BACKGROUND & AIMS:

背景与目标：

BACKGROUND & AIMS:

背景与目标：

BACKGROUND & AIMS:

背景与目标：

BACKGROUND & AIMS:

背景与目标：

BACKGROUND & AIMS: :Delta opioid receptors are implicated in a variety of psychiatric and neurological disorders. These receptors play a key role in the reinforcing properties of drugs of abuse, and polymorphisms in OPRD1 (the gene encoding delta opioid receptors) are associated with drug addiction. Delta opioid receptors are also involved in protecting neurons against hypoxic and ischemic stress. Here, we first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative. We hypothesized that common variants in OPRD1 would be associated with differences in brain structure, particularly in regions relevant to addictive and neurodegenerative disorders. One very common variant (rs678849) predicted differences in regional brain volumes. We replicated the association of this single-nucleotide polymorphism with regional tissue volumes in a large sample of young participants in the Queensland Twin Imaging study. Although the same allele was associated with reduced volumes in both cohorts, the brain regions affected differed between the two samples. In healthy elderly, exploratory analyses suggested that the genotype associated with reduced brain volumes in both cohorts may also predict cerebrospinal fluid levels of neurodegenerative biomarkers, but this requires confirmation. If opiate receptor genetic variants are related to individual differences in brain structure, genotyping of these variants may be helpful when designing clinical trials targeting delta opioid receptors to treat neurological disorders.

背景与目标： ：δ阿片样物质受体与多种精神病和神经疾病有关。这些受体在滥用药物的增强特性中起关键作用，OPRD1（编码阿片类阿片受体的基因）中的多态性与成瘾有关。三角洲阿片受体也参与保护神经元免受缺氧和缺血性应激。在这里，我们首先检查了738名老年参与者的大量样本，这些样本来自阿尔茨海默氏病神经影像学倡议组织的神经影像学和遗传数据。我们假设OPRD1中的常见变异与大脑结构的差异有关，尤其是在与成瘾性和神经退行性疾病有关的区域。一种非常常见的变体（rs678849）预测了局部大脑体积的差异。我们在昆士兰双胞胎成像研究的大量年轻参与者中复制了这种单核苷酸多态性与区域组织体积的关联。尽管两个队列中相同的等位基因与体积减少相关，但两个样本之间受影响的大脑区域有所不同。在健康的老年人中，探索性分析表明，两个队列中与脑容量减少相关的基因型也可能预测神经退行性生物标志物的脑脊液水平，但这需要证实。如果阿片受体的遗传变异与脑结构的个体差异有关，那么在设计针对δ阿片受体的临床试验以治疗神经系统疾病时，这些变异的基因分型可能会有所帮助。

BACKGROUND & AIMS: BACKGROUND:A recent study reported strong evidence for the involvement of a region on human chromosome 1 and genetic susceptibility to anorexia nervosa (AN). A more detailed analysis of this region has suggested 2 genes that may account for this susceptibility. These data suggest that polymorphisms in both the serotonin 1D (HTR1D) and opioid delta 1 (OPRD1) receptor genes show a significant association with restricting AN (RAN). METHODS:In the current study, we have conducted an independent association study on 226 females meeting DSM-IV criteria for AN and 678 matched volunteers. RESULTS:We genotyped 4 SNPs in HTR1D and 6 SNPs in OPRD1. 3 SNPs were found to be associated with both RAN and binge-purge AN (BPAN) within the gene for OPRD1. We also found evidence of association between 2 polymorphisms within HTR1D and RAN. CONCLUSIONS:These data support the hypothesis that polymorphisms within this region form a component of the genetic basis to susceptibility to RAN. However, further work is required to understand the processes that may be mediated by these genes.

背景与目标： 摘要背景：最近的一项研究报道了有力的证据表明，人类第1号染色体上的一个区域参与了遗传性神经性厌食症（AN）的遗传易感性。对该区域进行的更详细分析表明，有2个基因可能解释了这种敏感性。这些数据表明，血清素1D（HTR1D）和阿片类药物δ1（OPRD1）受体基因的多态性均与限制性AN（RAN）密切相关。
方法：在本研究中，我们对226名符合DSM-IV标准的AN和678名匹配志愿者进行了独立的关联研究。
结果：我们对HTR1D中的4个SNP和OPRD1中的6个SNP进行了基因分型。发现3个SNP与OPRD1基因内的RAN和狂暴清除AN（BPAN）相关。我们还发现HTR1D和RAN中2个多态性之间存在关联的证据。
结论：这些数据支持以下假设：该区域内的多态性构成了对RAN易感性的遗传基础的组成部分。但是，需要进一步的工作来理解这些基因可能介导的过程。

