Time course of morphine's effects on adult hippocampal subgranular zone reveals preferential inhibition of cells in S phase of the cell cycle and a subpopulation of immature neurons.
Time course of morphine's effects on adult hippocampal subgranular zone reveals preferential inhibition of cells in S phase of the cell cycle and a subpopulation of immature neurons.
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DOI：
10.1016/j.neuroscience.2008.08.064
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发表时间：
2008-11-11
期刊：
影响因子：
3.3
通讯作者：
Eisch AJ
中科院分区：
文献类型：
--
作者：
Arguello AA;Harburg GC;Schonborn JR;Mandyam CD;Yamaguchi M;Eisch AJ
阿片类药物，如吗啡，会减少成年海马齿状回颗粒下区（SGZ）的神经发生，这增加了神经发生减少导致阿片类药物诱导的认知缺陷的可能性。然而，对于细胞周期进程和祖细胞成熟的改变如何导致这种减少，人们的理解还不完整。本研究考察了吗啡如何调节祖细胞周期、细胞死亡以及未成熟的SGZ神经元（实验1），以及SGZ祖细胞在成熟关键阶段的进展情况（实验2）。在实验1中，小鼠接受假手术或吗啡丸（皮下注射，0小时和48小时），并在处死前2小时注射溴脱氧尿苷（BrdU）（24小时、72小时或96小时）。吗啡减少了S期细胞数量和总循环细胞数量，因为对S期标记物BrdU和细胞周期标记物Ki67有免疫反应（IR）的细胞更少。在注射吗啡24小时后，Ki67 - IR细胞中BrdU - IR细胞的百分比下降，但96小时后没有下降，这表明在这个时间点，相对于所有循环细胞，对S期细胞有不成比例的影响。细胞死亡（活化的半胱天冬酶 - 3计数）在24小时后增加，但96小时后没有增加。在实验2中，在吗啡或假手术前1天（0小时和48小时，96小时处死）给予BrdU的巢蛋白 - GFP小鼠，Ki67 - IR细胞更少，但BrdU - IR细胞数量没有变化，这表明这群BrdU - IR细胞对吗啡不太敏感。有趣的是，对祖细胞成熟关键阶段的检查显示，吗啡增加了BrdU - IR细胞中2b型细胞的百分比，并降低了未成熟神经元的百分比。这些数据表明，慢性吗啡通过抑制分裂细胞，特别是S期细胞，以及祖细胞向更成熟神经元阶段的进展，来减少SGZ的神经发生。
Opiates, such as morphine, decrease neurogenesis in the adult hippocampal subgranular zone (SGZ), raising the possibility that decreased neurogenesis contributes to opiate-induced cognitive deficits. However, there is an incomplete understanding of how alterations in cell cycle progression and progenitor maturation contribute to this decrease. The present study examined how morphine regulates progenitor cell cycle, cell death and immature SGZ neurons (Experiment 1) as well as the progression of SGZ progenitors through key stages of maturation (Experiment 2). In Experiment 1, mice received sham or morphine pellets (subcutaneous, 0 and 48 hrs) and bromodeoxyuridine (BrdU) 2 hrs prior to sacrifice (24, 72 or 96 hrs). Morphine decreased both the number of S phase and total cycling cells, as there were fewer cells immunoreactive (IR) for the S phase marker BrdU and the cell cycle marker Ki67. The percentage of Ki67-IR cells that were BrdU-IR was decreased after 24 but not 96 hrs of morphine, suggesting a disproportionate effect on S phase cells relative to all cycling cells at this time point. Cell death (activated caspase-3 counts) was increased after 24 but not 96 hrs. In Experiment 2, nestin-GFP mice given BrdU 1 day prior to morphine or sham surgery (0 and 48 hrs, sacrifice 96 hrs) had fewer Ki67-IR cells, but no change in BrdU-IR cell number, suggesting that this population of BrdU-IR cells were less sensitive to morphine. Interestingly, examination of key stages of progenitor cell maturation revealed that morphine increased the percent of BrdU-IR cells that were Type 2b and decreased the percent that were immature neurons. These data suggest that chronic morphine decreases SGZ neurogenesis by inhibiting dividing cells, particularly those in S phase, and progenitor cell progression to a more mature neuronal stage.
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影响因子：
2.5
作者：
Dayer, AG;Ford, AA;Cameron, HA
通讯作者：
Cameron, HA
影响因子：
7.8
作者：
Bauer, S;Patterson, PH
通讯作者：
Patterson, PH
DOI：
10.1073/pnas.120552597
发表时间：
2000-06-20
影响因子：
11.1
作者：
Eisch, AJ;Barrot, M;Nestler, EJ
通讯作者：
Nestler, EJ
DOI：
10.1073/pnas.0601992103
发表时间：
2006-05-23
影响因子：
11.1
作者：
Encinas, Juan M.;Vaahtokari, Anne;Enikolopov, Grigori
通讯作者：
Enikolopov, Grigori
影响因子：
3.3
作者：
Epp, J. R.;Spritzer, M. D.;Galea, L. A. M.
通讯作者：
Galea, L. A. M.