Cocaine, Parvalbumin, and Perineuronal Nets

可卡因、小清蛋白和神经周围网

• 批准号: 10585028
• 负责人: SUE A AICHER
• 金额: $ 73.76万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585028
• 关键词: Animals; Antibodies; Behavior; Binding; Brain; Brain region; Calcium; Cell physiology; Cells; Chondroitin ABC Lyase; Cocaine; Cocaine Dependence; Cocaine use disorder; Communication; Coupling; Cues; Data; Drug Controls; Electrophysiology (science); Equilibrium; Excision; Extracellular Matrix; FDA approved; Glutamates; Goals; Hippocampus; Homeobox; Human; Immunohistochemistry; Impairment; Individual; Intake; Interneurons; Ion Channel; Knock-in; Link; Measures; Medial; Mediating; Memory; Messenger RNA; Modeling; Modification; Molecular; Neurons; Output; Parvalbumins; Pathway interactions; Pattern; Permeability; Pharmaceutical Preparations; Prefrontal Cortex; Prevalence; Publishing; Pyramidal Cells; Rattus; Relapse; Resistance; Rodent; Rodent Model; Self Administration; Slice; Source; Structure; Synapses; Techniques; Testing; Tracer; Translating; Work; cocaine cue; cocaine relapse; cocaine seeking; cocaine self-administration; cocaine use; conditioned place preference; designer receptors exclusively activated by designer drugs; drug of abuse; drug relapse; drug seeking behavior; experimental study; genetic approach; hippocampal pyramidal neuron; in vivo; innovation; insight; memory consolidation; memory retrieval; novel; prevent; recruit; response; transcriptomics; translational potential

PROJECT SUMMARY/ABSTRACT Cocaine use disorder remains a prevalent problem with no FDA-approved treatment and profound societal consequences. Cocaine-associated memories are strong and resistant to modification but are the basis of relapse in many individuals. Our long-term goal is to diminish cocaine-associated memories to reduce drug relapse. The self-administration model in rodents best reproduces strong cocaine-associated memory. We have found that the removal of perineuronal nets (PNNs) in the rat medial prefrontal cortex (mPFC) disrupts cocaine self-administration memories by interfering with reconsolidation of these memories. PNNs form mainly around parvalbumin (PV)-containing, fast spiking interneurons that powerfully regulate mPFC output, and mPFC output is well known to control drug-seeking behavior in both animals and humans. PV neurons maintain cortical excitatory:inhibitory balance and contribute to theta and gamma oscillations vital for communication across brain regions, yet almost nothing is known about how mPFC PV neurons contribute to cocaine memory reconsolidation. Our Preliminary Data show that PNN removal in the mPFC: (1) decreases PV neuron firing and increases excitability of pyramidal cells in drug-naïve rats; (2) profoundly disrupts the reconsolidation of a self-administration cocaine memory, including cue-induced reinstatement and progressive ratio responding; and (3) disrupts the synchrony of theta and gamma oscillations within the mPFC and between the mPFC and hippocampus in response to a cocaine cue. These findings are significant because they are expected to give novel insights into brain oscillatory patterns that may signify disrupted cocaine memory and how to modify these persistent drug-associated memories. We hypothesize that PNNs allow PV neurons to stabilize and maintain cocaine memories and that, without PNNs, these memories can be destabilized and profoundly disrupted. We will use PV-Cre knock-in rats crossed with tdTomato knock-in rats throughout to determine in Aim 1 how PNN removal alters mPFC PV neuron function and in Aim 2 how PNN removal alters mPFC circuit function during cocaine memory reconsolidation. In Aim 3, we will assess two mechanistic pathways by which PNN removal blocks reconsolidation, including Cre-dependent, specific suppression of PNNs and Cre-dependent inhibition of PV neuron activity with Gi-DREADDs. We will use both slice and in vivo electrophysiology, transcriptomics, tract tracing, immunohistochemistry, molecular, and chemogenetic approaches to identify key factors in PV neuron-mediated control of cocaine-seeking behavior during cocaine memory reconsolidation. Our studies are expected to generate significant advances in understanding how to diminish powerful memories that drive cocaine-seeking behavior.

项目摘要/摘要 可卡因使用障碍仍然是一个普遍存在的问题，没有FDA批准的治疗方法，而且有深刻的社会影响 后果。与可卡因相关的记忆很强，对修饰具有抵抗力，但这是 在许多个体中复发。我们的长期目标是减少与可卡因相关的记忆，以减少 毒品复发。啮齿类动物的自我给药模式最好地再现了与可卡因相关的强烈记忆。 我们发现，去掉大鼠内侧前额叶皮质(MPFC)的周围神经网(PNNS)。 通过干扰可卡因自我管理记忆的重新巩固来扰乱这些记忆。PNNS 主要围绕着含有小白蛋白(PV)的快速放电的中间神经元形成，这些中间神经元有力地调节着mPFC 众所周知，mPFC的输出可以控制动物和人类的药物寻找行为。光伏 神经元维持皮质兴奋性：抑制性平衡，并对theta和Gamma振荡至关重要 跨大脑区域的交流，但几乎不知道mPFC PV神经元如何参与 可卡因记忆重新巩固。我们的初步数据表明，在mPFC中PNN的去除：(1)减少 PV神经元放电和增加药物幼稚大鼠锥体细胞的兴奋性；(2)深刻扰乱 自我给药可卡因记忆的再巩固，包括线索诱导的恢复和渐进性 比率响应；以及(3)扰乱mPFC内的theta和Gamma振荡的同步性 在mPFC和海马区之间，对可卡因线索作出反应。这些发现意义重大，因为 预计他们将为大脑振荡模式提供新的见解，这可能意味着被破坏的可卡因 以及如何修改这些持久的药物相关记忆。我们假设PNNS允许PV 神经元稳定和维持可卡因记忆，如果没有PNNS，这些记忆可以 动荡不安，严重混乱。我们将使用pv-Cre基因敲入大鼠与tdTomato基因杂交 在目标1中确定去PNN如何改变mPFC PV神经元功能，以及在目标2中如何改变mPFC PV神经元功能 去掉PNN改变了可卡因记忆再巩固过程中的mPFC电路功能。在目标3中，我们将评估 PNN去除阻碍重新巩固的两种机械途径，包括依赖于Cre的、特定的 GI-DREADDS抑制PNNS和Cre依赖性抑制PV神经元活性。我们将使用这两种方法 切片和活体电生理学、转录学、轨迹追踪、免疫组织化学、分子和 确定PV神经元介导的可卡因寻找行为控制的关键因素的化学遗传学方法 在可卡因记忆重新巩固的过程中。我们的研究有望在以下方面取得重大进展 了解如何消除驱动可卡因寻找行为的强大记忆。