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)的特点是药物消耗不可控的循环， 戒毒、戒毒、戒毒。对肥皂泡患者和动物模型的研究发现 由于反复使用药物和禁欲而导致的适应不良的大脑病理。例如，我们的 实验室发现，大脑前皮质(PRL)和核团对药物相关刺激的编码增加 在1个月(与1天)可卡因戒断后，伏隔神经(NAC)核心，这些变化是 伴随着毒瘾的加剧。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质区域之间的静息状态功能连接减少 (mPFC；包括催乳素)和NAC核心。此外，动物模型也有 证明反复服用可卡因后PRL活性降低与强迫性药物有因果关系 寻找。关键的是，这些数据与在患有肥胖症的患者中发现的类似，显示PFC活性增加到 与可卡因相关的线索，在总体PFC活动和皮质边缘休息状态降低的背景下 长期戒酒(如3-4个月)后的功能连接。总而言之，这些发现 证明长期的可卡因戒断与PFC和NAC活动的深刻变化有关 和功能连接，这可能在复发中发挥重要作用。然而，无论这些看似 不同的神经适应相互作用，而每种神经适应在持续寻求可卡因中的作用尚未直接 评估过了。此外，一种治疗肥胖症的创新策略将是恢复可卡因引起的缺陷。 在PFC-NAC功能中使用无创脑刺激(NIBS)。已经出现了几种用于NIB的技术， 包括经颅交流电刺激(TACS)，它使用正弦波电场，可以 用来直接调节长时间戒断可卡因后可能被破坏的皮质振荡。在……里面 与NIBS专家和这项应用的共同发起人，卡雷利实验室的Flavio Frohlich博士合作 开发了一种Tacs的翻译大鼠模型。我们的Tacs方法是相对无创的，足以 调节PFC-NAC通路的活性。目标1将使用活体电生理学来表征PRL神经元 短时间(1天)与长时间(1个月)的活动及其与NAC核心的功能连接 实验者强制实施的可卡因戒断。这将决定禁欲引起的总体改变 与线索诱发的活动在PRL-NAC核心通路中是相关的，并检查它们各自的关联 寻找可卡因。目标2将确定TAC是否可以减少寻求可卡因并恢复可卡因戒断- PRL-NAC核心活性的相关变化。这些实验将提供对神经生物学的重要洞察。 可卡因复吸的潜在机制以及NIBS，特别是TAC在治疗肥皂泡方面的作用。

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.