Early life adversity promotes resilience to opioid addiction-related phenotypes in male rats and sex-specific transcriptional changes
Early life adversity promotes resilience to opioid addiction-related phenotypes in male rats and sex-specific transcriptional changes
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早年逆境促进雄性大鼠对阿片类药物成瘾相关表型的恢复能力和性别特异性转录变化
DOI：
10.1073/pnas.2020173118
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Ardekani, Cory S.
中科院分区：
文献类型：
--
作者：
Ordoñes Sanchez, Evelyn;Bavley, Charlotte C.;Deutschmann, Andre U.;Carpenter, Rachel;Peterson, Drew R.;Karbalaei, Reza;Flowers, II, James;Rogers, Charleanne M.;Langrehr, Miranda G.;Ardekani, Cory S.
经历一些早期生活中的逆境可以产生一种“逆境”效应，促进成年后的恢复力。然而，应激接种的机制尚不清楚，也缺乏动物模型。在这里，我们使用有限的床上用品和嵌套（LBN）逆境模型来评估成瘾相关表型的应力接种。在黎巴嫩，出生后第2天至第9天的幼崽及其母鼠暴露于低资源环境。在成年期，他们被测试成瘾样表型，并与在标准住房条件下饲养的大鼠进行比较。高水平的冲动与药物滥用有关，但在男性中，LBN减少冲动的选择相比，控制。LBN男性也自我管理较少的吗啡，并有一个较低的断点比对照组的渐进比例强化计划。LBN对成瘾相关行为的影响在女性中没有发现。由于延髓核（NAc）介导这些行为，我们测试了LBN是否改变了药物初治大鼠和吗啡暴露大鼠的NAc生理学。LBN降低了男性自发兴奋性突触后电流的频率，但在女性中没有观察到类似的效果。只有在男性没有LBN防止吗啡诱导的AMPA/NMDA比率的增加。进行RNA测序以描绘与LBN衍生表型相关的NAc中的分子特征。LBN在转录方面产生了性别特异性变化，包括与谷氨酸传输相关的基因。总的来说，这些研究表明，LBN导致男性特定的压力接种效应对成瘾相关的表型。确定促进成瘾恢复力的因素可能会为患者提供新的治疗选择。
Experiencing some early life adversity can have an “inoculating” effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown, and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal days 2 to 9 and their dams were exposed to a low-resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions. High levels of impulsivity are associated with substance abuse, but in males, LBN reduced impulsive choice compared to controls. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. These effects of LBN on addiction-related behaviors were not found in females. Because the nucleus accumbens (NAc) mediates these behaviors, we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced the frequency of spontaneous excitatory postsynaptic currents in males, but a similar effect was not observed in females. Only in males did LBN prevent a morphine-induced increase in the AMPA/NMDA ratio. RNA sequencing was performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients.
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影响因子：
--
作者：
Leong KC;Cox S;King C;Becker H;Reichel CM
通讯作者：
Reichel CM
童年时期虐待和相关不良经历的持久影响。
影响因子：
1.9
作者：
R. Reading
通讯作者：
R. Reading
影响因子：
4.6
作者：
Cahill KM;Huo Z;Tseng GC;Logan RW;Seney ML
通讯作者：
Seney ML
早年与母亲的分离和社会孤立会增加冲动行为，但不会增加冲动选择。
影响因子：
1.9
作者：
V. Lovic;Darren Keen;P. Fletcher;A. Fleming
通讯作者：
A. Fleming
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK