Transgenerational inheritance of a Cocaine resistance phenotype

可卡因耐药表型的跨代遗传

基本信息

批准号：
10183208
负责人：
Robert Christopher Pierce
金额：
$ 47.74万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183208
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 Serine Slice Specificity Spermatogenesis Synaptic plasticity Testis Time Tissues Translating Work base cocaine exposure cocaine self-administration 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

项目摘要

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.

该研究项目的重点是父亲服用可卡因对生理和行为的影响后代（即后代和孙辈）。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，包括情景记忆障碍。我们的工作假设是，父亲接触可卡因会引起学习和突触可塑性损伤通过降低海马中的 D-丝氨酸水平/NMDA 受体信号传导来影响雄性后代和孙子。在具体目标 1、学习和记忆以及长时程增强 (LTP)，这是公认的生理学习相关性将在自我施用可卡因的公牛的后代中进行评估。基于对象的记忆分析的初步结果表明，男性（而非女性）的后代和接触可卡因的公牛的孙辈会损害海马体依赖性的物体位置记忆。父亲接触可卡因也会损害男性后代的海马 LTP。在具体目标 2 中，我们将评估假设可卡因成年后裔的这些学习和突触可塑性缺陷经验丰富的公牛是由于背侧海马 D-丝氨酸/NMDA 受体信号减弱所致，关键参与空间学习和突触可塑性。初步数据表明 D-丝氨酸水平可卡因雄性大鼠的背侧海马体减少。 D-氨基酸氧化酶 (DAAO) 催化 D-丝氨酸的氧化脱氨。初步数据表明 daao1 mRNA 水平可卡因雄性大鼠的背侧海马体增加。检查潜在的表观遗传机制在 daao1 mRNA 增加的基础上，与 daao1 相关的组蛋白翻译后修饰将在 F1 和 F2 代中进行检查。最后，将给予 D-丝氨酸、D-环丝氨酸或 DAAO 抑制剂进入可卡因后代或可卡因孙代大鼠的背侧海马体或海马切片上，我们将其预测将挽救空间学习和可塑性缺陷。在具体目标 3 中，我们将评估信息的表现方式通过评估经历过可卡因的公牛精子中 miRNA 的变化，在代际间进行转移他们的后代。初步数据表明，可卡因自我给药显着改变了四种 miRNA（miR- 1-3p、miR-206-3p、miR-1b、miR-362-3p）在父系精子中。为了确定 CNS 是否需要可卡因对精子 miRNA 的影响我们将比较自我施用的可卡因和轭可卡因甲碘化物，它不穿过血脑屏障。我们还将评估可卡因引起的变化的持续时间通过在自我施用可卡因后 1 或 90 天评估 miRNA 来检测精子。总的来说，这些实验将确定经历过可卡因的雄性后代的海马功能的变化导致这些动物的学习缺陷。我们还将检查可卡因引起的精子变化可能在代际间传递信息。总的来说，我们定义了一种可卡因诱导的遗传性新模型学习缺陷。这些结果对可卡因成瘾者的后代具有明确而重大的影响。