Investigating the role of the prelimbic cortex to nucleus accumbens core pathway in persistent cocaine seeking

项目摘要 物质使用障碍（SUD）的特征是不可控制的药物消耗周期， 戒毒和复吸。对SUD患者和动物模型的研究已经确定了 适应不良的大脑病理是重复使用毒品和禁欲的结果。比如我们 一个实验室已经证明，前边缘皮层（PrL）和核团对药物相关刺激的编码增加 可卡因戒断1个月（与1天相比）后的NAc核心，这些变化是 伴随着吸毒的加剧。有趣的是，其他研究表明，1个月的可卡因 禁欲导致内侧前额叶皮层区域之间的静息状态功能连接减少 (mPFC;其包括麻醉大鼠中的PrL）和NAc核心。此外，动物模型也 表明重复服用可卡因后PrL活性降低与强迫性药物有因果关系， 寻找重要的是，这些数据与SUD患者中的结果平行，显示PFC活性增加， 可卡因相关的线索，在减少的整体PFC活动和皮质边缘静息状态的背景下， 在延长的禁欲期（例如3-4个月）之后的功能连接。总的来说，这些发现 证明长期的可卡因戒断与PFC和NAc活性的深刻变化有关 和功能性连接，可能在复发中发挥重要作用。然而，这些看似 不同的神经适应相互作用，每一个在持续的可卡因寻求中的作用还没有被直接研究。 评估。此外，SUD的创新治疗策略将是恢复可卡因引起的缺陷 在PFC-NAc功能使用非侵入性脑刺激（NIBS）。NIBS的几种技术已经出现， 包括采用正弦波电场的经颅交流电刺激（tACS）， 用于直接调节可能在长期可卡因戒断后被破坏的皮质振荡。在 与NIBS的专家和该应用程序的共同赞助商Flavio Frohlich博士合作，Carelli实验室 开发了一种tACS的转化大鼠模型。我们的tACS方法相对无创，足以 调节PFC-NAc通路的活性。目的1将在体电生理学的特点，PrL神经元 短期（1天）与长期（1个月）后的活动及其与NAc核心的功能连接 实验者强制的可卡因戒断这将决定是否禁欲引起的改变， 与提示诱发的活动在PrL-NAc核心途径是相关的，并检查其各自的关联 寻找可卡因目标2将确定tACS是否可以减少可卡因寻求和恢复可卡因戒断- PrL-NAc核心活性的相关变化。这些实验将为神经生物学提供重要的见解。 可卡因使用复发的潜在机制和NIBS（特别是tACS）在治疗SUD中的效用。

Project Summary Substance use disorders (SUDs) are characterized by cycles of uncontrollable drug consumption, abstinence from drug use, and relapse. Investigations in individuals with SUDs and animal models have identified maladaptive brain pathologies that are a consequence of repeated drug use and abstinence. For example, our lab has demonstrated increased encoding of drug-associated stimuli by the prelimbic cortex (PrL) and nucleus accumbens (NAc) core following 1-month (compared to 1-day) cocaine abstinence and these changes are accompanied by heightened drug seeking. Interestingly, other studies have shown that 1-month cocaine abstinence leads to reduced resting state functional connectivity between regions of the medial prefrontal cortex (mPFC; which includes the PrL) and NAc core in anesthetized rats. Further, animal models have also demonstrated that reduced PrL activity following repeated cocaine taking is causally linked with compulsive drug seeking. Critically, these data parallel findings in individuals with SUDs showing increased PFC activity to cocaine-associated cues, against a background of reduced overall PFC activity and corticolimbic resting state functional connectivity following extended periods of abstinence (e.g. 3-4 months). Collectively, these findings demonstrate that prolonged cocaine abstinence is associated with profound changes in PFC and NAc activity and functional connectivity that likely play important roles in relapse. However, whether these seemingly divergent neuroadaptations interact, and the role of each in persistent cocaine seeking has not yet been directly assessed. Furthermore, an innovative treatment strategy for SUDs would be to restore cocaine-induced deficits in PFC—NAc function using non-invasive brain stimulation (NIBS). Several techniques for NIBS have emerged, including transcranial alternating current stimulation (tACS) which employs a sine-wave electric field that can be used to directly modulate cortical oscillations that may be disrupted following prolonged cocaine abstinence. In collaboration with an expert in NIBS and a co-sponsor on this application, Dr. Flavio Frohlich, the Carelli lab developed a translational rat model of tACS. Our tACS approach is relatively noninvasive and is sufficient to modulate activity in the PFC—NAc pathway. Aim 1 will use in vivo electrophysiology to characterize PrL neuronal activity and its functional connectivity with the NAc core following short (1-day) versus prolonged (1-month) experimenter-imposed cocaine abstinence. This will determine whether abstinence-induced alterations in overall versus cue-evoked activity in the PrL—NAc core pathway are related and examine their respective association with cocaine seeking. Aim 2 will determine if tACS can reduce cocaine seeking and restore cocaine abstinence- related changes in PrL—NAc core activity. These experiments will provide crucial insight into the neurobiological mechanisms underlying relapse to cocaine use and the utility of NIBS, particularly tACS, in treating SUDs.