Determining the effect of early resource scarcity on adolescent addiction-related behavior and cell-type specific transcription

确定早期资源稀缺对青少年成瘾相关行为和细胞类型特异性转录的影响

基本信息

批准号：
10825012
负责人：
Debra A Bangasser
金额：
$ 26.74万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10825012
关键词：
Address Adolescence Adolescent Adult Affect Animal Model Beds Behavior Behavior assessment Behavioral Brain Brain region Cells Data Development Drug usage Early-life trauma Environment Experimental Designs Exposure to Female Follow-Up Studies Future Gene Expression Genes Genetic Transcription Glutamates Heterogeneity Housing Impulsivity Intervention Life Life Experience Link Male Adolescents Medial Mediating Modeling Molecular Molecular Profiling Morphine Motivation Neurons Neurosciences Nucleus Accumbens Opioid Outcome Pathway Analysis Pathway interactions Pharmaceutical Preparations Phenotype Prefrontal Cortex Procedures Protocols documentation Publishing Rattus Resource-limited setting Resources Risk Risk Reduction Self Administration Stress Substance Use Disorder Testing Time Tissues Transcription Alteration Work addiction behavioral phenotyping cell type discounting disorder risk drug of abuse early experience early life adversity endophenotype glutamatergic signaling innovation insight male mature animal neural neurotransmission novel novel strategies pediatric trauma postnatal pre-clinical presynaptic promote resilience pup resilience reward circuitry sex single nucleus RNA-sequencing stress resilience stressor transcriptome transcriptomics validation studies vesicle transport

项目摘要

PROJECT SUMMARY Early life experiences can have long-lasting consequences on risk and resilience for developing substance use disorder (SUD). While trauma early in life increases risk for SUD, brief early stressor exposure can promote stress inoculation or later resilience. Much of the preclinical work studying how the early environment affects addiction-related behaviors has focused on outcomes in adult animals. However, this approach misses how early experiences alter the trajectory of the development of brain regions implicated in SUD and limits our ability to know if interventions for SUD would be effective earlier, such as in adolescence, when first exposure to drugs of abuse often occurs. This proposal addresses this gap and tests how a rat model of brief early resource scarcity alters adolescent impulsivity, opioid taking, and cell-type specific transcription in the medial prefrontal cortex (mPFC), a key part of the reward circuitry that is developing in adolescence. This proposal builds on our labs extensive work characterizing the effects of the limited bedding/nesting (LBN) manipulation on adult addiction- related outcomes. In LBN, dams and pups are in a low resource environment during pups first week of life and effects are compared to rats raised with adequate resources throughout development. We previously found that LBN causes sex-specific resilience to addiction-related behaviors, reducing impulsive choice and morphine taking, in adult male but not in adult female rats. We also found alterations in glutamatergic signaling in reward circuitry in adult LBN males that can contribute to resilience. This proposal will extend this work to determine, for the first time, whether LBN causes similar behavioral and molecular changes in adolescent rats. Aim 1 will used innovative new behavioral procedures that allow for testing impulsive choice with delayed discounting and morphine self-administration in adolescent rats. We expect that, like in adulthood, LBN will promote male-specific resilience to adolescent impulsivity and drug taking. Aim 2 will build on new unpublished single nucleus RNA sequencing (scRNAseq) assessing how LBN alters cell-type specific transcription in the adult mPFC. This approach overcomes limitations of past work using bulk tissue where transcriptomic alterations cannot be assigned to any particular cell type. In adults, we found that LBN alters genes in one subtype of excitatory glutamatergic neurons in the mPFC of only adult males and several of these genes are involved in vesicular transport, which could lead to altered presynaptic glutamate release. Here we will test the prediction that LBN causes similar male-specific transcriptional alterations in glutamatergic neurons in adolescents, while also discovering novel gene expression changes within genetically defined subtypes of cells in the mPFC. By combining this novel adolescent phenotyping with prior adult work, we can determine how LBN affects the developmental trajectory of addiction-related behaviors and the transcriptional dynamics of the mPFC. The data generated here will also serve as a valuable resource for the fields of SUD and developmental neuroscience.

项目概要早期的生活经历可能会对药物滥用的风险和恢复力产生长期的影响紊乱（SUD）。虽然生命早期的创伤会增加 SUD 的风险，但早期短暂的压力源暴露可以促进压力接种或后期恢复力。许多临床前工作研究早期环境如何影响与成瘾相关的行为主要集中在成年动物的结果上。然而，这种方法忽略了尽早经历改变了与 SUD 相关的大脑区域的发育轨迹，并限制了我们的能力尽早了解 SUD 干预措施是否有效，例如在青春期，当第一次接触药物时滥用行为经常发生。该提案解决了这一差距，并测试了短暂的早期资源稀缺的老鼠模型如何改变青少年冲动、阿片类药物服用和内侧前额叶皮层的细胞类型特异性转录（mPFC），是青春期发育的奖励回路的关键部分。该提案建立在我们的实验室基础上大量的工作描述了有限的床上用品/嵌套（LBN）操作对成人成瘾的影响 - 相关结果。在 LBN 中，母崽和幼崽在幼崽出生后的第一周都处于资源匮乏的环境中，将效果与在整个发育过程中使用充足资源饲养的老鼠进行比较。我们之前发现 LBN 会导致针对成瘾相关行为的性别特异性恢复力，减少冲动选择和吗啡在成年雄性大鼠中服用，但不在成年雌性大鼠中服用。我们还发现奖励中谷氨酸信号的改变成年 LBN 男性中有助于增强恢复力的电路。该提案将扩展这项工作以确定，首次研究 LBN 是否会引起青春期大鼠类似的行为和分子变化。将使用目标 1 创新的新行为程序，可以通过延迟折扣来测试冲动选择，青春期大鼠吗啡自我给药。我们预计，就像成年后一样，LBN 将促进男性特异性对青少年冲动和吸毒的抵抗力。目标 2 将建立在新的未发表的单核 RNA 的基础上测序 (scRNAseq) 评估 LBN 如何改变成人 mPFC 中的细胞类型特异性转录。这方法克服了过去使用大块组织进行转录组改变无法进行的工作的局限性分配给任何特定的细胞类型。在成人中，我们发现 LBN 改变了一种兴奋亚型的基因仅成年男性的 mPFC 中存在谷氨酸能神经元，其中一些基因与囊泡运输，这可能导致突触前谷氨酸释放的改变。这里我们将测试 LBN 的预测引起青少年谷氨酸能神经元中类似的男性特异性转录改变，同时也发现 mPFC 中基因定义的细胞亚型中新的基因表达变化。经过将这种新颖的青少年表型与之前的成人研究相结合，我们可以确定 LBN 如何影响成瘾相关行为的发展轨迹和 mPFC 的转录动态。数据这里产生的也将成为 SUD 和发育神经科学领域的宝贵资源。