Sex-specific effects of infant trauma on adult alcohol drinking: Role of amygdala intercalated neurons

婴儿创伤对成人饮酒的性别特异性影响：杏仁核嵌入神经元的作用

基本信息

批准号：
10193084
负责人：
Anna Kay Radke
金额：
$ 19.86万
依托单位：
MIAMI UNIVERSITY OXFORD
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10193084
关键词：
Adult Affect Alcohol consumption Alcohols Amygdaloid structure Animals Automobile Driving Behavior Behavioral Model Bioinformatics Cell Nucleus Cells Clinical Coupled Data Development Disease Exposure to Extinction (Psychology)FOXP2 gene Female Foundations Fright Gene Expression Genetic Genomics Impairment Individual Infant Intercalated Cell Interneurons Knowledge Learning Measures Mediating Modeling Molecular Target Mus National Institute on Alcohol Abuse and Alcoholism Neurons Patients Pattern Pharmacotherapy Post-Traumatic Stress Disorders Protocols documentation Publishing Rattus Receptor Gene Recording of previous events Regulation Research Research Personnel Resistance Reverse Transcriptase Polymerase Chain Reaction Rodent Role Series Stress Testing Time Trauma Universities Up-Regulation Viral Viral Vector Water Work alcohol comorbidity alcohol exposure alcohol use disorder comorbidity conditioned fear designer receptors exclusively activated by designer drugs drinking drinking behavior early life adversity early life stress experience experimental study functional genomics innovation mRNA Expression male mouse model mu opioid receptors novel pediatric trauma postnatal pre-clinical research preference receptor receptor expression relating to nervous system sex stressor transcriptome sequencing trauma exposure traumatic stress whole genome

项目摘要

Project Summary Childhood trauma confers vulnerability to comorbid PTSD/AUD, particularly in female patients. Because the neural substrates mediating vulnerability to PTSD and AUD may be similar, elucidating these common mechanisms may provide the foundation for novel treatment options for both. Infant trauma is a powerful, construct-valid model of PTSD and AUD. Trauma-exposed animals show potentiated fear learning, resistance to extinction, and increased alcohol drinking as adults and there is an enhanced vulnerability to these effects in females. This proposal explores the novel hypothesis that infant trauma produces enduring upregulation in MOR expression in amygdala intercalated neurons, ultimately disinhibiting neurons of the central amygdala. Our experiments will test this hypothesis through completion of three primary specific aims. In male and female mice, we will 1) determine whether MOR mRNA expression is increased in amygdala intercalated neurons following infant trauma 2) identify novel molecular targets in the ITC that are regulated by stress and alcohol, and 3) demonstrate a causal role for intercalated cells MORs in mediating the effects of infant trauma on alcohol drinking. Infant trauma will be modeled by delivering 15 footshocks on postnatal day 17. Alcohol drinking will be assessed in a two-bottle choice, drinking in the dark paradigm. Collectively, completion of these aims will provide support for a mechanism by which early life adversity may increase sensitivity to stressors and increase drinking in adulthood. Our work will also further validate a model of traumatic stress and sex- dependent effects on alcohol drinking.

项目摘要童年创伤赋予了合并症PTSD/AUD的脆弱性，尤其是在女性患者中。因为介导PTSD和AUD的神经底物可能相似，阐明了这些常见机制可以为两者的新型治疗选择提供基础。婴儿创伤是一个强大的 PTSD和AUD的构造valid模型。暴露创伤的动物表现出恐惧学习，抵抗力的增强灭绝，成年人的饮酒增加，并且在这些影响方面存在着增强的脆弱性女性。该提案探讨了新的假设，即婴儿创伤会产生持久的上调 MOR表达在杏仁核插入神经元中，最终抑制了中央杏仁核的神经元。我们的实验将通过完成三个主要特定目标来检验这一假设。在男性和女性小鼠，我们将1）确定在杏仁核插入神经元中MOR mRNA表达是否增加婴儿创伤后2）确定ITC中受压力和酒精调节的新型分子靶标的 3）证明了插入细胞在介导婴儿创伤对影响的作用中的因果作用饮酒。婴儿创伤将通过在产后第17天传递15个脚印来建模。饮酒将以两瓶选择进行评估，在深色范式中喝酒。共同完成这些目标将为早期逆境可能增加对压力源的敏感性提供支持并增加成年后的饮酒。我们的工作还将进一步验证创伤性压力和性别模型 - 对饮酒的依赖性影响。