Mechanisms of Nucleus Accumbens Cell-Type Specific Deep Brain Stimulation in Cocaine Reinstatement
Mechanisms of Nucleus Accumbens Cell-Type Specific Deep Brain Stimulation in Cocaine Reinstatement
批准号:
10536593
负责人:
Matthew T Rich
金额:
$4.92万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-01-08 至 2023-09-07
关键词:
AcuteAnimal ModelAttenuatedBehaviorBehavioralBilateralBrain regionCellsClinicalCocaineCocaine DependenceDataDeep Brain StimulationDopamineDopamine D1 ReceptorDopamine D2 ReceptorDoseEfferent NeuronsElectrophysiology (science)Enterobacteria phage P1 Cre recombinaseEquationExhibitsExtinctionFemaleFiber OpticsFrequenciesFutureGlobus PallidusGlutamatesGrantHalorhodopsinsHomosynaptic DepressionImplantIndividualInfusion proceduresInjectionsLightLong-Term DepressionMediatingMental disordersMethodologyModelingModificationNeuronsNucleus AccumbensOperative Surgical ProceduresPathway interactionsPharmaceutical PreparationsPharmacotherapyPhysiologicalPresynaptic TerminalsProceduresPublic HealthRat TransgeneRattusRegulationRelapseReportingRewardsSignal TransductionSiteSliceSpecificitySynapsesTestingTherapeuticTherapeutic EffectUnited StatesVentral Tegmental AreaViraladeno-associated viral vectorcell typecocaine relapsecocaine seekingcocaine self-administrationdesigndrug cravingdrug relapseeffective therapyexperimental studyimplantationinsightmalenervous system disorderneuralneural stimulationneurotransmissionoptical fiberoptogeneticspatch clamppostsynapticpre-clinicalpre-clinical researchpresynapticpreventreduce symptomsrelapse preventionselective expressionsubstance abuse treatment
中文摘要
项目总结/摘要
可卡因成瘾在美国是一个主要的公共卫生问题,目前没有有效的治疗方法。
针对预防复发的治疗。脑深部电刺激(DBS)已在临床上取得成功,
减少几种神经和精神疾病的症状,并已被提出作为一种潜在的
用于抑制药物渴望和复发的疗法。先前的临床前研究已经确定,
在脑桥核(NAc)壳中的常规DBS可以有效地防止
可卡因寻求,一个复发的动物模型。这项赠款将利用最近的方法进步,
检查细胞和生理机制的NAc DBS的疗效具有更大的特异性。
我们将研究光激活视紫红质通道(ChR 2)诱导的DBS样刺激的作用。
在NAc壳的特定神经元亚型中表达。神经元特异性将通过病毒
在D1多巴胺受体(D1 DR)中选择性表达Cre重组酶的转基因大鼠系中的表达-
或表达D2 DR的中型多刺神经元(MSN)。目的1将检查的电生理效应
在雄性和雌性大鼠中D1 DR-或D2 DR-MSN的光遗传学DBS样(opto-DBS)激活。全细胞
膜片钳实验将评估由opto-DBS参与的突触机制,并确定
是否存在细胞亚型特异性效应。目标2将包括平行的行为实验,
光脑深部电刺激对可卡因引发的恢复的影响。将光纤植入NAc外壳中,
D1 DR-或D2 DR-MSN将被光遗传学激活,在启动剂量为
可卡因,以评估这种操纵对可卡因寻求行为的影响。以往的调查结果和
初步的数据支持一个总体假设,即DBS的NAc壳块可卡因引发的
通过在D2 DR-MSN中特异性诱导突触去增强而恢复。未来的方向将研究
在精确的下游区域中选择性光遗传学抑制D1 DR-或D2 DR-MSN信号传导的作用。
将光纤植入腹侧苍白球(VP)或腹侧被盖区(VTA),
在可卡因引发期间,表达盐视紫红质的D1 DR-或D2 DR-轴突末端将被激活
复职这将确定NAc外壳MSN的DBS是否可以等同于
神经活动总之,确定DBS影响可卡因寻求的具体机制将有助于
为未来可卡因成瘾的细胞和途径特异性治疗提供重要见解。
英文摘要
Project Summary/Abstract
Cocaine addiction is a major public health issue in the United States, and there are currently no effective
treatments targeted towards preventing relapse. Deep brain stimulation (DBS) has been successful clinically at
reducing symptoms of several neurological and psychiatric disorders and has been proposed as a potential
therapy for the suppression of drug craving and relapse. Previous preclinical research has identified that
conventional DBS in the nucleus accumbens (NAc) shell can be effective at preventing reinstatement of
cocaine seeking, an animal model of relapse. This grant will exploit recent methodological advances in order to
examine the cellular and physiological mechanisms underlying the efficacy of NAc DBS with greater specificity.
