HIV and opiate interactions in behavioral and anterior cingulate cortex synaptic dysfunction

HIV 和阿片类药物在行为和前扣带皮层突触功能障碍中的相互作用

• 批准号: 10161069
• 负责人: Sara Nass
• 金额: $ 6.86万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-25 至 2023-04-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161069
• 关键词: 3-Dimensional; Affect; Anterior; Bathing; Behavior; Behavioral; Behavioral Assay; Brain; Cell physiology; Cells; Cellular Structures; Cerebrospinal Fluid; Corpus striatum structure; Data; Dendritic Spines; Doxycycline; Electrophysiology (science); Emotional; Equilibrium; Event; Exhibits; Exposure to; Frequencies; Functional disorder; GABA Agonists; Gene Expression; Glutamates; Goals; HIV; HIV Envelope Protein gp120; HIV-1; HIV-associated neurocognitive disorder; Homeostasis; Human; In Vitro; Individual; Injury; Interneurons; Ions; Measures; Mediating; Memory; Mental Depression; Molecular; Morphine; Morphology; Mus; Nerve Degeneration; Neuraxis; Neurocognitive Deficit; Neuronal Dysfunction; Neuronal Injury; Neurons; Opiate Addiction; Opioid; Parvalbumins; Pathogenesis; Pathologic; Pathology; Persons; Physiologic pulse; Physiological; Pluripotent Stem Cells; Prefrontal Cortex; Prevalence; Property; Proteins; Publishing; Pyramidal Cells; Reporter; Risk; Role; Signal Transduction; Site; Social Interaction; Structure; Swimming; Synapses; System; Testing; Therapeutic Intervention; Time; Transgenic Organisms; Varicosity; Vertebral column; Viral Proteins; Whole-Cell Recordings; antiretroviral therapy; biocytin; cingulate cortex; comorbidity; density; depressive symptoms; emotional functioning; excitotoxicity; executive function; experience; experimental study; gamma-Aminobutyric Acid; gephyrin; hippocampal pyramidal neuron; imaging study; induced pluripotent stem cell; inhibitory neuron; insight; mu opioid receptors; neuroAIDS; neurophysiology; opioid abuse; optogenetics; patch clamp; postsynaptic; presynaptic; prevent; reconstruction; response; synaptic function; synaptotagmin II; targeted treatment; tat Protein; voltage

PROJECT SUMMARY. Despite the prevalence of combination antiretroviral therapy (cART) many HIV-infected individuals experience neurocognitive deficits, including decreased emotional processing, impulse control, and memory that interfere with daily living. Opiates can further exacerbate HIV-1 associated neurocognitive deficits by altering neuronal structure and function. However, HIV does not uniformly target the brain and certain regions are differentially affected. The striatum exhibits increased dendritic pathology (varicosity formation, beading, fragmentation, and pruning) and dendritic spine losses; whereas the anterior cingulate cortex (ACC) within the prefrontal cortex exhibits alterations in inhibitory, but not excitatory, synaptic connections. These interneuronal deficits are accompanied by increased depressive-like behavior. Opiates impact HIV-induced behavioral dysfunction and we hypothesize that this is caused by disruptions to inhibitory synaptic function within the ACC resulting in a net disruption in the excitatory/inhibitory balance of ACC pyramidal cells and overexcitation. Aim 1 will characterize the impact of opiates on HIV-Tat-induced GABAergic neurophysiological dysfunction in ACC pyramidal neurons using whole-cell, patch-clamp recordings and associated depressive-like behavior. Neurons will be biocytin-filled and subsequently analyzed via 3D-reconstruction for dendritic pathology, spine density, and inhibitory puncta. The effects of morphine and HIV-Tat on interneuronal subpopulations within the ACC will also be assessed. Aim 2 will determine how GABA signaling impacts HIV/HIV-proteins and morphine changes in ACC neuron ion homeostasis (Ca2+ and Cl−), structure, and survival using Cre/TdTomatoflox/flox pyramidal neuron and Gad1-eGFP interneuron reporter mice, and human induced pluripotent stem cell (iPSC)-derived cortical neurons. The proposed studies will further our understanding of the mechanisms by which opiates exacerbate HIV-induced neurocognitive deficits and pathology within the ACC, and identify possible targets for therapeutic interventions.

项目摘要。 尽管组合抗逆转录病毒疗法（CART）仍有许多HIV感染者经历 神经认知定义，包括降低情绪处理，冲动控制和记忆 与日常生活。 Opates可以通过改变神经元来进一步加剧HIV-1相关的神经认知缺陷 结构和功能。但是，艾滋病毒并不统一靶向大脑，某些区域是差异的 做作的。纹状体表现出增加的树突状病理（静脉曲张的形成，串珠，碎片和 修剪）和树突状脊柱损失；而前额叶皮层内的前扣带回皮层（ACC） 表现出抑制性的变化，但没有兴奋性突触连接。这些神经元定义是 伴随着抑郁症状的行为增加。阿片类药物影响HIV引起的行为功能障碍和 我们假设这是由ACC内抑制性突触功能的中断引起的 ACC锥体细胞和过度激发的兴奋性/抑制平衡中的净破坏。目标1意志 表征操作学对ACC中HIV-TAT诱导的GABA能神经生理功能障碍的影响 使用全细胞，贴片钳记录和相关抑郁样行为的锥体神经元。神经元 将被填充生物细胞，随后通过3D重建来分析树突病理学，脊柱密度， 和抑制性点。吗啡和HIV-TAT对ACC内神经元亚群的影响 也可以评估。 AIM 2将确定GABA信号如何影响HIV/HIV蛋白质和吗啡的变化 在ACC神经元离子稳态（Ca2+和Cl-）中，结构和使用Cre/tdtomatomox/flox Pyramidal 神经元和GAD1-EGFP间神经元记者小鼠，以及人类诱导的多能干细胞（IPSC）衍生的 皮质神经元。拟议的研究将进一步理解优化的机制 加剧了ACC中HIV引起的艾滋病毒引起的神经认知缺陷和病理，并确定可能的靶标 治疗干预措施。