响， 从而在出生后引起广泛的神经和精神疾病。其中一个 有希望的干预方法在于加强内在保护机制 压倒触发的病理机制。因此，理解辩方 神经细胞使用的机制对于开发潜在的治疗方法是必不可少的 酒精引起的神经精神疾病。这项拟议的研究的目标是 初级纤毛抑制酒精对发育不利影响的新途径 皮质神经元。初级纤毛是一种独特的细胞器，被认为是 细胞感知并对环境变化做出反应。然而，纤毛在大脑中的作用 发育，特别是在严酷的产前环境中，如接触酒精或其他 环境压力在很大程度上仍不为人所知。通过结合纤毛的小鼠模型 特别是大脑皮层的缺陷和大脑萌芽阶段的酒精暴露， 我们发现了支持我们假设的证据；纤毛可能在保护大脑皮层方面发挥关键作用。 酒精诱导的树突状/脊椎变性或/和其他永久性神经元 形态改变。我们将通过表征皮质表型来检验这一假说。 酒精暴露的纤毛缺陷条件性基因敲除小鼠(Aim1)和测试候选者 纤毛依赖抑制树突状/棘状突起的分子机制 体内退行性变(AIM2)。

Project Summary/Abstract Prenatal alcohol exposure can lead to devastating effects on the developing cerebral cortex, thereby causing a wide spectrum of neurological and psychiatric conditions after birth. One of the promising intervention approaches lies in enhancing intrinsic protective mechanisms to overwhelm the triggered pathological mechanisms. Therefore, understanding the defense mechanisms deployed by neural cells is imperative for the development of potential therapies for alcohol-induced neuropsychiatric conditions. The goal of the proposed study is to characterize a new pathway by which primary cilia could suppress the adverse impact of alcohol on developing cortical neurons. The primary cilium is a unique organelle which is known to be essential for a cell to sense and respond to environmental changes. However, the role of cilia during brain development, particularly, in harsh prenatal environment such as exposure to alcohol or other environmental stressors remains largely unknown. By combining a mouse model of cilia deficiency specifically in the cerebral cortex and alcohol exposure during the brain sprout stage, we found evidences that support our hypothesis; cilia may play a critical role in protecting cortical neurons from alcohol-inducible dendritic/spine degeneration or/and other permanent morphological alterations. We will test this hypothesis by characterizing cortical phenotypes of cilia-deficient conditional knockout mice exposed to alcohol (Aim1), and testing candidate molecular mechanisms which may mediate cilia-dependent inhibition of dendritic/spine degeneration in vivo (Aim2).