Roles of Very Long Chain Fatty Acids in Neurobehavior Deficits in FASD

项目摘要 该应用程序的重点是调查胎儿神经行为问题的潜在机制， 酒精谱系障碍（FASD）使用小鼠模型。酒精会影响大脑发育， 多方面的过程，从而导致终身的认知和神经行为缺陷。以前的研究 显示FASD大脑中脂肪酸含量的紊乱，然而， 神经行为问题仍然是难以捉摸的。我们的初步研究确定了异常（过量） 在锥体细胞中表达脂肪酸相关基因，极长链脂肪酸延长4（Elov14）， 出生前酒精暴露（PAE）后很长时间年轻成年小鼠运动皮层神经元。鉴于脂肪酸 在大脑发育和神经功能中起着重要作用，我假设破坏脂肪酸 由于过量Elov14导致的生物发生导致PAE小鼠中运动技能学习受损。为了验证这一 假设，我将分析PAE运动皮层细胞膜磷脂中的脂肪酸种类。同样地， 确定Elov14过表达对脂肪酸谱的影响并与PAE的影响进行比较， 从而我们可以检查Elov14对PAE中脂肪酸破坏的贡献（目的1）。目标2：定义 将在细胞水平、膜动力学和突触可塑性上检查对神经元功能的影响 在Elov14过表达的神经元和PAE神经元中。最后，为了测试Elovl4的破坏是否 由于Elov14基因是导致PAE小鼠运动技能学习缺陷的原因，因此我将测试是否敲低Elov14基因， 改善受损的运动技能学习（目标3）。这项研究的结果可能揭示了迄今为止 由于FASD中脂肪酸生物合成的破坏导致的学习缺陷的未知病理机制， 从而导致潜在的干预。

PROJECT SUMMARY This application focuses on investigating the underlying mechanism of neurobehavioral problems in Fetal Alcohol Spectrum Disorders (FASD) using a mouse model. Alcohol damages developing brain by affecting multifaceted process, thereby leading to lifelong cognitive and neurobehavioral deficits. Previous studies showed the disturbances in fatty acid contents in FASD brains, however, the contribution of the disruption to the neurobehavioral problems still remain elusive. Our preliminary study identified abnormal (excess) expression of a fatty acid related gene, Elongation of Very Long Chain Fatty Acids 4 (Elovl4), in pyramidal neurons in motor cortex in young adult mice long after prenatal alcohol exposure (PAE). Given that fatty acids play imperative roles in brain development and neuronal function, I hypothesize that disrupted fatty acid biogenesis due to excess Elovl4 contributes to impairment of motor skill learning in PAE mice. To test this hypothesis, I will profile fatty acid species in phospholipids of cellular membrane in PAE motor cortex. Similarly, the effects of Elovl4 overexpression on fatty acid profile will be determined and compared with those of PAE, so that we can examine the contribution of Elovl4 to disruption of fatty acids in PAE (Aim 1). In aim 2, to define the effects on neuronal functions at cellular level, membrane dynamics and synaptic plasticity will be examined in the neurons with Elovl4 overexpression and the PAE neurons. Lastly, to test whether disruption of Elovl4 gene is responsible for motor skill learning deficits in PAE mice, I will test whether knocking down of Elovl4 ameliorates the impaired motor skill learning (Aim 3). The results of the proposed study may reveal hitherto unknown pathological mechanism of learning deficits due to disruption of fatty acid biogenesis in FASD, thereby leading to potential interventions.