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

• 批准号: 10491282
• 负责人: Anna Kay Radke
• 金额: $ 16.93万
• 依托单位: MIAMI UNIVERSITY OXFORD
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491282
• 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

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 儿童期创伤易合并PTSD/AUD，尤其是女性患者。因为 介导创伤后应激障碍和AUD易感性的神经基质可能是相似的，阐明了这些共同点。 机制可能为两者的新治疗选择提供基础。婴儿创伤是一个强大的， 构建PTSD和AUD的有效模型。暴露于创伤的动物表现出增强的恐惧学习，抵抗力 灭绝，以及成年后饮酒增加，并且对这些影响的脆弱性增加， 女性这项提案探讨了婴儿创伤导致脑内神经元表达持续上调的新假设。 杏仁核中的莫尔表达嵌入神经元，最终解除中央杏仁核神经元的抑制。 我们的实验将通过完成三个主要的具体目标来验证这一假设。雄性和雌性 小鼠，我们将1）确定是否莫尔mRNA表达增加杏仁核闰神经元 在婴儿创伤后，2）确定ITC中受压力和酒精调节的新分子靶点， 和3）证实了插入细胞MORs在介导婴儿创伤对新生儿的影响中的因果作用。 饮酒。将通过在出生后第17天提供15次足部电击来模拟婴儿创伤。醇 饮酒将在两瓶选择中进行评估，在黑暗中饮酒。总的来说，完成这些 aims将为一种机制提供支持，通过这种机制，早期生活逆境可能会增加对压力源的敏感性 成年后增加饮酒量我们的工作还将进一步验证创伤压力和性的模型- 对饮酒的依赖性影响。