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.

阿片类药物滥用加剧了神经助剂的病理和行为/认知缺陷。 HIV-1相关神经认知障碍（手）在几乎一半的感染者中仍然是证据。艾滋病毒不统一针对大脑。一些大脑区域，例如巴萨神经节，一个对药物奖励至关重要的区域富含阿片类药物受体（MOR）的人受HIV-1的影响很大，而其他区域受影响较小。之内基底神经节，例如HIV，TAT和GP120会导致纹状体介质的突触核心复杂性损失棘神经元（MSN）和吗啡加剧了这些作用。但是，dospite明显损坏了一些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）显示出明显更大的结构和功能性脆弱性在TAT诱导后14 d时表达MSNS（D1 MSN）的多巴胺D1受体（DRD1A）当焦虑症和学习/记忆定义时，但没有运动障碍（以后发生）。此外，多皮增强的总体敏感性，一些D2 MSN不受影响，表明其他表型差异，例如，MOR的表达（D2 MSN之间的不同）也有助于TAT和吗啡 - D2 MSN诱导损伤。基于此和其他证据，我们假设表型不同 MSN亚型有选择地容易受到TAT和吗啡共曝光的影响，并且结构和特定神经回路中的功能定义是特定行为功能障碍的基础。解决这个问题假设，在雄性和雌性小鼠中提出了以下特定目标。 AIM 1将检查短（14 d）和长时间（2个月）TAT和吗啡暴露。 DRD2-EGFP-MOR-MCHERRY和TAT INTREBRED小鼠将是暴露于吗啡/TAT 14 d（当认知（而不是电动机）定义为证据时）或2个月（当存在认知和运动定义）。 AIM 2将检查延迟D1±MOR MSN的性质和时机 TAT TG; DRD1A-TDTOMATO报道小鼠的突触don损伤。在目标1和2中，认知和运动性能将与电生理学和形态学相关（3D重建 D1±MOR和D2±MORNS中的突触/树突和立体学发现。 AIM 3将解决为什么特定MSN亚型更容易受到HIV TAT±吗啡的问题，这将提供对互动毒性的基本机制的深入了解。 AIM 3将在体外使用方法以检查多巴胺能，谷氨酰胺能和BDNF（TRKB，p75ntr）接收器的程度信号传导可能会选择性地挽救HIV，TAT或GP120暴露D1± MOR和D2±MOR MSN亚型。特定的兴奋毒性途径（例如，通过NMDA的NA+影响，ATP部署， CA2+过载），突触型损伤和生存将检查以评估多巴胺能的作用， HIV后介导MSN亚型脆弱性并优化暴露时，谷氨酸能和BDNF信号传导。

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）

Morphine and HIV-1 Tat interact to cause region-specific hyperphosphorylation of tau in transgenic mice.

DOI：
10.1016/j.neulet.2020.135502
发表时间：
2021-01-10
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Ohene-Nyako M;Nass SR;Hahn YK;Knapp PE;Hauser KF
通讯作者：
Hauser KF

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：
10.1152/ajpcell.00397.2021
发表时间：
2022
期刊：
American journal of physiology. Cell physiology
影响因子：
0
作者：
Yarotskyy,Viktor;Lark,AriannaRS;Nass,SaraR;Hahn,YunK;Marone,MichaelG;McQuiston,ARory;Knapp,PamelaE;Hauser,KurtF
通讯作者：
Hauser,KurtF

Depressive-like Behavior Is Accompanied by Prefrontal Cortical Innate Immune Fatigue and Dendritic Spine Losses after HIV-1 Tat and Morphine Exposure.

DOI：
10.3390/v15030590
发表时间：
2023-02-21
期刊：
Viruses
影响因子：
0
作者：
Nass SR;Hahn YK;Ohene-Nyako M;McLane VD;Damaj MI;Thacker LR 2nd;Knapp PE;Hauser KF
通讯作者：
Hauser KF

Conditional expression of HIV-1 tat in the mouse alters the onset and progression of tonic, inflammatory and neuropathic hypersensitivity in a sex-dependent manner.

DOI：
10.1002/ejp.1618
发表时间：
2020-09
期刊：
European journal of pain (London, England)
影响因子：
0
作者：
Bagdas D;Paris JJ;Carper M;Wodarski R;Rice ASC;Knapp PE;Hauser KF;Damaj MI
通讯作者：
Damaj MI

Casein Kinase 2 Mediates HIV- and Opioid-Induced Pathologic Phosphorylation of TAR DNA Binding Protein 43 in the Basal Ganglia.

DOI：
10.1177/17590914231158218
发表时间：
2023-01
期刊：
ASN NEURO
影响因子：
4.7
作者：
Ohene-Nyako, Michael;Nass, Sara R.;Richard, Hope T.;Lukande, Robert;Nicol, Melanie R.;McRae, MaryPeace;Knapp, Pamela E.;Hauser, Kurt F.
通讯作者：
Hauser, Kurt F.