Cortical pathophysiology in cocaine sef-administering HIV-1 transgenic rats

可卡因自我给药 HIV-1 转基因大鼠的皮质病理生理学

基本信息

批准号：
8507202
负责人：
XIU-TI HU
金额：
$ 22.03万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507202
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Acute Adult Age Age-Months Behavior Biochemical Brain Brain Injuries Brain region Cells Cessation of life Chronic Cocaine Cocaine Abuse Cognition Comorbidity Diltiazem Disease Elderly Emotions Exhibits Frequencies Functional disorder Future Genetic Transcription Gliosis Goals HIV HIV Infections HIV-1 Harvest Homeostasis Human Immunohistochemistry In Vitro Individual Infection Injury Intervention Investigation Knowledge Lead Literature Medial Mediating Membrane Methods Microglia Modeling Molecular Molecular Target N-Methyl-D-Aspartate Receptors Nature Neurocognitive Neurons Neuropathogenesis Outcome Outcomes Research Pathogenesis Pathology Prefrontal Cortex Prosencephalon Proteins Protocols documentation Pyramidal Cells Rattus Reporting Research Rewards Role Saline Self Administration Self-Administered Severities Site Slice Societies Staging Stimulus Techniques Testing Therapeutic Time Toxic effect Toxin Training Trans-Activators Transgenic Organisms Up-Regulation Viral Proteins Western Blotting addiction antiretroviral therapy channel blockers drug abstinence dual diagnosis experience hippocampal pyramidal neuron innovation macrophage molecular site neuronal excitability neuropathology neuropsychiatry novel novel therapeutics patch clamp preclinical study programs research study response therapeutic target young adult

项目摘要

DESCRIPTION (provided by applicant): Cocaine-abusing, HIV+ individuals experience more severe and rapidly evolving neuropsychiatric disorders and HIV-associated neurocognitive disorders (HAND) than non-abusing HIV+ individuals. These disorders reflect in part, a dysregulation of the medial prefrontal cortex (mPFC), but the underlying mechanisms are unclear. To significantly advance understanding of this phenomenon, we submit this R21 application to implement a new rat model of the comorbid human condition wherein critical features of both HIV+ and cocaine abuse are emulated to investigate the functional state of mPFC neurons. The research objectives are: (1) To reveal dysfunction of the mPFC in non-infectious, young (10-12 week old) adult HIV-1 transgenic (Tg) rats that chronically express multiple HIV-1 protein toxins in the brain, but do not exhibit the overt pathologies seen in old Tg rats (i.e., 10-12 months of age). (2 To determine if an exaggerated pathophysiology exists in the mPFC of HIV-1 Tg rats trained to self-administer cocaine. Our central hypothesis is that mPFC pyramidal neurons are more prone to over-activation in cocaine self-administering Tg rats than in saline-treated Tg rats or cocaine self-administering non-Tg rats. We will test this hypothesis with two Specific Aims. Aim 1 will validate [the level of microgliosis] in the mPFC, and determine their association with abnormally- enhanced neuronal excitability mediated via over-activated L-type Ca2+ channels in the young adult Tg rats. Non-Tg rats will serve as controls. Functional activity of mPFC pyramidal neurons will be assessed in ex vivo brain slices using patch-clamp recording techniques. We expect that the Tg rats will show [mPFC microgliosis] and hyper-excitability of pyramidal neurons mediated by over-activated L-channels, reflected by abnormally-increased responses to excitatory stimuli. Aim 2 will determine that cocaine self- administration enhances the pyramidal cell pathophysiology seen in the Tg rats. We expect that cocaine will exacerbate the hyper-excitability of mPFC pyramidal neurons observed in the Tg rats. This research is significant and innovative because it will provide the first means to ascertain the functional consequences of the chronic brain exposure of HIV-1 proteins under conditions of cocaine self-administration; in so doing, it will provide a completely novel method to investigate the molecular and cellular mechanisms responsible for this comorbid condition. The outcomes expected by the end of two years will determine that the HIV-1 proteins-induced pathology and cocaine abuse converge to dysregulate mPFC neuronal function via over- activated L-channels. These outcomes will guide our future investigations on mechanisms underlying the dysregulated Ca2+ homeostasis in the mPFC. Thus, this bold research will vertically elevate our understanding of the mechanisms that may contribute to the neuropathogenesis of HAND and neuropsychiatric disorders associated with HIV+ and cocaine abuse. This new knowledge will also lead to a R01 application in which novel therapeutic strategies will be developed to reduce such pathology.

描述（由申请人提供）：与非滥用可卡因的 HIV+ 个体相比，滥用可卡因的 HIV+ 个体会经历更严重且快速发展的神经精神疾病和 HIV 相关神经认知障碍 (HAND)。这些疾病部分反映了内侧前额皮质（mPFC）的失调，但其潜在机制尚不清楚。为了显着促进对这一现象的理解，我们提交了此 R21 申请，以实施一种新的人类共病大鼠模型，其中模拟 HIV+ 和可卡因滥用的关键特征来研究 mPFC 神经元的功能状态。研究目标是：(1) 揭示非传染性、年轻（10-12 周龄）成年 HIV-1 转基因 (Tg) 大鼠的 mPFC 功能障碍，这些大鼠的大脑中长期表达多种 HIV-1 蛋白毒素，但不表现出老年 Tg 大鼠（即 10-12 个月大）中观察到的明显病理。（2 确定接受自我注射可卡因训练的 HIV-1 Tg 大鼠的 mPFC 中是否存在夸大的病理生理学。我们的中心假设是，自我注射可卡因的 Tg 大鼠的 mPFC 锥体神经元比生理盐水更容易过度激活。 - 治疗的 Tg 大鼠或自我施用可卡因的非 Tg 大鼠我们将用两个具体目标 1 来验证这一假设。 mPFC 中的小胶质细胞增生，并确定其与年轻成年非 Tg 大鼠中过度激活的 L 型 Ca2+ 通道介导的神经元兴奋性异常增强的关系，将作为 mPFC 锥体神经元的功能活动。使用膜片钳记录技术对离体脑切片进行评估，我们预计 Tg 大鼠将表现出 [mPFC 小胶质细胞增生] 和过度激活介导的锥体神经元的过度兴奋。 L 通道，反映为对兴奋性刺激的异常增加的反应，目标 2 将确定可卡因自我施用增强 Tg 大鼠中所见的锥体细胞病理生理学。我们预计可卡因会加剧 Tg 大鼠中 mPFC 锥体神经元的过度兴奋。这项研究具有重要意义和创新性，因为它将提供第一种方法来确定在可卡因自我给药条件下大脑长期暴露于 HIV-1 蛋白的功能后果；这样做，它将提供一种全新的方法来研究导致这种共病的分子和细胞机制。预计两年后的结果将确定 HIV-1 蛋白诱导的病理学和可卡因滥用通过过度激活的 L 通道共同导致 mPFC 神经元功能失调。这些结果将指导我们未来对 mPFC 中 Ca2+ 稳态失调的机制的研究。因此，这项大胆的研究将垂直提升我们对可能导致 HAND 神经发病机制以及与 HIV+ 和可卡因滥用相关的神经精神疾病的机制的理解。这一新知识也将导致 R01 应用，其中将开发新的治疗策略来减少此类病理。