We will examine the effects of DBS-like stimulation induced by light activation of channelrhodopsin (ChR2)
expressed in specific neuronal subtypes of the NAc shell. Neuronal specificity will be achieved through viral
expression in transgenic rat lines that express Cre recombinase selectively in D1 dopamine receptor (D1DR)-
or D2DR-expressing medium spiny neurons (MSNs). Aim 1 will examine the electrophysiological effects of
optogenetic DBS-like (opto-DBS) activation of D1DR- or D2DR-MSNs in male and female rats. Whole cell
patch clamp experiments will assess the synaptic mechanisms that are engaged by opto-DBS, and determine
if there are cell subtype-specific effects. Aim 2 will consist of parallel behavioral experiments to examine the
effects of opto-DBS on cocaine-primed reinstatement. Optic fibers will be implanted in the NAc shell, and
D1DR- or D2DR-MSNs will be activated optogenetically, at DBS-like frequencies following a priming dose of
cocaine to assess the effects of this manipulation on cocaine-seeking behavior. Previous findings and
preliminary data support the overarching hypothesis that DBS of the NAc shell blocks cocaine-primed
reinstatement by inducing synaptic depotentiation specifically in D2DR-MSNs. Future directions will examine
the effects of selective optogenetic inhibition of D1DR- or D2DR-MSN signaling in precise downstream regions.
Optic fibers will be implanted in either the ventral pallidum (VP) or ventral tegmental area (VTA) and
halorhodopsin-expressing D1DR- or D2DR- axon terminals will be activated during cocaine-primed
reinstatement. This will determine whether DBS of NAc shell MSNs can be equated to overall suppression of
neural activity. Overall, identification of the specific mechanisms by which DBS influences cocaine seeking will
provide critical insights for future cell- and pathway-specific therapeutics for cocaine addiction.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1126/sciadv.adf6039
发表时间:
2023-10-20
期刊:
SCIENCE ADVANCES
影响因子:
13.6
作者:
[Rich, Matthew T., Worobey, Samantha J., Mankame, Sharvari, Pang, Zhiping P., Swinford-Jackson, Sarah E., Pierce, R. Christopher]
通讯作者:
Pierce, R. Christopher
Addiction neuroscience goes nuclear: A role for the transcription factor RXRα.
成瘾神经科学走向核心:转录因子 RXRα 的作用。
DOI:
10.1016/j.neuron.2023.04.002
发表时间:
2023
期刊:
Neuron
影响因子:
16.2
作者:
[Pierce,RChristopher, Rich,MatthewT, Swinford-Jackson,SarahE]
通讯作者:
Swinford-Jackson,SarahE
Mechanisms of Nucleus Accumbens Cell-Type Specific Deep Brain Stimulation in Cocaine Reinstatement
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批准号:10314536
-
项目类别:
-
资助金额:$6.86万
-
财政年份:2022
-
负责人:Matthew T Rich
-
依托单位:
The Role of Amygdalar CaMKII in Cocaine-Associated Memory Extinction and Reconsolidation
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批准号:9045201
-
项目类别:
-
资助金额:$4.36万
-
财政年份:2016
-
负责人:Matthew T Rich
-
依托单位:
海外基金