One-year study of spatial memory performance, brain morphology, and cholinergic markers after moderate controlled cortical impact in rats
One-year study of spatial memory performance, brain morphology, and cholinergic markers after moderate controlled cortical impact in rats
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DOI：
10.1089/neu.1999.16.109
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发表时间：
1999-02-01
影响因子：
4.2
通讯作者：
DeKosky, ST
中科院分区：
文献类型：
--
作者：
Dixon, CE;Kochanek, PM;DeKosky, ST
持续性认知缺陷是人类颅脑损伤最重要的后遗症之一。为了模拟慢性脑损伤后发生的一些结构和神经药理学变化，我们使用Morris水迷宫（MWM）测试、形态学和囊泡乙酰胆碱（ACh）转运体（VAChT）和毒毒碱受体亚型2 （M-2）免疫组织化学检查了中度垂直控制皮质冲击（CCI）对地方学习和记忆的纵向影响。雄性Sprague-Dawley大鼠（n = 10）采用垂直CCI（左顶叶皮质，4 m/sec, 2.5 mm; n = 10）或开颅术（假手术）。分别于伤后2周、4周、3个月、6个月和12个月在不同的迷宫象限使用逃生平台进行地点学习测试。在每个间隔，大鼠接受5天的水迷宫获取（寻找隐藏平台的潜伏期），一个探针试验来测量位置记忆，以及2天的可见平台试验来控制非特异性缺陷。3周时，一半的动物被处死进行组织学检查。在这些损伤参数下，在损伤后2周、4周或6个月，CCI对受伤大鼠和假大鼠的位置学习没有显著差异。然而，在3个月和12个月时，受伤大鼠找到隐藏平台的时间明显长于假手术大鼠。损伤后12个月，损伤大鼠（25.73 +/- 2.1%，平均标准误差）与假手术大鼠（44.09 +/- 7.0%,p < 0.05）的探针试验性能仅存在差异。1年后的迷宫缺陷不是由于表现恶化，而可能是由于受伤大鼠从以前的水迷宫经验中获益的能力降低。损伤后3周，半球损失30.4 +/- 5.5 mm(3)（与假手术相比）。然而，损伤后1年，半球损失几乎翻了一番（51.5 +/- 8.5 mm，与其他所有组相比p < 0.05）。进行性组织损失也反映在损伤后3周至1年内同侧心室容积增加3至4倍。损伤后1年，海马和皮质各部位VAChT免疫染色显著增加。同侧海马毒蕈碱受体亚型2 （M-2）免疫反应性显著降低。这表明胆碱能神经元的代偿反应增加了乙酰胆碱神经传递的效率。中度CCI在大鼠中产生细微的MWM表现缺陷，伴随M-2和VAChT免疫组化的持续改变和进行性组织萎缩。受伤大鼠无法从重复暴露于MWM中获益，可能代表了与海马胆碱能系统变化无关的程序性记忆缺陷。
Persistent cognitive deficits are one of the most important sequelae of head injury in humans. In an effort to model some of the structural and neuropharmacological changes that occur in chronic postinjury brains, we examined the longitudinal effects of moderate vertical controlled cortical impact (CCI) on place learning and memory using the Morris water maze (MWM) test, morphology, and vesicular acetylcholine (ACh) transporter (VAChT) and muscarinic receptor subtype 2 (M-2) immunohistochemistry. Vertical CCI (left parietal cortex, 4 m/sec, 2.5 mm; n = 10) or craniotomy (sham) was produced in male Sprague-Dawley rats (n = 10). Place learning was tested at 2 weeks, 4 weeks, 3 months, 6 months, and 12 months postinjury with the escape platform in a different maze quadrant for each time point. At each interval, rats received 5 days of water maze acquisition (latency to find hidden platform), a probe trial to measure place memory, and 2 days of visible platform trials to control for nonspecific deficits. At 3 weeks, half the animals were sacrificed for histology. At these injury parameters, CCI produced no significant differences in place learning between injured and sham rats at 2 weeks, 4 weeks, or 6 months after injury. However, at 3 and 12 months, the injured rats took significantly longer to find the hidden platform than the sham rats. Probe trial performance differed only at 12 months postinjury between injured (25.73 +/- 2.1%, standard error of the mean) and sham rats (44.09 +/- 7.0%, p < 0.05). The maze deficits at 1 year were not due to a worsening of performance, but may have resulted from a reduced ability of injured rats to benefit from previous water maze experience. Hemispheric loss of 30.4 +/- 5.5 mm(3) was seen at 3 weeks after injury (versus respective sham). However, hemispheric loss almost doubled by 1 year after injury (51.5 +/- 8.5 mm(3), p < 0.05 versus all other groups). Progressive tissue loss was also reflected by a three- to fourfold increase in ipsilateral ventricular volume between 3 weeks and 1 year after injury. At 1 year after injury, immunostaining for VAChT was dramatically increased in all sectors of the hippocampus and cortex after injury. Muscarinic receptor subtype 2 (M-2) immunoreactivity was dramatically decreased in the ipsilateral hippocampus. This suggests ai compensatory response of cholinergic neurons to increase the efficiency of ACh neurotransmission. Moderate CCI in rats produces subtle MWM performance deficits accompanied by persistent alteration in M-2 and VAChT immunohistochemistry and progressive tissue atrophy. The inability of injured rats to benefit from repeated exposures to the MWM may represent a deficit in procedural memory that is independent of changes in hippocampal cholinergic systems.