Simultaneous prenatal alcohol and cannabinoid exposure & offspring corticostriatal neurocircuitry
产前同时接触酒精和大麻素
基本信息
- 批准号:10615012
- 负责人:
- 金额:$ 6.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:2-arachidonylglycerolATAC-seqActinsAcuteAddressAgeAlcohol consumptionAlcoholsApplications GrantsBehaviorBehavioralBehavioral AssayBiologicalBiological AssayCNR1 geneCannabinoidsCannabisChildChromatinClinical assessmentsCodeConsumptionCorpus striatum structureCytoskeletal ProteinsDataDevelopmentDrug CombinationsDrug ExposureDrug usageEconomicsEndocannabinoidsEnvironmentEnzyme-Linked Immunosorbent AssayEthanolExhibitsExposure toFemaleFetal Alcohol ExposureFetal DevelopmentFutureGenesGeneticGlutamatesGoalsGrowthHealthHumanHyperactivityImpairmentIndividualInhalationKnowledgeLigandsLinkLiteratureLong-Term DepressionLongevityMentorsMentorshipMessenger RNAModificationMothersMotorMusNeurologicNeuronsNuclearOutputPatient Self-ReportPharmaceutical PreparationsPhysiologicalPre-Clinical ModelPregnancyProteinsProteomicsPsychotropic DrugsQuality of lifeRecording of previous eventsRecordsResearchResearch PersonnelRiskSelf AdministrationSignal PathwaySocietiesSourceSynapsesSynaptic TransmissionSynaptic plasticitySynaptosomesTechnical ExpertiseTeratologyTestingTherapeuticTherapeutic InterventionTrainingTransposaseadverse outcomealcohol exposurealcohol seeking behavioranandamidebehavioral impairmentbehavioral phenotypingbrain tissuecareerchild bearingdesigndevelopmental diseasedisabilitydrug seeking behaviorendocannabinoid signalingendogenous cannabinoid systemexperimental studyfetalfetal drug exposurefetal marijuana exposurefield studygene networkimprovedin uterolocomotor deficitmalemarijuana usermotor deficitmotor disordermotor impairmentnerve stem cellneural circuitneurodevelopmentneurogenesisneurophysiologyoffspringpre-clinicalpreferenceprenatalprenatal exposurepresynapticprotein expressionpsychosocialreceptorsexsocial stigmasynthetic cannabinoidtargeted treatmenttranscriptome sequencingyoung adult
项目摘要
PROJECT SUMMARY
Prenatal alcohol exposure (PAE) is the most common cause of developmental disorders, though concurrent
exposure to other psychoactive substances may exacerbate adverse outcomes. Recent preference for
simultaneous use of alcohol and cannabis (SAC) among young adults of child-bearing age combined with early
preclinical evidence for synergistic developmental harm, support a premise for investigating SAC as a specific
developmental source of disability. Despite indications that both PAE and prenatal cannabinoid exposure (PCE)
alter endocannabinoid signaling through cannabinoid receptor 1 (CNR1) in offspring, it is yet unknown whether
impairments to CNR1 – a receptor essential to healthy fetal neurodevelopment – underly impairments associated
with SAC. Notably, PAE impairs CNR1-regulated synaptic transmission from striatal-projecting cortical neurons.
In drug-naïve mice, impaired striatal CNR1-regulated activity contributes to motor dysfunction, hyperactivity and
increased drug-seeking behaviors, deficits observed in humans with PAE and PCE. Therefore, the objective of
this proposal is to investigate the impact of SAC on CNR1-associated neural circuits and behaviors in exposed
offspring. Preliminary data from our lab have shown that a CNR1-associated gene network that regulates striatal
synaptic activity is changed by acute fetal ethanol exposure, and combined SAC exposure augments growth
deficits in neural stem cells from single-drug and drug-free exposures. Collectively, the literature and these data
inform our central hypothesis that SAC offspring will exhibit impaired CNR1-linked synaptic mechanisms within
the striatum corresponding with increased motor deficits and drug-seeking behaviors.
We will test this hypothesis in the following aims: Specific Aim 1) To assess SAC-induced changes in genes
that regulate corticostriatal synaptic activity. We will use integrative RNAseq and ATAC-seq to investigate a pre-
determined gene network associated with CNR1-regulated corticostriatal synaptic plasticity in prenatally
exposed offspring. Specific Aim 2) To assess whether SAC augments behavioral deficits and striatal protein
expression. We will perform a battery of behavioral assays investigating native deficits in motor function and
ethanol-seeking behaviors in prenatally exposed offspring. We will compare behavioral deficits with striatal
protein expression using sandwich ELISAs, quantifying CNR1 and endogenous cannabinoid ligands
anandamide and 2-arachidonylglycerol. Prenatal drug exposure will occur from gestational days 12-15, a period
of peak neurogenesis for corticostriatal neurons, and will incorporate vaporized ethanol inhalation and i.p
administration of synthetic cannabinoid CP-55940. Successful completion of this proposal will identify specific
mechanistic changes underlying SAC, a translationally-relevant but under-investigated form of prenatal drug
exposure, and inform future targets for therapeutic intervention. Furthermore, the proposed experiments will
provide the framework for an excellent training environment, including mentorship from multiple sponsors and
collaborators, and will subsequently inform a scientifically rigorous K99/R00 grant application.
