Reversal of Opioid-Induced Pathological Neuroplasticity Through Timed Electrical Stimulation

该项目致力于开发电刺激大脑的方法来逆转药物引起的病理改变。 神经可塑性。成瘾很难治疗，部分原因是滥用药物改变了奖励和决定- 制造循环，以导致持续渴望的方式持续地重塑它们。因此，复发率 即使有黄金标准的治疗，也是很高的。利用光遗传学和相关技术进行动物研究 提示药物诱导的可塑性可以通过有针对性的电路操作来逆转。这是 与伏隔核(NAC)相关的回路尤其如此，NAC是大脑奖励回路的“中枢”。为 例如，合作者Pi Thomas表明，小鼠长期接触吗啡增强了下缘皮质(IL)。 到NAC Synapse。削弱相同的突触阻止了在一段时间后寻求毒品的恢复 禁欲(旧病复发的典范)。挑战在于我们为动物设计的电路导向工具不能翻译 对人类来说很容易。脑深部电刺激(DBS)，特别是伏隔核(NAC)，是 在有毒瘾的人身上是可行的，但在目前的形式下似乎不可靠。这部分是因为 临床NAC DBS使用为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，基于时间依赖可塑性的概念。简而言之，如果一个结构(NAC)是 只有在对另一个人(IL)活动的变化做出反应时，才会受到刺激，这时之间的突触可以 具体加强或削弱，完全基于两个事件之间的时间安排。共同派·威奇有 开发了这种依赖活动的刺激方法来调节与恐惧相关的杏仁核回路。的确有 使用类似方法进行脊髓损伤和中风康复的传统由来已久。我们会申请 作为第一步，电刺激改变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连通性测量工具 (目标1)并确定可抑制IL-NAC的电刺激参数(时间、强度) 联系(目标2a)。然后，我们将把这些优化的方法应用于暴露在条件吗啡中的大鼠 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 接近。我们假设这种依赖活动的电学方法将同样有效，同时还 翻译起来容易多了。成功将具有近期的临床潜力。威奇博士既是一位神经学家 工程师和脑刺激精神病学家，具有南汽星展的特殊经验。这两个PI都隶属于 国家资助的成瘾治疗发展计划。我们处于有利地位，可以将潜力转化为 将这一努力的成果转化为新的、机制知情的成瘾治疗方法。

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.