妊娠不同阶段睡眠剥夺对子代大鼠认知功能影响及其突触可塑性机制研究

Sleep disturbance during pregnancy is very common. One of the severe consequences from maternal sleep deprivation is children’s cognitive development deficiency. However, there is no effective treatment for cognitive deficiency, because there is little research directly examining how sleep deprivation affects offspring. Synaptic plasticity was known as cellular mechanism underlying learning and memory. In the present study, we want to examine synaptic plasticity mechanism underlying the effect of maternal sleep deprivation. We will use offspring of maternal sleep deprivation animal model, combined with behavioral tests to test the effect of maternal sleep deprivation on fetal learning and memory. We will examine synaptic formation with electron microscope. Using in vivo electrophysiological recording techniques, we will detect hippocampal Schaffer-CA1 pathway synaptic plasticity. Spontaneous excitatory postsynaptic currents and AMPA/NMDA current ratio will be recorded by patching clamp technique on adult rat hippocampal slices in vitro. We will use western blotting to examine hippocampal synapse AMPA receptor subunits expression. In this study, we will also try drug to reverse the effect of maternal sleep deprivation. Through deepening our understanding the molecular and synaptic mechanisms responsible for the fetal cognitive decline at molecular, cellular and whole-organism levels, knowledge gained from this study may provide novel approaches to reverse the fetal learning and memory deficiency induced by maternal sleep deprivation.

孕期睡眠不足是非常普遍的问题。孕期睡眠不足的严重后果之一是导致子代认知障碍。然而,迄今为止,还没有改善子代认知障碍的有效方法，究其原因是孕期睡眠不足影响子代认知的神经机制不清楚。突触可塑性是学习记忆的细胞分子基础，被广泛认为是学习记忆的模型。因此，本项目拟从学习记忆的突触可塑性机理来探索孕期睡眠不足损伤子代认知的神经机制。在妊娠不同阶段睡眠剥夺的大鼠模型所产的子代大鼠上，用水迷宫等行为学方法研究学习记忆的形成和维持；电镜方法检测海马突触结构可塑性变化，电生理方法研究海马突触功能可塑性及突触可塑性相关受体功能变化；用生化方法分析海马突触小体上突触可塑性相关受体的表达变化；用药物逆转孕期睡眠不足导致的突触可塑性变化，改善孕期睡眠不足带来的子代认知损伤。从分子、细胞、脑片和整体不同层面阐述孕期睡眠不足损伤子代认知功能的突触可塑性机理及分子机制，为临床开发改善认知功能损伤的药物提供新思路。

孕期睡眠不足是非常普遍的问题。孕期睡眠不足的严重后果之一是导致子代认知障碍。然而,迄今为止,还没有改善子代认知障碍的有效方法，究其原因是孕期睡眠不足影响子代认知的神经机制不清楚。本项目研究发现：在妊娠不同阶段睡眠剥夺大鼠所产的子代大鼠模型上，水迷宫实验结果表明孕期睡眠剥夺损伤子代大鼠的空间学习和记忆能力；高架十字迷宫和强迫游泳实验表明孕期睡眠剥夺增加子代大鼠的焦虑和抑郁样行为；免疫荧光实验结果表明孕期睡眠剥夺损伤子代大鼠的成年神经发生；电生理实验表明孕期睡眠剥夺损伤子代大鼠的LTP而易化LTD。在此基础上，我们进一步研究发现：孕期睡眠剥夺导致子代大鼠海马突触后膜上AMPA受体的GluA2亚基内吞增加，从而损伤LTP和易化LTD，引起认知功能障碍；通过人工合成多肽Tat-GluA23Y抑制AMPA受体内吞，可以恢复受损的LTP和LTD，改善孕期睡眠剥夺导致子代大鼠的空间学习记忆能力损伤，并降低焦虑和抑郁样行为。这些研究结果提示孕期睡眠剥夺引起子代大鼠海马突触后膜上AMPA受体内吞增加，从而损伤突触可塑性，进而引起认知和情感障碍，为临床开发改善认知功能损伤的药物提供新思路。