项目总结
产前酒精暴露(PAE)是导致发育障碍的最常见原因,尽管是同时发生的
接触其他精神活性物质可能会加剧不良后果。最近的偏好是
同时使用酒精和大麻(SAC)的育龄青壮年合并早期
协同性发育损害的临床前证据,支持将SAC作为特异性研究的前提
残疾的发育来源。尽管有迹象表明PAE和产前大麻素暴露(PCE)
通过大麻素受体1(CNR1)改变子代的内源性大麻素信号,目前尚不清楚
CNR1--对健康胎儿神经发育至关重要的受体--的损害--与此相关的损害
与SAC合作。值得注意的是,PAE损害了CNR1调节的纹状体皮质投射神经元的突触传递。
在药物幼稚的小鼠中,纹状体CNR1调节的活性受损导致运动功能障碍、多动和
在PAE和PCE患者中观察到的药物寻求行为增加和缺陷。因此,它的目标是
本研究旨在探讨SAC对暴露大鼠CNR1相关神经回路和行为的影响。
后代。我们实验室的初步数据显示,调节纹状体的CNR1相关基因网络
急性胎儿酒精暴露可改变突触活性,联合SAC暴露可促进生长
单一药物和非药物暴露导致的神经干细胞缺陷。总的来说,这些文献和这些数据
告诉我们的中心假设SAC子代将表现出CNR1连接的突触机制受损
纹状体对应着运动缺陷和寻求毒品行为的增加。
我们将在以下目标中检验这一假设:具体目标1)评估SAC诱导的基因变化
调节皮质纹状体突触活动的物质。我们将使用整合的RNAseq和ATAC-seq来调查
CNR1调节的胎儿期皮质纹状体突触可塑性相关基因网络的确定
暴露的后代。具体目的2)评估SAC是否增加行为缺陷和纹状体蛋白
表情。我们将进行一系列的行为分析,调查天生的运动功能缺陷和
胎儿期接触酒精的后代的酒精寻觅行为。我们会将行为缺陷与纹状体进行比较
用夹心ELISA技术进行蛋白质表达,定量CNR1和内源性大麻素配体
花椒胺和2-花生四烯基甘油。产前药物暴露将发生在怀孕12-15天,一个时期
皮质纹状体神经元的神经发生高峰,并将结合雾化乙醇吸入和ip
给药合成大麻素CP-55940。成功完成本建议书将确定具体的
SAC是一种与翻译相关但研究不足的产前用药形式,其机制变化
暴露,并告知未来的治疗干预目标。此外,拟议的实验将
为良好的培训环境提供框架,包括来自多个赞助商和
合作者,并将随后通知科学严格的K99/R00赠款申请。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The importance of promoting scientific advocacy & outreach for trainees.
- DOI:10.1038/s41386-023-01530-6
- 发表时间:2023-04
- 期刊:
- 影响因子:7.6
- 作者:Rouzer, Siara Kate;Kalinowski, Leanna Marie;Kaseda, Erin Taniyo
- 通讯作者:Kaseda, Erin Taniyo
Microbiota and nutrition as risk and resiliency factors following prenatal alcohol exposure.
- DOI:10.3389/fnins.2023.1182635
- 发表时间:2023
- 期刊:
- 影响因子:4.3
- 作者:Upreti, Deepa;Rouzer, Siara K. K.;Bowring, Abigail;Labbe, Emma;Kumar, Rosaline;Miranda, Rajesh C. C.;Mahnke, Amanda H. H.
- 通讯作者:Mahnke, Amanda H. H.
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Siara Rouzer其他文献
Siara Rouzer的其他文献
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{{ truncateString('Siara Rouzer', 18)}}的其他基金
Prenatal Alcohol Exposure, CRF and Adolescent Anxiety
产前酒精暴露、CRF 和青少年焦虑
- 批准号:
9910898 - 财政年份:2019
- 资助金额:
$ 6.91万 - 项目类别:
Prenatal Alcohol Exposure, CRF and Adolescent Anxiety
产前酒精暴露、CRF 和青少年焦虑
- 批准号:
10023141 - 财政年份:2019
- 资助金额:
$ 6.91万 - 项目类别:
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