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。 尽管联合抗逆转录病毒治疗（cART）的流行，许多艾滋病毒感染者经历 神经认知缺陷，包括情绪处理，冲动控制和记忆的减少， 与日常生活。阿片类药物可以通过改变神经元的功能，进一步加重HIV-1相关的神经认知缺陷。 结构和功能。然而，艾滋病毒并不均匀地靶向大脑，某些区域是不同的。 影响。纹状体表现出增加的树突病理学（静脉曲张形成、串珠状、碎片化， 修剪）和树突棘损失;而前额叶皮层内的前扣带皮层（ACC） 表现出抑制性突触连接的改变，但不表现出兴奋性突触连接的改变。这些神经元间的缺陷是 伴随着抑郁样行为的增加。阿片类药物影响艾滋病毒诱导的行为功能障碍， 我们假设这是由于ACC内抑制性突触功能的破坏导致的， ACC锥体细胞兴奋/抑制平衡的净破坏和过度兴奋。目标1将 描述阿片类药物对ACC中HIV-Tat诱导的GABA能神经生理功能障碍的影响 锥体神经元使用全细胞，膜片钳记录和相关的抑郁样行为。神经元 将被生物细胞素填充，随后通过3D重建分析树突病理学，棘密度， 和抑制点。吗啡和HIV-Tat对ACC内神经元间亚群的影响将 也要进行评估。目标2将确定GABA信号如何影响HIV/HIV蛋白和吗啡变化 在ACC神经元离子稳态（Ca 2+和Cl−）、结构和存活中，使用Cre/TdTomatoflox/flox锥体 神经元和Gad 1-eGFP中间神经元报告小鼠，以及人诱导多能干细胞（iPSC）衍生的 皮质神经元拟议的研究将进一步加深我们对阿片类药物 加剧ACC内HIV诱导的神经认知缺陷和病理，并确定可能的靶点， 治疗干预。