Reversal of Opioid-Induced Pathological Neuroplasticity Through Timed Electrical Stimulation

该项目旨在开发脑电刺激方法，以逆转药物引起的病理性 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定- 制造电路，持续地重塑它们，导致持续的渴望。因此，复发率 即使在金标准治疗下也很高。使用光遗传学和相关技术的动物研究 这表明药物诱导的可塑性可以通过靶向回路操作来逆转。这是 尤其是在与大脑奖赏回路的“中枢”--丘脑核（NAc）相关的回路中。为 例如，共同研究员托马斯发现，小鼠长期接触吗啡， 到NAc突触。在一段时间后，削弱同样的突触会阻止药物寻求的恢复。 戒断（复发的模式）。挑战在于，我们的电路导向动物工具并不翻译 对人类来说很容易。脑深部电刺激（DBS），特别是脑桥核（NAc）， 在成瘾的人类中是可行的，但以目前的形式似乎并不可靠。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 只有在响应另一个（IL）活动的变化时才受到刺激，然后之间的突触可以被激活。 特别是加强或削弱，完全取决于这两个事件之间的时间。联合PI Widge 开发了这种依赖于活动的刺激方法，用于调节与恐惧相关的杏仁核回路。有 使用类似方法进行脊髓损伤和中风康复的悠久传统。我们将应用 活动依赖性电刺激以修改Long-Evans大鼠的IL-NAc回路，作为第一步 人类大脑刺激疗法我们将开发实时IL-NAc连接测量工具 (Aim 1）并确定可以去促进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大鼠暴露于吗啡在一个条件反射。 位置偏好范式（Aim 2b），将我们的电方法与托马斯博士现有的光遗传学方法进行比较 approach.我们假设这种依赖于活动的电方法同样有效，同时也 更容易翻译。成功将具有近期临床潜力。威奇博士既是一个神经 工程师和脑刺激精神科医生，具有NAc DBS的特定经验。这两个PI都隶属于 国家资助的戒毒治疗发展倡议。我们有能力将潜力转化为 这一努力的成果转化为新的，机制知情的成瘾治疗。

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.