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:
- 金额:$ 41.6万
- 依托单位:
- 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:
- 关键词:3-DimensionalAddressAffectAnxietyAreaBasal GangliaBehavioralBrainBrain regionBrain-Derived Neurotrophic FactorCessation of lifeCognitiveCognitive deficitsCorpus striatum structureDARPPDataDefectDendritesDopamineDopamine D1 ReceptorDopamine D2 ReceptorElectrophysiology (science)EventExposure toFemaleFunctional disorderGlutamatesGoalsHIVHIV Envelope Protein gp120HIV-1HIV-associated neurocognitive disorderHomeostasisImmunosuppressionIn VitroIndividualInflammationInjuryIonsLearningLifeMediatingMemory impairmentMorphineMorphologyMotorMusN-MethylaspartateNGFR ProteinNatureNerve DegenerationNeurocognitiveNeuronal InjuryNeuronsOpioidPathologicPathway interactionsPatientsPerformancePeripheralPharmaceutical PreparationsPhenotypePopulationPredispositionReceptor SignalingReporterResistanceRoleSignal TransductionSubgroupSynapsesTherapeuticToxic effectVirusantiretroviral therapyanxiety-like behaviorbasebiocytincomorbiditydrug rewardexcitotoxicitygait examinationimprovedin vivoinsightmalemotor deficitmu opioid receptorsneural circuitneuroAIDSneurophysiologyopioid abuseopioid exposurepatch clamppreventreconstructiontargeted 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neuroAIDS的病理和行为/认知缺陷。HIV-1相关
神经认知障碍(HAND)在近一半的感染者中仍然很明显。艾滋病毒并不总是
瞄准大脑一些大脑区域,如基底神经节,这是一个对药物奖励至关重要的区域,
富含μ阿片受体(莫尔)的区域受HIV-1的影响很大,而其他区域受影响较小。内
基底神经节,例如,HIV、达特和gp 120导致纹状体介质突触-树突复杂性的损失
多刺神经元(MSN)和吗啡加剧了这些影响;然而,尽管明显损害,
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(Drd 2)
表达MSNs(D2 MSNs)的细胞对达特的结构和功能的脆弱性显著增加。
在达特诱导后14 d,吗啡比多巴胺D1受体(Drd 1a)表达的MSN(D1 MSN
当焦虑样和学习/记忆缺陷,但不是运动障碍(发生后)。此外,尽管
增强的总体易感性,一些D2 MSN不受影响,表明额外的表型
差异,例如,莫尔的表达(其在D2 MSN中不同)也有助于达特和吗啡-
在D2 MSN中诱导损伤。基于这一点和其他证据,我们假设,
MSN亚型选择性地易受达特和吗啡共暴露的影响,
特定神经回路的功能缺陷是特定行为功能障碍的基础。为了解决这个
假设,在雄性和雌性小鼠中提出了以下具体目标。目标1将审查
纹状体D2 ±莫尔MSN亚组中短(14 d)和短(14 d)后突触树突损伤的性质和时间,
延长(2个月)达特和吗啡暴露。Drd 2-eGFP-MOR-mCherry和达特杂交小鼠将在
暴露于吗啡/达特达14天(当认知,但不是运动,缺陷是明显的)或2个月(当
存在认知和运动缺陷)。目标2将检查延迟D1 ±莫尔MSN的性质和时间
达特tg; Drd 1a-tdTomato报告小鼠中突触树突损伤。在目标1和2中,认知和运动
性能将与电生理学和形态学(3D重建)相关。
突触/树突和体视学)在D1 ±莫尔和D2 ±莫尔MSN中的发现。目标3将解决
为什么特定的MSN亚型更容易受到HIV达特±吗啡的影响,这将提供
对相互作用毒性的基本机制有相当深入的了解。Aim 3将在体外使用
检测多巴胺能、多巴胺能和BDNF(TrkB,p75 NTR)受体
在HIV、达特或gp 120暴露的D1+细胞中,信号传导可能选择性地挽救突触树突损伤和功能障碍。
莫尔和D2 ±莫尔MSN亚型。特异性兴奋性毒性途径(例如,通过NMDA的Na+内流,ATP耗竭,
Ca 2+超载)、突触树突损伤和存活将被检查以评估多巴胺能,
在HIV和阿片类药物暴露后介导MSN亚型脆弱性中的神经递质和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:
- 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:
- 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:
- 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.
HIV-1 TAT在小鼠中的有条件表达改变了以性依赖性方式的增强性,炎症性和神经性超敏反应的发作和进展。
- DOI:10.1002/ejp.1618
- 发表时间:2020-09
- 期刊:
- 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:
- 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.
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Kurt F Hauser其他文献
Kurt F Hauser的其他文献
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{{ truncateString('Kurt F Hauser', 18)}}的其他基金
Chloride channel-dependent mechanisms of opiate and HIV-induced synaptodendritic injury
阿片类药物和 HIV 诱导的突触树突损伤的氯离子通道依赖性机制
- 批准号:
10704734 - 财政年份:2022
- 资助金额:
$ 41.6万 - 项目类别:
Chloride channel-dependent mechanisms of opiate and HIV-induced synaptodendritic injury
阿片类药物和 HIV 诱导的突触树突损伤的氯离子通道依赖性机制
- 批准号:
10548312 - 财政年份:2022
- 资助金额:
$ 41.6万 - 项目类别:
Innovative therapeutic approaches to address excitotoxic CNS/neuronal damage in opioid-neuroHIV comorbidity
解决阿片类药物-神经艾滋病毒合并症中的兴奋性中枢神经系统/神经元损伤的创新治疗方法
- 批准号:
10573827 - 财政年份:2022
- 资助金额:
$ 41.6万 - 项目类别:
Innovative therapeutic approaches to address excitotoxic CNS/neuronal damage in opioid-neuroHIV comorbidity
解决阿片类药物-神经艾滋病毒合并症中的兴奋性中枢神经系统/神经元损伤的创新治疗方法
- 批准号:
10684110 - 财政年份:2022
- 资助金额:
$ 41.6万 - 项目类别:
HIV opiate interactions in white matter pathology
HIV阿片类药物在白质病理学中的相互作用
- 批准号:
9419501 - 财政年份:2017
- 资助金额:
$ 41.6万 - 项目类别:
HIV opiate interactions in white matter pathology
HIV阿片类药物在白质病理学中的相互作用
- 批准号:
10189540 - 财政年份:2017
- 资助金额:
$ 41.6万 - 项目类别:
Bivalent Ligands as Chemical Probes to Study Opioid Abuse-enhanced HIV Infection
二价配体作为化学探针研究阿片类药物滥用增强的 HIV 感染
- 批准号:
9924466 - 财政年份:2017
- 资助金额:
$ 41.6万 - 项目类别:
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