BACKGROUND & AIMS: :Opioid receptors and their endogenous peptide ligands play important roles in neurotransmission and neuromodulation in response to addictive drugs such as heroin, cocaine, and alcohol. In an earlier study, we reported that variation in the genes encoding the kappa-opioid receptor (OPRK1) and its peptide ligand (PDYN) were associated with the risk for alcoholism. We continued our investigation of the role of the opioid system in alcohol dependence by analyzing the genes encoding the micro- and delta-opioid receptors and their peptide ligands. We analyzed 18 OPRM1 SNPs, 18 OPRD1 SNPs, 7 PENK SNPs, and 7 POMC SNPs in a sample of 1923 European Americans from 219 multiplex alcohol dependent families. Employing a family-based test of association, we found no evidence that these four genes were significantly associated with alcohol dependence. We also did not find association between these genes and illicit drug dependence. Secondary analyses employing the narrower phenotype of opioid dependence (83 affected individuals) demonstrated association with SNPs in PENK and POMC, but not in OPRM1 or OPRD1. Haplotype analyses provided further support for the association of PENK and POMC with opioid dependence. Therefore, our data provide no support for the idea that variations in OPRM1, OPRD1, PENK and POMC are associated with alcohol dependence or general illicit drug dependence, but variations in PENK and POMC appear to be associated with the narrower phenotype of opioid dependence in these families.

背景与目标： 阿片受体及其内源肽配体在对海洛因，可卡因和酒精等成瘾药物的反应中，在神经传递和神经调节中起重要作用。在较早的研究中，我们报道了编码κ阿片受体（OPRK1）及其肽配体（PDYN）的基因变异与酗酒风险有关。我们通过分析编码微阿片受体和δ阿片受体及其肽配体的基因，继续研究阿片样物质系统在酒精依赖中的作用。我们在来自219个多重酒精依赖家庭的1923个欧洲美国人的样本中分析了18个OPRM1 SNP，18个OPRD1 SNP，7个PENK SNP和7个POMC SNP。使用基于家庭的关联测试，我们没有发现这四个基因与酒精依赖显着相关的证据。我们还没有发现这些基因与非法药物依赖性之间的关联。使用较窄的阿片类药物依赖表型（83个受影响的个体）进行的次要分析表明，PENK和POMC中与SNP相关，而OPRM1或OPRD1中与SNP不相关。单倍型分析为将PENK和POMC与阿片类药物依赖性相关提供了进一步的支持。因此，我们的数据不支持以下观点：OPRM1，OPRD1，PENK和POMC的变异与酒精依赖或一般非法药物依赖有关，但PENK和POMC的变异似乎与这些患者中阿片样物质依赖的较窄表型有关。家庭。

BACKGROUND & AIMS: :The three opioid receptor genes, and in particular the mu and delta loci (OPRM1 and OPRD1, respectively), are compelling candidates to influence risk for substance dependence. Previous study of a variant at the OPRD1 locus, T921C, has shown association with opioid dependence. This variant does not alter protein sequence, and could not be directly responsible for a physiologic effect. We sequenced the OPRD1 coding region in six individuals with differing T921C alleles, to identify new common variants more likely to explain the association with phenotype. We identified one novel variant in exon 1, 80T-->G, which predicts a change in amino acid sequence from phenylalanine (80T) to cysteine (80G) (F27C). We present here basic population genetics of this variant, and population genetic data for the T921C variant. We found significant differences in allele frequency between populations, and a maximum frequency of the 80G allele of 9%, in each of two European populations. This variant could contribute to the previously reported association results.

