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）：可卡因虐待，HIV+个体比非虐待HIV+个体更为严重，更迅速地发展神经精神疾病和与HIV相关的神经认知疾病（手）。这些疾病部分反映了内侧前额叶皮层（MPFC）的失调，但基本机制尚不清楚。为了显着提高对这一现象的理解，我们提交了R21应用程序，以实现合并症人类状况的新大鼠模型，其中模拟了HIV+和可卡因的关键特征，以研究MPFC神经元的功能状态。研究目标是：（1）揭示MPFC在非感染，年轻（10-12周大的）成人HIV-1转基因（TG）大鼠中的功能障碍，这些大脑长期表达大脑中多种HIV-1蛋白毒素，但没有在旧TG大鼠（即10-12个月）中显示出明显的病理学。 (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用两个特定的目标测试该假设。使用贴片钳记录技术。我们预计可卡因会加剧TG大鼠中观察到的MPFC锥体神经元的高启示性。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，HIV-1蛋白慢性大脑暴露的功能后果。这样一来，它将提供一种完全新颖的方法，以研究负责这种合并症的分子和细胞机制。到两年结束时预期的结果将确定HIV-1蛋白诱导的病理学和可卡因滥用会通过过量活化的L通道融合到失调的MPFC神经元功能。这些结果将指导我们对MPFC中CA2+稳态失调的机制的未来调查。因此，这项大胆的研究将垂直提高我们对可能有助于与HIV+和可卡因滥用相关的手和神经精神疾病的神经病发生的机制的理解。这种新知识还将导致R01应用，其中将开发出新的治疗策略来减少这种病理。