Reversal of Opioid-Induced Pathological Neuroplasticity Through Timed Electrical Stimulation

该项目旨在开发脑电刺激方法来逆转药物引起的病理学 神经可塑性。成瘾很难治疗，部分原因是滥用药物会改变奖励和决策—— 制造电路，不断地重塑它们，从而产生持久的渴望。结果，复发率 即使采用金标准治疗，也很高。使用光遗传学和相关技术的动物研究 表明药物引起的可塑性可以通过有针对性的电路操作来逆转。这是 在与伏隔核（NAc）相关的电路中尤其如此，伏隔核是大脑奖励电路的“枢纽”。对于 例如，共同 PI Thomas 表明，小鼠长期接触吗啡会增强边缘下皮层 (IL) 到 NAc 突触。削弱同一突触会在一段时间后阻止药物寻求的恢复。 禁欲（复发的模型）。挑战在于我们针对动物的电路导向工具无法翻译 对人类来说很容易。电深部脑刺激 (DBS)，特别是伏隔核 (NAc)， 对于成瘾的人类来说是可行的，但目前的形式似乎并不可靠。这部分是因为 临床 NAc DBS 使用针对帕金森病开发的方法，而不考虑成瘾生物学。 也就是说，它没有解决神经可塑性问题。 我们建议开发一种专门针对病理性 IL-NAc 的电干预 连接性，基于时间依赖性可塑性的概念。简而言之，如果一种结构（NAc）是 仅响应另一个（IL）活动的变化而受到刺激，然后之间的突触可以是 具体加强或削弱，完全取决于两个事件之间的时间安排。联合 PI Widge 拥有 开发了这种依赖于活动的刺激方法来调节与恐惧相关的杏仁核回路。有 使用类似方法康复脊髓损伤和中风的悠久传统。我们将申请 第一步是通过活动依赖性电刺激来改变 Long-Evans 大鼠的 IL-NAc 回路 走向人脑刺激疗法。我们将开发实时 IL-NAc 连接测量工具 （目标 1）并确定可阻碍 IL-NAc 的电刺激参数（时间、强度） 连接（目标 2a）。然后，我们将这些优化的方法应用于在条件条件下暴露于吗啡的大鼠。 位置偏好范式（目标 2b），将我们的电学方法与 Thomas 博士现有的光遗传学进行比较 方法。我们假设这种依赖于活动的电方法将同样有效，同时也 更容易翻译。成功将具有近期临床潜力。 Dr. Widge 既是神经元 工程师和脑刺激精神病学家，在 NAc DBS 方面拥有丰富的经验。两位 PI 均隶属于 国家资助的成瘾治疗发展举措。我们有能力转化潜力 这项努力的成果是针对成瘾的新颖的、基于机制的治疗方法。

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.