Chronic Cocaine Exposure & HIV-1 Tat: Dysregulation of the Medical Prefrontal Cor

描述(申请人提供)：艾滋病毒/艾滋病患者前额叶皮质的调节失调和进行性神经变性影响认知功能，并与艾滋病毒相关性神经认知障碍(HAD)有关，包括艾滋病毒相关性痴呆(HAD)。尽管HAD/HAND的确切机制尚不清楚，但很可能与HIV-1病毒蛋白有关。一个突出的例子是HIV-1Tat(Tat)，它是一种HIV-1反式激活蛋白，在体外会导致皮质/纹状体神经元和星形胶质细胞的失调并最终死亡。在大脑中，TAT由感染艾滋病毒的小胶质细胞、巨噬细胞和单核细胞释放。TAT的体外神经毒性作用是由于L型钙通道钙离子内流异常增加、离子亲性谷氨酸受体激活和细胞内钙离子释放增加所致的细胞内游离钙离子浓度升高所致。可卡因滥用增加了艾滋病毒/艾滋病相关病理的发病率和死亡率，加剧了认知、心理社会和运动缺陷。尽管内侧前额叶皮质(MPFC)被认为是控制这些行为和成瘾的关键脑区，但其在可卡因滥用-HIV/AIDS共病中的调节失调的机制尚未被研究。此外，目前的艾滋病毒/艾滋病研究主要集中在细胞培养上，因此，与电路相关的过程尚不清楚。这两种情况延迟了我们对这种共病的神经发病机制的理解。我们最近对大鼠的研究表明，慢性可卡因暴露通过选择性上调mPFC内锥体神经元的L型钙通道功能而显著增加钙内流。这些新的发现有力地表明，体内长期暴露于可卡因可能会加剧TAT诱导的mPFC的调节失调和随后的神经变性。根据这些证据，本项目的目标是确定mPFC中针对艾滋病毒/艾滋病的可卡因滥用的共同生物底物。这些实验将验证这样一种假设，即体内长期接触可卡因通过增加锥体细胞中L型钙通道的钙内流，增加mPFC对HIV-1 TAT的易感性和易感性，这些变化参与了可卡因滥用和HAD的发病机制。这项试点研究具有创新性和重要意义，因为它将提供信息丰富的初步数据，指出可卡因滥用-HAD共病的潜在机制。这些研究的结果将用于开发R01应用程序，专注于这种共病和假定的治疗目标，以帮助治疗双重疾病患者。与公共卫生相关：这项拨款申请的标题是：“慢性可卡因暴露与HIV-1TAT：内侧前额叶皮质的调节失调。”我们的目标是探索可卡因滥用和HIV感染导致大脑和行为障碍的机制。这两个问题的结合导致了更严重的情况，不幸的是，这种结合正在我们的社会中蔓延。该项目将确定艾滋病毒感染细胞产生的一种蛋白质(TAT)如何改变内侧前额叶皮质神经元的活动。这一大脑区域同时涉及奖励和判断，在可卡因成瘾和艾滋病方面都受到影响。我们认为，由HIV蛋白TAT诱导的内侧前额叶皮质神经元活动的变化将被反复的可卡因暴露所增强。这项研究的发现将有助于我们验证可卡因滥用和艾滋病毒感染的共同目标，这对于开发更有效的治疗可卡因滥用和艾滋病毒相关的大脑/行为缺陷的方法将非常重要。

DESCRIPTION (provided by applicant): Dysregulation and progressive neurodegeneration in the prefrontal cortex of HIV/AIDS patients affect cognitive function and are implicated in HIV-associated neurocognitive disorders (HAND), including HIV- associated dementia (HAD). Although the precise mechanisms that underlie HAD/HAND remain unknown, HIV-1 viral proteins are most likely involved. A prominent example is HIV-1 Tat (Tat), a HIV-1 transactivating protein, causes dysregulation and ultimately death of cortical/striatal neurons and astrocytes in vitro. In the brain, Tat is released by HIV-infected microglia, macrophages and monocytes. The neurotoxic effects of Tat in vitro result from an excessive increase of cytosolic free Ca2+ levels caused by abnormally enhanced Ca2+ influx via L-type Ca2+ channels, activation of ionotropic glutamate receptors and intracellular Ca2+ release. Cocaine abuse increases the morbidity and mortality of HIV/AIDS-associated pathology with exacerbation of cognitive, psychosocial and motor deficits. Even though the medial prefrontal cortex (mPFC) is well- recognized as a critical brain region in the control of these behaviors, as well as of addiction, the mechanisms underlying its dysregulation in the cocaine abuse-HIV/AIDS comorbidity have not been examined. Also, current HIV/AIDS studies predominantly focus on cell cultures, thus, the circuit-related processes are unknown. These two situations have delayed our understanding of the neuropathogenesis of this comorbidity. Our recent work with rats demonstrate that chronic cocaine exposure significantly increases Ca2+ influx by selectively upregulating L-type Ca2+ channel function in pyramidal neurons localized in the mPFC. These novel findings strongly suggest that chronic exposure to cocaine in vivo may potentiate the dysregulation and consequent neurodegeneration of the mPFC induced by Tat. Based on these evidences, the objective of the current project is to ascertain a common biological substrate in the mPFC for cocaine abuse on HIV/AIDS. The designed experiments will test the hypothesis that chronic cocaine exposure in vivo increases susceptibility and vulnerability of the mPFC to HIV-1 Tat by increasing Ca2+ influx via L-type Ca2+ channels in pyramidal cells, and these changes contribute to the pathogenesis of cocaine abuse and HAD. This pilot study is innovative and significant because it will provide informative preliminary data pointing to the mechanisms underlying the cocaine abuse-HAD comorbidity. Results from these studies will used to develop a R01 application focusing on this comorbidity and putative therapeutic targets to help treat dually afflicted individuals. PUBLIC HEALTH RELEVANCE: This grant application is titled: "Chronic cocaine exposure & HIV-1 Tat: Dysregulation of the medial prefrontal cortex." Our goal is to explore the mechanisms of the brain and behavioral deficits induced by cocaine abuse and HIV infection. The combination of these two problems results in a much more severe condition, and unfortunately the combination is spreading in our society. This project will determine how a protein (Tat) produced by HIV-infected cells alters activity of neurons in the medial prefrontal cortex. This brain region is involved both in reward and in judgment, and it is compromised in both cocaine addiction and AIDS. We propose that changes in neuronal activity in the medial prefrontal cortex induced by the HIV protein Tat will be potentiated by repeated cocaine exposure. Findings from this study will help us to verify the common target of cocaine abuse and HIV infection, which will be very important for developing more effective treatments for cocaine abuse and HIV-related brain/behavioral deficits.