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

摘要 从一个发展的里程碑，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、社会和行为。任何负面的经验， 这一关键的发展时期可能会对结果产生重大影响， 坚持到成年。由于相关的耻辱感，这一问题在艾滋病毒阳性青少年中进一步加剧， 社会上的负面态度和偏见。社会失败（SD）采用居民入侵者范式模仿 在人类中的欺凌，并被认为是一个相关的动物模型的心理社会压力，在失败的个人。 虽然先前的文献报道了社会压力的经历与更高的发病率相关， 压力相关的精神和成瘾性疾病，分子机制有助于这些结果仍然 仍然不清楚。我们的目标是辨别分子机制，并侧重于解码的作用， 细胞外囊泡（EV）在HIV+患者中加重突触功能和促使处方阿片类药物使用 SD后的青少年。我们使用临床前模型的初步研究：HIV转基因大鼠已经揭示了 脑源性EV（BDEV）大小的改变与HIV感染有关。基于这一前提，我们的中央 假设HIV+青春期大鼠的SD进一步加剧了BDEV动力学，加重了突触损伤， 促使处方阿片类药物的使用。在目标1下，我们试图阐明HIV+青春期大鼠的SD是否失调 BDEV生物发生的动力学和增加处方阿片类药物使用的脆弱性。在目标2中，我们将描述 与SD后青少年HIV+ BDEV相关的机制引起更高的炎症并加剧 突触损伤在完成这些目标后，我们预计将大大提高我们对 BDEV调节HIV+青少年SD后的脑功能，并鉴定新的BDEV蛋白标志物。 收集到的这些信息将进一步推动机制研究，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系统结果。

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.