背景与目标： ：三个阿片样物质受体基因，特别是mu和delta位点（分别为OPRM1和OPRD1），是影响物质依赖风险的诱人候选物。先前对OPRD1基因座的变体T921C的研究表明与阿片样物质依赖性有关。该变体不改变蛋白质序列，并且不能直接负责生理作用。我们在六个具有不同T921C等位基因的个体中对OPRD1编码区进行了测序，以鉴定出更可能解释与表型关联的新的常见变体。我们在第1外显子80T-> G中鉴定出一个新的变异体，该变异体预测了氨基酸序列从苯丙氨酸（80T）变为半胱氨酸（80G）（F27C）的变化。我们在这里介绍了该变种的基本种群遗传学，以及T921C变种的种群遗传数据。我们发现在两个欧洲人群中，人群之间的等位基因频率存在显着差异，而80G等位基因的最大频率为9％。此变体可能有助于先前报告的关联结果。

BACKGROUND & AIMS: BACKGROUND:Pain clinicians have always been challenged by the variability of response to pain treatment. Differences in the degree of pain stimulation and pain sensitivity, weight and age differences, prior opioid use and tolerance, as well as the differences in bioavailability of various opioid formulations have been cited as causes for the wide variability in analgesia seen with opioids. Genetics may explain the variability of responses and help to predict more effective (or less dangerous) medication choices and doses. Genetics may also help to predict the response to specific opioids and antidepressants. OBJECTIVES:In this review article, we discuss the genetic influence of nociception, analgesia, and hyoanalgesia. The CYP450 enzymes involved in the metabolism and activity of opioids and adjuvant analgesics are genetically controlled, as are the opioid receptors and a variety of brain chemistries. METHODS:This article discusses the specific pain implications of genetic variations in CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A7, OPRM1, OPRK1, OPRD1, COMT, GABA, UGT, MC1R, GCH1, ABCB1, P-glycoprotein, 5HTR1A, 5HTR2A, MTHFR, CACNA2D2, and 5-HTTLPR. RESULTS:Recent research findings suggest the relationship between genetic predisposition and clinical behavior, including the risk of opioid misuse and addiction. While urine drug testing may hint at genetic issues regarding opioid metabolism, cheek swab DNA testing has become economically viable, and we review the current and future genetic pain issues that may influence the decisions that pain clinicians make every day. CONCLUSION:Genetic testing may explain and predict many of the clinical responses seen with opioids and adjuvant medications, and may help the clinician identify those patients at genetic risk of opioid misuse and addiction.

背景与目标： 背景：疼痛临床医生一直受到对疼痛治疗反应的可变性的挑战。疼痛刺激和疼痛敏感性程度的差异，体重和年龄的差异，先前使用阿片类药物和耐受性的差异以及各种阿片类药物制剂的生物利用度差异被认为是阿片类药物镇痛广泛差异的原因。遗传学可以解释反应的变异性，并有助于预测更有效（或更危险）的药物选择和剂量。遗传学也可能有助于预测对特定阿片类药物和抗抑郁药的反应。
目的：在这篇综述文章中，我们讨论了伤害感受，镇痛和镇痛的遗传影响。涉及阿片类药物和辅助镇痛药的代谢和活性的CYP450酶，阿片受体和各种脑化学物质均受到基因控制。
方法：本文讨论CYP1A2，CYP2C8，CYP2C9，CYP2C19，CYP2D6，CYP2E1，CYP3A4，CYP3A7，OPRM1，OPRK1，OPRD1，COMT，GABA，UGT，MC1R，G1蛋白的遗传变异对特定疼痛的影响，5HTR1A，5HTR2A，MTHFR，CACNA2D2和5-HTTLPR。
结果：最近的研究结果表明遗传易感性与临床行为之间的关系，包括阿片类药物滥用和成瘾的风险。虽然尿液药物检测可能提示有关阿片类药物代谢的遗传问题，但颊拭子DNA检测已在经济上可行，我们将回顾当前和未来的遗传性疼痛问题，这些问题可能会影响临床医生每天做出的决定。
结论：基因检测可以解释和预测使用阿片类药物和辅助药物所见的许多临床反应，并可以帮助临床医生识别出有阿片类药物滥用和成瘾的遗传风险的患者。

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVES:Drug addiction is a serious illness with deleterious functional and social consequences for both the affected individuals, their families, and society at large. In spite of the abundant research on substance dependence, there are few effective treatments for this disease. Given the crucial role of the endogenous opioid system in the development and maintenance of substance abuse disorders, this review focuses on the opioidergic system and examines the role of opioidergic genes in the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addiction. METHODS:Scopus (all databases) and Pubmed were systematically searched with no language or year restrictions, up to July 2014, for studies that focused on the relationship between polymorphisms of opioidergic genes and the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addictions. Selected search terms were opioid, gene, polymorphism, drug therapy, substance abuse, and response. RESULTS AND CONCLUSIONS:The genetic variability of μ-, δ- and κ-opioid receptors genes OPRM1, OPRD1, and OPRK1 modulates the efficacy of opioid antagonist treatments such as naltrexone and methadone, as well as the cocaine vaccine. Despite the number of promising reports, data from additional cohorts are needed to substantiate these findings. SCIENTIFIC SIGNIFICANCE:Gene variant profiling could help predict treatment response and assist in developing effective treatments for alcohol, opioid, and cocaine addiction.

