Transgenerational inheritance of a Cocaine resistance phenotype

可卡因耐药表型的跨代遗传

• 批准号: 9176554
• 负责人: Robert Christopher Pierce
• 金额: $ 49.12万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176554
• 关键词: Adult; Anatomy; Animals; Anxiety; Behavior; Behavioral; Binding; Binding Sites; Biological Assay; Blood - brain barrier anatomy; Brain; Characteristics; Cocaine; Cocaine Dependence; Cycloserine; D-Amino Acid Dehydrogenase; Data; Deamination; Dorsal; Electrophysiology (science); Enzymes; Epigenetic Process; Episodic memory; Gene Expression; Generations; Genetic Transcription; Glutamates; Grant; Heritability; Hippocampus (Brain); Histones; Human; Impaired cognition; Impairment; Inherited; Learning; Link; Location; Long-Term Potentiation; Memory; Memory impairment; Messenger RNA; Methodology; MicroRNAs; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; Neurons; Phenotype; Physiological; Physiology; Post-Translational Protein Processing; Rattus; Receptor Activation; Receptor Signaling; Research; Resistance; Saline; Self Administration; Self-Administered; Serine; Slice; Specificity; Spermatogenesis; Synaptic plasticity; Testis; Time; Tissues; Translating; Work; base; cocaine exposure; epidemiologic data; epigenome; episodic memory impairment; expectation; experience; experimental study; histone modification; inhibitor/antagonist; male; novel; object recognition; offspring; programs; serine racemase; sex; sperm cell; transgenerational epigenetic inheritance

The focus of this research program is the influence of paternal cocaine taking on the physiology and behavior of subsequent generations (i.e. offspring and grandoffspring). Human epidemiological data indicates that cocaine addiction is often accompanied by cognitive decline including episodic memory impairments. Our working hypothesis is that paternal cocaine exposure elicits learning and synaptic plasticity impairments in male offspring and grandoffspring by reducing D-serine levels/NMDA receptor signaling in the hippocampus. In Specific Aim 1, learning and memory as well as long term potentiation (LTP), a generally accepted physiological learning correlate, will be assessed in the offspring of sires that self-administered cocaine. Preliminary findings from object-based memory assays indicate that male, but not female, offspring and grandoffspring of cocaine-exposed sires have impaired hippocampus-dependent object location memory. Paternal cocaine exposure also impairs hippocampal LTP in male offspring. In Specific Aim 2 we will evaluate the hypothesis that these learning and synaptic plasticity deficits in the adult descendants of cocaine- experienced sires are due to decreased dorsal hippocampal D-serine/NMDA receptor signaling, which are critically involved in spatial learning and synaptic plasticity. Preliminary data indicate that D-serine levels are decreased in the dorsal hippocampus of cocaine-sired male rats. The enzyme D-amino acid oxidase (DAAO) catalyzes the oxidative deamination of D-serine. Preliminary data indicate that daao1 mRNA levels are increased in the dorsal hippocampus of cocaine-sired male rats. To examine potential epigenetic mechanisms underlying the increase in daao1 mRNA, histone posttranslational modifications associated with daao1 will be examined in F1 and F2 generations. Finally, D-serine, D-cycloserine or a DAAO inhibitor will be administered into the dorsal hippocampus or onto hippocampal slices of cocaine-sired or cocaine-grandsired rats, which we predict will rescue spatial learning and plasticity deficits. In Specific Aim 3 we will evaluate how information is transferred between generations by assessing miRNA changes in the sperm of cocaine-experienced sires and their offspring. Preliminary data indicate that cocaine self-administration significantly altered four miRNAs (miR- 1-3p, miR-206-3p, miR-1b, miR-362-3p) in sire sperm. In order to determine if the CNS is required for the effect of cocaine on sperm miRNAs we will compare self-administered cocaine to yoked cocaine methiodide, which does not cross the blood-brain barrier. We also will assess the duration of cocaine-induced changes in sperm by evaluating miRNAs 1 or 90 days following cocaine self-administration. Collectively, these experiments will determine changes in hippocampal function in the descendants of cocaine-experienced sires that contribute to learning deficits in these animals. We also will examine cocaine-induced changes in sperm that may carry information between generations. Overall, we define a novel model of heritable cocaine-induced learning deficits. These results have clear and significant implications for the descendants of cocaine addicts.

该研究计划的重点是父亲可卡因对生理和行为的影响 随后的世代（即后代和grandoffspring）。人类流行病学数据表明 可卡因成瘾通常伴随着认知能力下降，包括情节记忆障碍。我们的 工作假设是父亲可卡因暴露会引起学习和突触可塑性障碍 通过降低海马中的D丝氨酸水平/NMDA受体信号传导，雄性后代和grandoffspring。在 特定的目标1，学习和记忆以及长期增强（LTP），公认 生理学习相关，将在自我管理可卡因的父亲的后代中进行评估。 基于对象的内存测定的初步发现表明，男性，但不是女性，后代和 可卡因暴露的sires的grandoffspring损害了海马依赖的对象位置记忆。 父亲可卡因的暴露还会损害男性后代海马LTP。在特定目标2中，我们将评估 可卡因成年后代的这些学习和突触可塑性缺陷的假设 经验丰富的父亲是由于背部海马D-丝氨酸/NMDA受体信号的降低所致，这是 与空间学习和突触可塑性进行了严格的参与。初步数据表明D丝氨酸水平是 可卡因租用的雄性大鼠的背侧海马减少。酶D-氨基酸氧化酶（DAAO） 催化D丝氨酸的氧化脱氨基。初步数据表明DAAO1 mRNA水平是 可卡因租用的雄性大鼠的背侧海马增加。检查潜在的表观遗传机制 DAAO1 mRNA的增加，与DAAO1相关的翻译后修饰将是 在F1和F2世代检查。最后，将施用D-丝氨酸，D-胞丝烯或DAAO抑制剂 进入背侧海马或可卡因诱的或可卡因偏见的大鼠的海马切片，我们是我们的 预测将挽救空间学习和可塑性缺陷。在特定目标3中，我们将评估信息的方式 通过评估可卡因经验经验的sires的精子中的miRNA变化，在世代之间转移 他们的后代。初步数据表明，可卡因自我给药显着改变了四个miRNA（mir- 父亲精子中的1-3p，mir-206-3p，mir-1b，mir-362-3p）。为了确定是否需要CNS 可卡因对精子miRNA的影响，我们将比较自我管理的可卡因与甲基甲碘的甲基甲碘化物， 不会越过血脑屏障。我们还将评估可卡因引起的变化的持续时间 通过评估可卡因自我管理后1或90天的miRNA 1或90天的精子。总的来说，这些 实验将确定可卡因经验的后代的海马功能变化 这有助于这些动物的学习缺陷。我们还将检查可卡因诱导的精子变化 这可能会在几代人之间提供信息。总体而言，我们定义了可卡因诱导的新型模型 学习缺陷。这些结果对可卡因成瘾者的后代具有明显的影响。