Reversal of Opioid-Induced Pathological Neuroplasticity Through Timed Electrical Stimulation
通过定时电刺激逆转阿片类药物引起的病理性神经可塑性
基本信息
- 批准号:10359133
- 负责人:
- 金额:$ 19.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AbstinenceAmericasAmygdaloid structureAnimalsAnxietyBehaviorBehavioralBiologyBrainChronicClinicalClinical TrialsDecision MakingDeep Brain StimulationElectric StimulationElectrical Stimulation of the BrainElectrodesEngineeringEventEvoked PotentialsExposure toFrequenciesFrightFundingGoldHumanIndustryInterventionLeadLong-Evans RatsLong-Term DepressionMeasurementMeasuresMedical DeviceMethodsMinnesotaModelingMorphineMusNational Institute of Drug AbuseNeuronal PlasticityNeuronsNucleus AccumbensOperative Surgical ProceduresOpiate AddictionOpioidOutcomeParkinson DiseasePathologicPathway interactionsPharmaceutical PreparationsPhysiologic pulsePlant RootsPositioning AttributeProtocols documentationPsychiatristRattusRehabilitation therapyRelapseResearchResearch PersonnelRewardsRodentRoleSafetySpinal cord injuryStrokeStructureSynapsesTechnologyTimeTranslatingTranslationsWorkactive controladdictionbasecohortconditioned place preferenceconditioningcravingdrug of abusedrug seeking behaviorexperienceinsightinterestmotor disorderneuropsychiatric disordernovelnovel strategiesopioid epidemicoptogeneticsrelating to nervous systemresponsereward circuitrystandard caresuccesstherapy developmenttooltranslational potential
项目摘要
This project seeks to develop electrical brain stimulation methods to reverse drug-induced pathological
neuroplasticity. Addictions are difficult to treat in part because drugs of abuse transform reward and decision-
making circuits, persistently remodeling them in ways that lead to persistent cravings. As a result, relapse rates
are high even with gold-standard treatment. Animal studies using optogenetics and related technologies
suggest that drug-induced plasticity can be reversed by targeted circuit manipulations. This is
particularly true in circuits related to the nucleus accumbens (NAc), a “hub” of brain reward circuitry. For
instance, co-PI Thomas showed that chronic morphine exposure in mice strengthened an infralimbic cortex (IL)
to NAc synapse. Weakening this same synapse blocked reinstatement of drug-seeking after a period of
abstinence (a model of relapse). The challenge is that our circuit-directed tools for animals do not translate
readily to humans. Electrical deep brain stimulation (DBS), particularly of the nucleus accumbens (NAc), is
feasible in humans with addiction, but appears not to work reliably in its current form. This is in part because
clinical NAc DBS uses approaches developed for Parkinson disease, without considering addiction biology.
That is, it does not address the neuroplasticity problem.
We propose to develop an electrical intervention that specifically targets pathological IL-NAc
connectivity, based around the concept of timing-dependent plasticity. In short, if one structure (NAc) is
stimulated only in response to changes in another’s (IL’s) activity, the synapses between then can be
specifically strengthened or weakened, based entirely on the timing between the two events. Co-PI Widge has
developed such activity-dependent stimulation methods for modulating fear-related amygdala circuitry. There is
a long tradition of using similar approaches for rehabilitation of spinal cord injury and stroke. We will apply
activity-dependent electrical stimulation to modify the IL-NAc circuit of Long-Evans rats, as a first step
towards a human brain stimulation therapy. We will develop real-time IL-NAc connectivity measurement tools
(Aim 1) and identify the electrical stimulation parameters (timing, intensity) that can de-facilitate the IL-NAc
connection (Aim 2a). We will then apply those optimized methods to rats exposed to morphine in a conditioned
place preference paradigm (Aim 2b), comparing our electrical approach to Dr. Thomas’ existing optogenetic
approach. We hypothesize that this activity-dependent electrical approach will be equally effective, while also
being much easier to translate. Success would have near-term clinical potential. Dr. Widge is both a neural
engineer and a brain stimulation psychiatrist, with specific experience in NAc DBS. Both PIs are affiliated with
state-funded initiatives in addiction treatment development. We are well positioned to translate potential
outcomes from this effort into novel, mechanism-informed treatments for addiction.
本项目旨在开发脑电刺激方法来逆转药物引起的病理
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mark John Thomas其他文献
Mark John Thomas的其他文献
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{{ truncateString('Mark John Thomas', 18)}}的其他基金
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