Nuclear receptor subfamily 1, group D, member 1 (Nr1d1) (also known as Rev-erb alpha) has been linked to circadian rhythm regulation, mood-related behaviour and disorders associated with social deficits. Recent work from our laboratory found striking decreases in Nr1d1 in the nucleus accumbens (NAc) in the maternal condition and indirect evidence that Nr1d1 was interacting with numerous addiction and reward-related genes to modulate social reward. In this study, we applied our insights from the maternal state to nonparental adult mice to determine whether decreases in Nr1d1 expression in the NAc via adeno-associated viral (AAV) vectors and short hairpin RNA (shRNA)-mediated gene knockdown were sufficient to modulate social behaviours and mood-related behaviours. Knockdown of Nr1d1 in the NAc enhanced sociability and reduced anxiety, but did not affect depressive-like traits in female mice. In male mice, Nr1d1 knockdown had no significant behavioural effects. Microarray analysis of Nr1d1 knockdown in females identified changes in circadian rhythm and histone deacetylase genes and suggested possible drugs, including histone deacetylase inhibitors, that could mimic actions of Nr1d1 knockdown. Quantitative real-time PCR (qPCR) analysis confirmed expression upregulation of gene period circadian clock 1 (Per1) and period circadian clock 2 (Per2) with Nr1d1 knockdown. The evidence for roles for opioid-related genes opioid receptor, delta 1 (Oprd1) and preproenkephalin (Penk) was also found. Together, these results suggest that Nr1d1 in the NAc modulates sociability and anxiety-related behaviour in a sex-specific manner, and circadian, histone deacetylase and opioid-related genes may be involved in the expression of these behavioural phenotypes.

译文

:核受体亚家族1,D组,成员1(Nr1d1)(也称为Rev-erb alpha)与昼夜节律调节,与情绪有关的行为以及与社会缺陷相关的疾病有关。我们实验室的最新工作发现,孕产妇伏隔核(NAc)中Nr1d1显着下降,间接证据表明Nr1d1正在与众多成瘾和与奖励相关的基因相互作用,以调节社会奖励。在这项研究中,我们运用了从母体状态到非亲本成年小鼠的见解,以确定通过腺相关病毒(AAV)载体和短发夹RNA(shRNA)介导的基因敲低的NAc中Nr1d1表达的降低是否足以调节社会行为和与情绪有关的行为。击倒Nc1中的Nr1d1增强了社交能力并减少了焦虑,但并未影响雌性小鼠的抑郁样特征。在雄性小鼠中,Nr1d1敲低没有明显的行为影响。对女性Nr1d1敲除的微阵列分析确定了昼夜节律和组蛋白脱乙酰基酶基因的变化,并提出了可能模仿Nr1d1敲除作用的药物,包括组蛋白脱乙酰基酶抑制剂。定量实时PCR(qPCR)分析证实基因周期昼夜节律时钟1(Per1)和周期昼夜节律时钟2(Per2)的表达上调,同时敲低Nr1d1。还发现了阿片相关基因阿片受体,δ1(Oprd1)和前原脑啡肽(Penk)的作用证据。总之,这些结果表明,NAc中的Nr1d1以性别特异性方式调节社交和焦虑相关行为,并且昼夜节律,组蛋白脱乙酰基酶和阿片样物质相关基因可能参与了这些行为表型的表达。

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