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

• 批准号: 10359133
• 负责人: Mark John Thomas
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10359133
• 关键词: Abstinence; Americas; Amygdaloid structure; Animals; Anxiety; Behavior; Behavioral; Biology; Brain; Chronic; Clinical; Clinical Trials; Decision Making; Deep Brain Stimulation; Electric Stimulation; Electrical Stimulation of the Brain; Electrodes; Engineering; Event; Evoked Potentials; Exposure to; Frequencies; Fright; Funding; Gold; Human; Industry; Intervention; Lead; Long-Evans Rats; Long-Term Depression; Measurement; Measures; Medical Device; Methods; Minnesota; Modeling; Morphine; Mus; National Institute of Drug Abuse; Neuronal Plasticity; Neurons; Nucleus Accumbens; Operative Surgical Procedures; Opiate Addiction; Opioid; Outcome; Parkinson Disease; Pathologic; Pathway interactions; Pharmaceutical Preparations; Physiologic pulse; Plant Roots; Positioning Attribute; Protocols documentation; Psychiatrist; Rattus; Rehabilitation therapy; Relapse; Research; Research Personnel; Rewards; Rodent; Role; Safety; Spinal cord injury; Stroke; Structure; Synapses; Technology; Time; Translating; Translations; Work; active control; addiction; base; cohort; conditioned place preference; conditioning; craving; drug of abuse; drug seeking behavior; experience; insight; interest; motor disorder; neuropsychiatric disorder; novel; novel strategies; opioid epidemic; optogenetics; relating to nervous system; response; reward circuitry; standard care; success; therapy development; tool; translational potential

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