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

项目摘要 童年创伤使人更容易患上创伤后应激障碍/非精神病症，尤其是女性患者。因为 调节创伤后应激障碍和AUD易感性的神经底物可能是相似的，解释了这些共同的 机制可能为两者的新治疗选择提供基础。婴儿创伤是一种强大的， 构建有效的创伤后应激障碍和AUD模型。暴露在创伤中的动物表现出增强的恐惧学习和抵抗力 在成年后更容易受到这些影响的影响 女性。这项建议探索了一种新的假设，即婴儿创伤会在 MOR在杏仁核间的神经元中表达，最终抑制中央杏仁核的神经元。 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。在男性和女性中 小鼠，我们将1)确定杏仁核间质神经元中MOR mRNA的表达是否增加 在婴儿创伤后2)确定ITC中受压力和酒精调控的新分子靶点， 3)证实了嵌入细胞MORS在婴儿创伤的影响中的因果作用。 酗酒。婴儿创伤的模型是在出生后第17天进行15次足电击。 饮酒将在两瓶酒的选择中进行评估，在黑暗范例中饮酒。总体而言，完成这些 AIMS将为一种机制提供支持，通过这种机制，早期生活中的逆境可能会增加对压力源的敏感性 并在成年后增加饮酒。我们的工作还将进一步验证创伤应激和性行为的模型- 对饮酒的依赖影响。

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.