Selective vulnerability of discrete neural circuits in the striatum to HIV-opiate comorbidity

纹状体中离散神经回路对艾滋病毒-阿片类共病的选择性脆弱性

基本信息

批准号：
10317037
负责人：
Kurt F Hauser
金额：
$ 41.6万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317037
关键词：
3-Dimensional Address Affect Anxiety Area Basal Ganglia Behavioral Brain Brain region Brain-Derived Neurotrophic Factor Cessation of life Cognitive Cognitive deficits Corpus striatum structure DARPP Data Defect Dendrites Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Electrophysiology (science)Event Exposure to Female Functional disorder Glutamates Goals HIV HIV Envelope Protein gp120 HIV-1 HIV-associated neurocognitive disorder Homeostasis Immunosuppression In Vitro Individual Inflammation Injury Ions Learning Life Mediating Memory impairment Morphine Morphology Motor Mus N-Methylaspartate NGFR Protein Nature Nerve Degeneration Neurocognitive Neuronal Injury Neurons Opioid Pathologic Pathway interactions Patients Performance Peripheral Pharmaceutical Preparations Phenotype Population Predisposition Receptor Signaling Reporter Resistance Role Signal Transduction Subgroup Synapses Therapeutic Toxic effect Virus antiretroviral therapy anxiety-like behavior base biocytin comorbidity drug reward excitotoxicity gait examination improved in vivo insight male motor deficit mu opioid receptors neural circuit neuroAIDS neurophysiology opioid abuse opioid exposure patch clamp prevent reconstruction targeted treatment

项目摘要

Opioid drug abuse exacerbates pathological and behavioral/cognitive deficits of neuroAIDS. HIV-1-associated neurocognitive disorders (HAND) remain evident in nearly half the individuals infected. HIV does not uniformly target the brain. Some brain regions, such as the basal ganglia, a region critical for drug reward and highly enriched in µ opioid receptors (MOR), are greatly affected by HIV-1, while other areas are less affected. Within the basal ganglia, e.g., HIV, Tat and gp120 causes losses in the synaptodendritic complexity of striatal medium spiny neurons (MSNs) and morphine exacerbates these effects; however, despite the pronounced damage to some MSNs, other striatal MSNs appear unaffected. We discovered that dopamine D2 receptor (Drd2) expressing MSNs (D2 MSNs) showed significantly greater structural and functional vulnerability to Tat ± morphine than dopamine D1 receptor (Drd1a) expressing MSNs (D1 MSNs) at 14 d following Tat induction when anxiety-like and learning/memory deficits, but not motor disorders (which occur later). Moreover, despite enhanced overall susceptibility, some D2 MSNs were unaffected suggesting that additional phenotypic differences, e.g., expression of MOR (which differs among D2 MSNs), also contribute to Tat and morphine- induced injury in D2 MSNs. Based on this and other evidence, we hypothesize that phenotypically distinct MSN subtypes are selectively vulnerable to Tat and morphine coexposure and that the structural and functional deficits in specific neural circuits underlie specific behavioral dysfunctions. To address this hypothesis, the following specific aims are proposed in both male and female mice. Aim 1 will examine the nature and timing of synaptodendritic injury in striatal D2 ± MOR MSN subgroups after short (14 d) and prolonged (2 month) Tat and morphine exposure. Drd2-eGFP-MOR-mCherry and Tat interbred mice will be exposed to morphine/Tat for 14 d (when cognitive, but not motor, deficits are evident) or 2 months (when cognitive and motor deficits are present). Aim 2 will examine the nature and timing of delayed D1 ± MOR MSN synaptodendritic injury in Tat tg;Drd1a-tdTomato reporter mice. In Aims 1 and 2, cognitive and motor performance will be correlated with the electrophysiologic and morphologic (3D reconstruction of synapses/dendrites and stereology) findings in D1 ± MOR and D2 ± MOR MSNs. Aim 3 will address the question of why specific MSN subtypes are more vulnerable to HIV Tat ± morphine, which will provide considerable insight into fundamental mechanisms underlying the interactive toxicity. Aim 3 will use in vitro approaches to examine the extent to which dopaminergic, glutaminergic and BDNF (TrkB, p75NTR) receptor signaling might selectively rescue synaptodendritic injury and dysfunction in HIV, Tat, or gp120-exposed D1 ± MOR and D2 ± MOR MSN subtypes. Specific excitotoxic pathways (e.g., Na+ influx via NMDA, ATP depletion, Ca2+ overload), synaptodendritic injury, and survival will be examined to gauge the role of dopaminergic, glutamatergic, and BDNF signaling in mediating MSN subtype vulnerability following HIV and opiate exposure.