背景与目标： 背景与目的：药物成瘾是一种严重的疾病，对受影响的个人，他们的家庭和整个社会都具有有害的功能和社会后果。尽管对物质依赖性进行了大量研究，但是对于这种疾病几乎没有有效的治疗方法。鉴于内源性阿片类药物系统在滥用药物的发生和维持中的关键作用，本综述着重于阿片类药物系统，并研究了阿片类药物基因在酒精，阿片类药物和可卡因成瘾药物治疗中的作用。
方法：直到2014年7月，系统地搜索Scopus（所有数据库）和Pubmed，没有语言或年份限制，研究重点在于阿片类药物基因多态性与酒精，阿片类药物和可卡因成瘾药物治疗结果之间的关系。选择的搜索词是阿片类药物，基因，多态性，药物治疗，药物滥用和反应。
结果与结论：μ，δ和κ阿片受体基因OPRM1，OPRD1和OPRK1的遗传变异性可调节纳曲酮和美沙酮等阿片拮抗剂治疗以及可卡因疫苗的疗效。尽管有大量有希望的报告，但仍需要来自其他队列的数据来证实这些发现。
科学意义：基因变异分析可以帮助预测治疗反应，并帮助开发有效的治疗酒精，阿片类药物和可卡因成瘾的方法。

BACKGROUND & AIMS: The endogenous opioid peptides have been reported to be involved in the regulation of reproductive physiology. Many of the studies conclude with sentences around the harmful effect of opioids in male fertility but, actually, there is only one study regarding the real fertility potential of spermatozoa that have been exposed to mu specific opioids. The aim of the present study was to see if the modulation of delta (OPRD1) and kappa (OPRK1) opioid receptors in mouse sperm during capacitation was able to vary the embryo production after in vitro fertilization (IVF). The presence of OPRD1 and OPRK1 in mouse mature spermatozoa was analyzed by RT-PCR and immunofluorescence. Incubating the sperm with, on one hand, the delta specific agonist DPDPE and/or antagonist naltrindole, and, on the other hand, the kappa specific agonist U-50488 and antagonist nor-binaltorphimine, we analyzed the involvement of OPRD1 and OPRK1 on IVF and preimplantational embryo development. We verified the presence of OPRD1 and OPRK1 in mouse mature spermatozoa, not only at the mRNA level but also at protein level. Moreover, the sperm incubation with DPDPE, before the IVF, had an effect on the fertilization rate of sperm and reduced the number of reached blastocysts, which was reverted by naltrindole. Instead, the use of the kappa agonist U-50488 and the antagonist nor-binaltophimine did not have any effect on the amount and the quality of the achieved blastocysts. Although nowadays the pure delta or kappa opioid ligands are not used for the clinic, clinical trials are being conducted to be used in the near future, so it would be interesting to know if the modulation of these receptors in sperm would generate any consequence in relation to fertilization capacity.

背景与目标： 据报道内源性阿片样物质肽参与生殖生理的调节。许多研究以关于阿片类药物对男性生育的有害影响的句子作为结尾，但实际上，只有一项研究涉及暴露于μ特定阿片类物质的精子的实际生育潜力。本研究的目的是观察在获能过程中小鼠精子中δ（OPRD1）和κ（OPRK1）阿片受体的调节是否能够改变体外受精（IVF）后的胚胎产量。通过RT-PCR和免疫荧光分析小鼠成熟精子中OPRD1和OPRK1的存在。一方面，将精子与δ特异性激动剂DPDPE和/或拮抗剂纳曲酮一起孵育，另一方面与κ特异性激动剂U-50488和拮抗剂去甲双萘酚胺一起孵育，我们分析了OPRD1和OPRK1对IVF的影响和植入前的胚胎发育。我们验证了小鼠成熟精子中OPRD1和OPRK1的存在，不仅在mRNA水平而且在蛋白质水平。此外，在体外受精前用DPDPE孵育精子，对精子的受精率有影响，并减少了到达的胚泡数目，而纳达尔酮可逆转胚泡。取而代之的是，使用κ激动剂U-50488和拮抗剂去甲倍萘啶对获得的胚泡的数量和质量没有任何影响。尽管如今，纯三角洲或κ阿片类药物配体尚未用于临床，但正在进行临床试验以在不久的将来使用，因此，了解这些受体在精子中的调节是否会产生任何相关的结果将是很有趣的。到受精能力。

