Pathway-specific Intervention in Prelimbic Cortical Circuitry Decreases Cocaine-seeking

对前额皮质回路进行特定通路干预可减少可卡因寻求

• 批准号: 10453594
• 负责人: Jacqueline F. McGinty
• 金额: $ 33.98万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453594
• 关键词: Abstinence; Anxiety; Brain-Derived Neurotrophic Factor; CREB1 gene; Caliber; Cocaine; Cocaine Dependence; Coupled; Cues; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dendritic Spines; Drug abuse; Early Intervention; Electrophysiology (science); Environment; Extracellular Signal Regulated Kinases; Female; Functional disorder; Future; Glutamates; Head; Image; Individual; Infusion procedures; Intervention; Mediating; Nature; Neurobiology; Neurons; Pathway interactions; Performance; Pharmaceutical Preparations; Phase; Phosphorylation; Pre-Clinical Model; Prefrontal Cortex; Protein Dephosphorylation; Protein Kinase A Inhibitor; Proteins; Rattus; Regulation; Relapse; Research; Rewards; Role; Signal Transduction; Slice; Structure of paraventricular nucleus of thalamus; Substance Use Disorder; Synaptic plasticity; Testing; Time; Viral Vector; Withdrawal; Woman; addiction; anxiety-related behavior; cocaine self-administration; combinatorial; designer receptors exclusively activated by designer drugs; effective therapy; insight; male; men; neuroadaptation; new therapeutic target; novel; pre-clinical; prevent; relating to nervous system; retrograde transport; transmission process; withdrawal-induced anxiety

Specific Aims A major challenge for individuals suffering from substance use disorders (SUDs) is the lack of effective treatments that reduce relapse vulnerability. Drug predictive cues in the environment are powerful triggers for relapse and understanding how these persistent associations are formed and maintained is a critical focus of preclinical SUD research. In this proposal, we have built on our discovery that immediately after the end of cocaine self administration (SA), an infusion of brain-derived neurotrophic factor (BDNF) into the prelimbic (PL) prefrontal cortex prevents the cocaine SA-induced dephosphorylation of key glutamatergic-related plasticity- related proteins (PRPs), including GluN2A, GluN2B, ERK MAP kinase, and CREB32,96. This early intervention with BDNF also prevents prolonged cocaine-induced deficits in PL-NA core glutamatergic transmission that promote subsequent cocaine seeking9. In contrast, by the end of the first week of abstinence, protein kinase A (PKA)-dependent augmentation of GluA1 and CREB phosphorylation emerges. At that time, intra-PL BDNF has no effect on relapse8 but intra-PL infusion of a PKA inhibitor, Rp-cAMPs, reverses the hyperphosphorylation and decreases relapse70,92. More recently, we have shown that the biphasic changes in GluA1 and pCREB within the first week of abstinence are associated with similar biphasic changes in the head diameters (dH) of dendritic spines of PL–NA core neurons89. These data have spurred the overall hypothesis that interventions to decrease drug seeking must be tailored to the dynamic changes in neuroadaptations that emerge during different phases of the addiction cycle. In chemogenetic studies to investigate the contribution of specific pathways originating in PL cortex to drug seeking, we discovered that PL-NA core and PL-posterior paraventricular thalamic nucleus (pPVT) pathways oppose each others’ effects during early withdrawal. Selective cre-dependent DREADD inhibition of PL-NA core neurons infected with a retrogradely transported cre-AAV immediately after cocaine SA has no effect by itself, but reverses the suppressive effect of intra-PL BDNF on subsequent drug seeking31. In contrast, selective inhibition of the PL-pPVT pathway immediately after cocaine SA decreases subsequent cocaine- seeking, an effect that is prevented by intra-PL BDNF31. Interestingly, we also found that selective inhibition of the PL-pPVT pathway reduces anxiety-related behavior in rats withdrawing from cocaine and inactivation of pPVT decreases conditioned aversion to cocaine, suggesting that cocaine’s engagement of anxiety- and aversion-related circuitry that contributes to drug seeking includes pPVT. Taken together, our new findings suggest the novel hypothesis that cocaine SA produces differential regulation of PL-NA core and PL-pPVT pathways and that these two distinct circuits conspire to support future drug seeking. In this proposal, we will use pathway-specific, combinatorial chemogenetic approaches, slice electrophysiology, and state-of-the-art dendritic spine and PRP imaging in PL-NA core and PL-pPVT circuitry to explore the time-dependent plasticity occurring in this network that influences cocaine seeking and aversion. We will use these approaches in the following aims that will be performed in male and female rats. Aim 1. BDNF regulation of PRPs and structural and synaptic plasticity in PL-NA core vs. PL-pPVT neurons during early withdrawal. Using viral vector approaches, we will investigate the effects of intra-PL BDNF infusion on (A) dendritic spine plasticity and PRP changes and (B) synaptic plasticity in PL-NA core vs. PL-PVT neurons during early withdrawal. Aim 2. PKA regulation of PRPs and structural and synaptic plasticity in PL-NA core vs. PL-pPVT neurons after 7 and 30 days of abstinence. (A) We will investigate the effects of inhibiting cAMP/PKA signaling on (A) dendritic spine plasticity and PRP changes and (B) synaptic plasticity in PL-NA core vs. PL- PVT neurons after 7 or 30 days of abstinence with or without relapse testing. Aim 3. The role of PL-NA core and PL-pPVT neurons in cocaine-induced anxiety and aversion in relationship to cocaine seeking after abstinence. We will use a retro-Gi DREADD approach to test the effects of inhibiting PL-NA core or PL-pPVT neurons (A) on withdrawal-induced anxiety immediately after the end of cocaine SA and (B) on conditioned avoidance of cocaine in an operant runway task before or after cocaine SA followed by cue-induced relapse testing. Scientific Impact: These studies will expand our understanding of how to reverse critical neuroadaptations underlying prefrontal dysfunctions during different phases of the addiction cycle that trigger relapse to drug- seeking. By understanding temporally dynamic, differential neuroadaptations in the PL networks regulating reward and aversion, we may be able to discover novel therapeutic targets to decrease drug-seeking.