阿片类药物滥用会加剧 HIV-1 相关的病理和行为/认知缺陷。近一半的艾滋病毒感染者仍存在明显的神经认知障碍（HAND）。靶向大脑的某些区域，例如基底神经节，该区域对药物奖赏至关重要且高度敏感。富含μ阿片受体（MOR）的区域受HIV-1影响很大，而其他区域则受影响较小。基底神经节，例如 HIV、Tat 和 gp120 导致纹状体介质的突触树突复杂性损失然而，尽管多棘神经元（MSN）和吗啡对神经元造成了明显的损害，但它们却加剧了这些影响；一些 MSN，其他纹状体 MSN 似乎不受影响。我们发现多巴胺 D2 受体 (Drd2)。表达 MSN (D2 MSN) 的结构和功能对 Tat 的脆弱性显着增强 ± 在 Tat 诱导后 14 d，吗啡比表达 MSN (D1 MSN) 的多巴胺 D1 受体 (Drd1a) 的效果要好当出现类似焦虑和学习/记忆缺陷，但不是运动障碍（稍后发生）时。总体易感性增强，一些 D2 MSN 未受影响，这表明额外的表型差异，例如 MOR 的表达（D2 MSN 之间不同），也有助于 Tat 和吗啡- 基于此和其他证据，我们发现了 D2 MSN 中的表型差异。 MSN 亚型选择性地容易受到 Tat 和吗啡共暴露的影响，并且结构和特定神经回路的功能缺陷是特定行为功能障碍的基础。假设，在雄性和雌性小鼠中提出以下具体目标，目标 1 将检查纹状体 D2 ± MOR MSN 亚组短暂（14 d）和后突触树突损伤的性质和时间长期（2 个月）Tat 和吗啡暴露会导致 Drd2-eGFP-MOR-mCherry 和 Tat 杂交小鼠。暴露于吗啡/Tat 14 天（当认知缺陷而非运动缺陷明显时）或 2 个月（当存在认知和运动缺陷）目标 2 将检查 D1 ± MOR MSN 延迟的性质和时间。 Tat tg;Drd1a-tdTomato 报告小鼠的突触树突损伤在目标 1 和 2 中，认知和运动。表现将与电生理学和形态学（3D 重建突触/树突和立体学）D1 ± MOR 和 D2 ± MOR MSN 中的发现将解决目标 3。为什么特定的 MSN 亚型更容易受到 HIV Tat ± 吗啡的影响，这将提供 Aim 3 将在体外使用对交互毒性基本机制的深入了解。检查多巴胺能、谷氨酰胺能和 BDNF（TrkB、p75NTR）受体程度的方法信号传导可能选择性地挽救 HIV、Tat 或 gp120 暴露的 D1 中的突触树突损伤和功能障碍 ± MOR 和 D2 ± MOR MSN 亚型。特定的兴奋性毒性途径（例如，Na+ 通过 NMDA 流入、ATP 消耗、将检查 Ca2+ 超载）、突触树突损伤和存活，以衡量多巴胺能、谷氨酸能和 BDNF 信号在介导 HIV 和阿片类药物暴露后 MSN 亚型脆弱性中的作用。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Opioid and neuroHIV Comorbidity - Current and Future Perspectives.

阿片类药物和神经艾滋病毒合并症 - 当前和未来的观点。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Fitting, Sylvia;McRae, MaryPeace;Hauser, Kurt F
通讯作者：
Hauser, Kurt F

HIV-1 Tat and morphine decrease murine inter-male social interactions and associated oxytocin levels in the prefrontal cortex, amygdala, and hypothalamic paraventricular nucleus.

HIV-1 Tat 和吗啡会降低小鼠雄性间的社交互动以及前额皮质、杏仁核和下丘脑室旁核中相关催产素水平。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Nass, Sara R;Lark, Arianna R S;Hahn, Yun K;McLane, Virginia D;Ihrig, Therese M;Contois, Liangru;Napier, T Celeste;Knapp, Pamela E;Hauser, Kurt F
通讯作者：
Hauser, Kurt F

Chloride channels with ClC-1-like properties differentially regulate the excitability of dopamine receptor D1- and D2-expressing striatal medium spiny neurons.

具有 ClC-1 样特性的氯离子通道差异调节表达多巴胺受体 D1 和 D2 的纹状体中型多棘神经元的兴奋性。

DOI：
发表时间：
2022-03-01
期刊：
影响因子：
0
作者：
Yarotskyy, Viktor;Lark, Arianna R S;Nass, Sara R;Hahn, Yun K;Marone, Michael G;McQuiston, A Rory;Knapp, Pamela E;Hauser, Kurt F
通讯作者：
Hauser, Kurt F

HIV and opiates dysregulate K+- Cl- cotransporter 2 (KCC2) to cause GABAergic dysfunction in primary human neurons and Tat-transgenic mice.

HIV 和阿片类药物使 K-Cl-协同转运蛋白 2 (KCC2) 失调，导致原代人类神经元和 Tat 转基因小鼠的 GABA 能功能障碍。