BDNF in the Reward Circuit for DBS-Induced Opioid Extinction

摘要/摘要 脑深部刺激(DBS)是一种神经外科手术，用于治疗神经病学和 精神障碍。最近对动物和人类的研究表明，DBS可能是 一种治疗难治性成瘾的有效方法。我们之前建议使用星展银行作为治疗手段 在大鼠动物模型上寻找药物行为，并发现高频DBS(HF-DBS) 腹侧纹状体/伏隔核(VS/NAC)对吗啡诱导的消退的影响 条件性位置偏爱(CPP)，而低频DBS(LF-DBS)增强消退 记忆(减少寻药行为)。有趣的是，我们还发现LF-DBS 显著缩短药物持续期(LF-DBS~10d与Sham-DBS~40d)。在… 在分子水平上，我们发现DBS处理的动物增加了脑源性神经营养因子的表达。 海马(HPC)。然而，在LF-DBS-DBS中，药物恢复没有明显的预防作用。 仅在绝育过程中进行刺激时才对动物进行处理。在这一转型中 在成绩确定的资助周期之间，我们建议进一步提高药物方面的知识- 寻求行为，以及在潜在的DBS的作用机制中，通过使用药理学 和化学发生的方法。因此，在本研究中，目标1a-c将决定是否 在消亡期间应用LF-DBS，除了在脑电刺激阶段 药物恢复可防止在更高比例的动物中寻求药物。此外，BDNF 将测量HPC以及其他大脑区域，即杏仁核、VS/NAC、 内侧前额叶皮质(MPFC)。Aim 2a将使用一种药理学方法通过注入 脑源性神经营养因子和TrkB拮抗剂(ANA-12)在VS/NAC消退中的作用 吗啡CPP。由于HPC中的谷氨酸能神经元包含一个神经元亚群 表达BDNF，目标2b中的方法是使用化学发生工具，称为Designer 由特制药物(DREADD)特异性激活的受体可激活HPC谷氨酸能 神经元中存在ANA-12，防止吗啡CPP消退。激活 DREADDS将与氯氮平N-氧化物(CNO)一起完成。AIM 2c将停用HPC-NAC 谷氨酸/BDN能投射将阻止LF-DBS的有益影响。我们的 这项研究代表了一种基于电路的方法，以更好地了解药物的作用机制 寻找和灭绝。因为药物灭绝的啮齿动物模型类似于基于暴露的 在人类的治疗中，有可能靶向电刺激和DBS-增加 表达促进消亡的分子可能代表着未来减少 成瘾症状和阿片类药物使用障碍(OUD)。

Abstract/Summary Deep brain stimulation (DBS) is a neurosurgical procedure that is used to treat neurologic and psychiatric disorders. Recent research in both animals and humans has shown that DBS may be an effective procedure for refractory addiction. We previously propose to use DBS as treatment for drug-seeking behaviors in a rat animal model, and found that high frequency DBS (HF-DBS) of the ventral striatum/nucleus accumbens (VS/NAc) impaired extinction of morphine-induced conditioned place preference (CPP), whereas low frequency DBS (LF-DBS) enhanced extinction memory (reducing drug seeking behavior). Interestingly, we also found that LF-DBS significatively shortens the persistency of the drug (LF-DBS~10 days vs sham-DBS~40 days). At the molecular level, we found that DBS-treated animals increased BDNF expression in the hippocampus (HPC). However, drug reinstatement was not significatively prevented in LF-DBS- treated animals when stimulation was applied only during extinction sessions. In this transition between the SCORE-SuRE grant cycle, we propose to further advance the knowledge in drug- seeking behavior, and in the underlying DBS’ mechanisms of action, by using pharmacological and chemogenetic approaches. Therefore, in the present study, Aim 1a-c will determine whether LF-DBS applied during extinction, in addition to provide electrical stimulation in the phase of drug reinstatement prevents drug seeking in a higher percentage of animals. Also, BDNF expression will be measured in the HPC, as well as in other brain regions, i.e., amygdala, VS/NAc, and medial prefrontal cortex (mPFC). Aim 2a will use a pharmacological approach by infusing BDNF and TrkB antagonist (ANA-12) in the VS/NAc to determine their effects in extinction of morphine CPP. Since glutamatergic neurons in the HPC encompass a subpopulation of neurons expressing BDNF, the approach in Aim 2b is to use the chemogenetic tool, known as designer receptors exclusively activated by designer drugs (DREADDs) to activate HPC glutamatergic neurons in the presence of ANA-12, to prevent extinction of morphine CPP. Activation of DREADDs will be done with clozapine N-oxide (CNO). Aim 2c will inactivate HPC-NAc glutamatergic/BDNFergic projections that will prevent the beneficial effects of LF-DBS. Our study represents a circuit-based approach to better understand the action mechanisms of drug- seeking and extinction. Because rodent models of drug extinction resemble exposure-based therapies in humans, it is possible that targeted electrical stimulation and the DBS-increased expression of pro-extinction molecules might represent an effective future approach to reduce the symptoms of addiction and opioid use disorders (OUD).