具体目标 患有药物使用障碍（SUD）的人的主要挑战是缺乏有效 减少救济脆弱性的治疗方法。环境中的药物预测提示是强大的触发因素 继电器和理解如何形成和维护这些持久关联是 临床前SUD研究。在这项提议中，我们建立了我们的发现，即结束后立即 可卡因自我给药（SA），注入脑衍生的神经营养因子（BDNF） 前额叶皮层阻止可卡因SA诱导的关键谷氨酸能相关塑性的去磷酸化 - 相关蛋白质（PRP），包括Glun2a，Glun2b，Erk Map激酶和CREB32,96。这项早期干预 使用BDNF还可以防止可卡因诱导的PL-NA核心谷氨酸能传播中延长可卡因诱导的缺陷 促进随后的可卡因寻求9。相反，到节制的第一周结束时，蛋白激酶A （PKA）依赖性GLUA1和CREB磷酸化的增强出现。当时，bdnf Intra-pl 对浮雕没有影响8，但是PPA抑制剂的内部输注RP训练会逆转 高磷酸化并减少退休70,92。最近，我们表明双相变化 禁欲的第一周内GLUA1和PCREB与头部类似的双相变化有关 PL -NA核心神经元的树突状刺的直径（DH）。这些数据刺激了总体假设 减少药物寻求药物的干预措施必须根据神经适应的动态变化量身定制 在成瘾周期的不同阶段出现。 在化学生成研究中，研究了PL皮质中特定途径对药物的贡献 寻求时，我们发现PL-NA核心和PL形成型室室丘脑核（PPVT）途径 在提早撤离期间反对彼此的效果。选择性CRE依赖性的Dreadd抑制PL-NA 可卡因SA后立即感染了逆行运输的Cre-aav的核心神经元没有影响 本身，但逆转了bdnf内部对随后的药物寻求的抑制作用31。相比之下， 可卡因SA后立即对PL-PPVT途径的选择性抑制会降低可卡因 - 寻求，这是由bdnf31内部阻止的效果。有趣的是，我们还发现选择性抑制 PL-PPVT途径减少了从可卡因撤离和失活的大鼠的焦虑相关行为 PPVT减少了对可卡因的条件厌恶，这表明可卡因的动画和 造成药物寻求药物的厌恶相关电路包括PPVT。 综上所述，我们的新发现表明可卡因SA产生差异化的新假设 PL-NA核心和PL-PPVT途径的调节，这两个不同的电路共同支持未来 寻求毒品。在此提案中，我们将使用特定途径的组合化学生成方法，切片 PL-NA核心和PL-PPVT电路中的电生理学以及最先进的树突状脊柱和PRP成像 探索该网络中发生的时间依赖性可塑性，从而影响可卡因寻求和厌恶。 我们将在以下目标中使用这些方法，这些方法将在男性和雌性大鼠中执行。 AIM1。BDNF调节PL-NA核心与PL-PPVT中的结构和突触可塑性 提早戒断期间的神经元。使用病毒载体方法，我们将研究Intra-pl的影响 BDNF对（a）树突状脊柱可塑性和PRP的变化以及（b）PL-NA核心中的突触可塑性。 PL-PVT神经元早期撤离。 AIM 2。PKA调节PL-NA核心与PL-PPVT中的PRP，结构和突触可塑性 7天和30天后的神经元。 （a）我们将研究抑制营/PKA的影响 （a）树突状脊柱可塑性和PRP的信号变化以及（b）PL-NA核心与PL-的突触可塑性 在禁欲7或30天后进行的PVT神经元，有或没有继电器测试。 AIM 3。PL-NA核心和PL-PPVT神经元在可卡因引起的焦虑和厌恶中的作用 与可卡因寻求戒酒后的关系。我们将使用Retro-Gi Dreadd方法测试 抑制PL-NA核或PL-PPVT神经元（a）对戒断引起的焦虑的影响 可卡因SA和（b）在操作跑道任务中或之后的有条件避免可卡因 可卡因SA，然后进行提示引起的继电器测试。 科学影响：这些研究将扩大我们对如何逆转关键神经照射的理解 在成瘾周期的不同阶段，潜在的前额叶功能障碍会导致药物缓解 寻求。通过了解调节的PL网络中暂时动态的差异神经适应 奖励和厌恶，我们也许能够发现新颖的治疗靶标，以减少寻求药物。