Simultaneous prenatal alcohol and cannabinoid exposure & offspring corticostriatal neurocircuitry

产前同时接触酒精和大麻素

• 批准号: 10615012
• 负责人: Siara Rouzer
• 金额: $ 6.91万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10615012
• 关键词: 2-arachidonylglycerol; ATAC-seq; Actins; Acute; Address; Age; Alcohol consumption; Alcohols; Applications Grants; Behavior; Behavioral; Behavioral Assay; Biological; Biological Assay; CNR1 gene; Cannabinoids; Cannabis; Child; Chromatin; Clinical assessments; Code; Consumption; Corpus striatum structure; Cytoskeletal Proteins; Data; Development; Drug Combinations; Drug Exposure; Drug usage; Economics; Endocannabinoids; Environment; Enzyme-Linked Immunosorbent Assay; Ethanol; Exhibits; Exposure to; Female; Fetal Alcohol Exposure; Fetal Development; Future; Genes; Genetic; Glutamates; Goals; Growth; Health; Human; Hyperactivity; Impairment; Individual; Inhalation; Knowledge; Ligands; Link; Literature; Long-Term Depression; Longevity; Mentors; Mentorship; Messenger RNA; Modification; Mothers; Motor; Mus; Neurologic; Neurons; Nuclear; Output; Patient Self-Report; Pharmaceutical Preparations; Physiological; Pre-Clinical Model; Pregnancy; Proteins; Proteomics; Psychotropic Drugs; Quality of life; Recording of previous events; Records; Research; Research Personnel; Risk; Self Administration; Signal Pathway; Societies; Source; Synapses; Synaptic Transmission; Synaptic plasticity; Synaptosomes; Technical Expertise; Teratology; Testing; Therapeutic; Therapeutic Intervention; Training; Transposase; adverse outcome; alcohol exposure; alcohol seeking behavior; anandamide; behavioral impairment; behavioral phenotyping; brain tissue; career; child bearing; design; developmental disease; disability; drug seeking behavior; endocannabinoid signaling; endogenous cannabinoid system; experimental study; fetal; fetal drug exposure; fetal marijuana exposure; field study; gene network; improved; in utero; locomotor deficit; male; marijuana user; motor deficit; motor disorder; motor impairment; nerve stem cell; neural circuit; neurodevelopment; neurogenesis; neurophysiology; offspring; pre-clinical; preference; prenatal; prenatal exposure; presynaptic; protein expression; psychosocial; receptor; sex; social stigma; synthetic cannabinoid; targeted treatment; transcriptome sequencing; young adult

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.

项目摘要 产前酒精暴露（PAE）是发育障碍的最常见原因，尽管并发 接触其他精神活性物质可能会加剧广告结果。最近偏爱 同时使用酒精和大麻（SAC）的育龄年轻人与早期结合 协同发展危害的临床前证据，支持将SAC作为特定的前提 残疾的发展来源。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）在后代中改变内源性大麻素信号传导，尚不清楚是否尚不清楚 CNR1的损害 - 健康胎儿神经发育必不可少的受体 - 与基本损害相关 与囊。值得注意的是，PAE会损害CNR1调节的突触传播，从纹状体注射的皮质神经元传播。 在没有药物的小鼠中，纹状体CNR1调节的活性受损会导致运动功能障碍，多动症和 在患有PAE和PCE的人类中观察到的定义的毒品行为增加。因此，目的 该建议是研究SAC对CNR1相关的神经回路和行为的影响 后代。我们实验室的初步数据表明，调节纹状体的CNR1相关基因网络 突触活动通过急性胎儿乙醇暴露而改变，结合SAC暴露增加了生长 单药和无药物暴露的神经元干细胞缺乏。总体而言，文献和这些数据 告知我们的中心假设，即SAC后代将暴露于CNR1连接的突触机制受损 与运动增加相对应的纹状体定义了和寻求药物的行为。 我们将在以下目的中检验这一假设：特定目的1）评估SAC诱导基因变化的变化 调节皮质纹状体突触活性。我们将使用集成的RNASEQ和ATAC-SEQ来研究 确定与CNR1调节的基因网络在产前中的皮质纹状体突触可塑性 暴露后代。具体目标2）评估SAC是否会增加行为定义和纹状体蛋白 表达。我们将执行一系列调查本机在运动功能中定义的行为分析和 产前暴露的后代中寻求乙醇的行为。我们将比较行为定义与纹状体 使用三明治ELISA，量化CNR1和内源性大麻素配体的蛋白质表达 anandamide和2-芳基甘油甘油。产前药物暴露将从妊娠天12-15发生 皮质神经元的峰神经发生，并将掺入蒸发乙醇和i.p 合成大麻素CP-55940的给药。该提案的成功完成将确定具体 SAC的机械变化是一种翻译的和不介绍的产前药物形式 暴露，并告知未来的热干预目标。此外，提出的实验将 为出色的培训环境提供框架，包括来自多个赞助商的精通制度和 合作者，随后将为科学严格的K99/R00赠款申请提供信息。

项目成果

The importance of promoting scientific advocacy & outreach for trainees.

• DOI: 10.1038/s41386-023-01530-6
• 发表时间: 2023-04
• 期刊: NEUROPSYCHOPHARMACOLOGY
• 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: FRONTIERS IN NEUROSCIENCE
• 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.