BACKGROUND & AIMS: :Pharmacological and electrophysiological evidence has shown that opioid receptors are involved in the mechanism of heroin dependence. Thus, opioid receptors are appropriate candidate genes for case-control association studies of heroin dependence. Previously, two single nucleotide polymorphisms (SNPs), OPRD1 921T > C and 80G > T, of the human delta opioid receptor gene were used in population-based studies of heroin dependence. One study in a German population found that OPRD1 921T > C was associated with heroin dependence. This finding, however, was not replicated in a different German sample. To test the hypothesis that OPRD1 or a closely linked gene is associated with heroin dependence, we used 5' nuclease assays to genotype both OPRD1 SNPs in 450 Chinese heroin dependent patients and 304 unaffected controls from the same population. In addition, five SNPs distributed in four other genes: ADH2, ALDH2, OPRM1, and DRD1, were used as genomic control loci to test the case and control populations for stratification bias. Genotype and allele frequencies at OPRD1 921T > C were not significantly different, and the OPRD1 80G was absent from both Chinese opioid dependence patients and controls. Based on the genotype and allele frequencies of the genomic control loci, there was no evidence for stratification bias capable of masking an association of OPRD1 to heroin dependence in this large and homogenous Chinese sample. Therefore, these data do not support an association between the OPRD1 gene and heroin dependence in the Chinese population.

背景与目标： ：药理和电生理证据表明，阿片受体参与海洛因依赖的机制。因此，阿片受体是海洛因依赖病例对照研究的合适候选基因。以前，人类三角洲阿片样物质受体基因的两个单核苷酸多态性（SNP）OPRD1 921T> C和80G> T被用于基于人群的海洛因依赖研究。一项针对德国人群的研究发现，OPRD1 921T> C与海洛因依赖有关。但是，这一发现并未在其他德国样品中重复出现。为了检验OPRD1或紧密联系的基因与海洛因依赖相关的假设，我们使用5'核酸酶分析对450例中国海洛因依赖患者和304例未患相同对照的两个OPRD1 SNP进行基因分型。另外，将五个分布在其他四个基因（ADH2，ALDH2，OPRM1和DRD1）中的SNP用作基因组控制位点，以测试病例和对照人群的分层偏倚。 OPRD1 921T> C的基因型和等位基因频率无显着差异，中国阿片类药物依赖患者和对照组均没有OPRD1 80G。根据基因组控制位点的基因型和等位基因频率，在这一大而均质的中国样本中，没有证据能够证明分层偏倚能够掩盖OPRD1与海洛因依赖性的关联。因此，这些数据不支持中国人群中OPRD1基因与海洛因依赖之间的关联。

BACKGROUND & AIMS: :Pharmacological data suggest that delta opioid receptors modulate learning and memory processes. In the present study, we investigated whether inactivation of the delta opioid receptor modifies hippocampus (HPC)- and striatum-dependent behaviors. We first assessed HPC-dependent learning in mice lacking the receptor (Oprd1(-/-) mice) or wild-type (WT) mice treated with the delta opioid antagonist naltrindole using novel object recognition, and a dual-solution cross-maze task. Second, we subjected mutant animals to memory tests addressing striatum-dependent learning using a single-solution response cross-maze task and a motor skill-learning task. Genetic and pharmacological inactivation of delta opioid receptors reduced performance in HPC-dependent object place recognition. Place learning was also altered in Oprd1(-/-) animals, whereas striatum-dependent response and procedural learning were facilitated. Third, we investigated the expression levels for a large set of genes involved in neurotransmission in both HPC and striatum of Oprd1(-/-) mice. Gene expression was modified for several key genes that may contribute to alter hippocampal and striatal functions, and bias striatal output towards striatonigral activity. To test this hypothesis, we finally examined locomotor effects of dopamine receptor agonists. We found that Oprd1(-/-) and naltrindole-treated WT mice were more sensitive to the stimulant locomotor effect of SKF-81297 (D1/D5), supporting the hypothesis of facilitated striatonigral output. These data suggest, for the first time, that delta receptor activity tonically inhibits striatal function, and demonstrate that delta opioid receptors modulate learning and memory performance by regulating the HPC/striatum balance.

