Mechanisms underlying prescription opioid use post social defeat in HIV+ adolescents

摘要 从发展的里程碑来看，青春期是一个非常关键的阶段，因为有太多的变化 发生在不同的层面--身体、认知、情感、社交和行为。是否有任何负面体验 这一关键的发展时期可能会对结果产生重大影响，其严重后果可能 坚持到成年。由于相关的耻辱，这一问题在艾滋病毒青少年中进一步加剧， 社会中的消极态度和偏见。使用居民-入侵者模仿范式的社交失败(SD) 在人类中的欺凌行为，被认为是失败者心理社会压力的相关动物模型。 虽然以前的文献报道了社交压力的经历与更高的发病率相关 与应激相关的精神和成瘾障碍，导致这些结果的分子机制仍然 目前仍不清楚。我们的目标是识别分子机制，并专注于破译 细胞外小泡(EV)在加剧HIV突触功能和催促处方阿片类药物使用中的作用 青少年后SD。我们使用临床前模型进行的初步研究：HIV转基因大鼠揭示了 随着HIV感染，脑源性EV(BDEV)大小的变化。基于这一前提，我们最重要的中央 假设在HIV青春期大鼠中SD会进一步加剧BDEV动力学，从而加剧突触损伤和 加速处方类阿片类药物的使用。在目标1下，我们试图阐明SD在HIV青春期大鼠中是否存在调节失调 BDEV生物发生的动力学，并增加了对处方阿片类药物使用的脆弱性。在目标2中，我们将描述 与青少年SD后HIV BDEV相关的机制引发更高的炎症并加剧 突触损伤。在完成这些目标后，我们期望显著提高我们对以下角色的认识 BDEV用于调节HIV青少年SD后的脑功能，并鉴定新的BDEV蛋白标记物。 收集到的这些信息将进一步推动机械研究，并最终帮助制定未来的战略 治疗和改善这一弱势群体的神经学结果。

Abstract From a developmental milestone, adolescence is a very critical phase since there are a plethora of changes occurring on different tiers - physical, cognitive, emotional, social, and behavioral. Any negative experiences at this critical developmental period can significantly impact the outcomes with serious ramifications that could persist into adulthood. This problem is further aggravated in HIV+ adolescents due to the associated stigma, negative attitudes, and prejudice in society. Social defeat (SD) employing a resident-intruder paradigm mimics bullying in humans and is considered a relevant animal model of psychosocial stress in defeated individuals. While previous literature has reported the experience of social stress to correlate with a higher incidence of stress-related psychiatric and addictive disorders, molecular mechanisms contributing to these outcomes still remain unclear. Our goal is on discerning molecular mechanisms and focuses on decoding the role of extracellular vesicles (EV) in exacerbating synaptic function and precipitating prescription opioid use in HIV+ adolescents post SD. Our preliminary studies using a preclinical model: HIV transgenic rats have revealed alterations in brain derived EV (BDEV) sizes with HIV infection. Based on this premise, our overarching central hypothesis is SD in HIV+ adolescent rats further exacerbate BDEV dynamics that aggravate synaptic injury and precipitates prescription opioid use. Under Aim 1, we seek to elucidate if SD in HIV+ adolescent rats dysregulate dynamics of BDEV biogenesis and increases vulnerability to prescription opioid use. In Aim 2 we will delineate mechanisms associated with adolescent HIV+ BDEVs post SD elicit higher inflammation and exacerbate synaptic injury. Upon completion of these goals, we expect to significantly enhance our knowledge of the role of BDEVs to regulate brain function post SD in HIV+ adolescents and identification of novel BDEV protein markers. Such information gleaned will further fuel mechanistic studies and eventually help develop future strategies to treat and improve neurological outcomes in this vulnerable population.