背景与目标： ：药理学数据表明，δ阿片受体可调节学习和记忆过程。在本研究中，我们调查了阿片类阿片受体的失活是否会改变海马（HPC）和纹状体依赖性行为。我们首先评估了缺乏受体（Oprd1（-/-）小鼠）或野生型（WT）小鼠的HPC依赖型学习，该小鼠使用新颖的目标识别和双重解决方案交叉迷宫任务用δ阿片类拮抗剂纳曲酮治疗。其次，我们对突变动物进行了记忆测试，以使用单溶液响应交叉迷宫任务和运动技能学习任务来解决纹状体依赖型学习。 δ阿片受体的遗传和药理失活降低了HPC依赖的物体位置识别的性能。在Oprd1（-/-）动物中，位置学习也发生了变化，而纹状体依赖性反应和程序学习得到了促进。第三，我们调查了HPrd和Oprd1（-/-）小鼠纹状体中涉及神经传递的大量基因的表达水平。修改了几个关键基因的基因表达，这些关键基因可能有助于改变海马和纹状体的功能，并使纹状体的输出偏向于纹状体的活动。为了检验该假设，我们最终检查了多巴胺受体激动剂的运动作用。我们发现，Oprd1（-/-）和纳那多尔治疗的WT小鼠对SKF-81297（D1 / D5）的刺激运动效果更敏感，支持了纹状体神经输出促进的假设。这些数据首次表明，δ受体活性在声调上抑制纹状体功能，并证明δ阿片受体通过调节HPC /纹状体平衡来调节学习和记忆性能。

BACKGROUND & AIMS: :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.

背景与目标： ：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。

BACKGROUND & AIMS: :Mice with cytotoxic lesions of the dorsal hippocampus (DH) underestimated 15 s and 45 s target durations in a bi-peak procedure as evidenced by proportional leftward shifts of the peak functions that emerged during training as a result of decreases in both 'start' and 'stop' times. In contrast, mice with lesions of the ventral hippocampus (VH) displayed rightward shifts that were immediately present and were largely limited to increases in the 'stop' time for the 45 s target duration. Moreover, the effects of the DH lesions were congruent with the scalar property of interval timing in that the 15 s and 45 s functions superimposed when plotted on a relative timescale, whereas the effects of the VH lesions violated the scalar property. Mice with DH lesions also showed enhanced reversal learning in comparison to control and VH lesioned mice. These results are compared with the timing distortions observed in mice lacking δ-opioid receptors (Oprd1(-/-)) which were similar to mice with DH lesions. Taken together, these results suggest a balance between hippocampal-striatal interactions for interval timing and demonstrate possible functional dissociations along the septotemporal axis of the hippocampus in terms of motivation, timed response thresholds and encoding in temporal memory.

背景与目标： ：双峰过程中具有背海马（DH）细胞毒性损伤的小鼠低估了15 s和45 s的目标持续时间，这是由训练过程中由于两个“开始”次数减少导致的峰值功能按比例向左移动所证明的和“停止”时间。相反，具有腹侧海马（VH）损伤的小鼠表现出立即向右移动，并且在45 s目标持续时间内很大程度上受限于“停止”时间的增加。此外，DH病灶的影响与间隔时间的标量特性是一致的，因为在相对时间尺度上绘制时，15 s和45 s函数是重叠的，而VH病灶的影响却违反了标量特性。与对照组和VH损伤小鼠相比，具有DH损伤的小鼠还显示出增强的逆向学习能力。将这些结果与缺少δ阿片受体（Oprd1（-/-））的小鼠中观察到的时间畸变进行了比较，这些小鼠与DH损伤的小鼠相似。两者合计，这些结果表明间隔时间的海马-纹状体相互作用之间的平衡，并证明了在动机，定时反应阈值和时间记忆编码方面沿着海马间隔时轴的可能功能分离。