Role of Perineuronal Nets in Methamphetamine-Induced Hypofrontality and Cognitive Deficits

神经周围网络在甲基苯丙胺引起的额叶下垂和认知缺陷中的作用

• 批准号: 10675330
• 负责人: ANTONIETA LAVIN
• 金额: $ 22.4万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675330
• 关键词: Address; Attentional deficit; Behavior; Behavioral; Brain; Chronic; Cognition; Cognitive; Cognitive deficits; Data; Dendrites; Development; Digestion; Disease; Drug Addiction; Drug Exposure; Drug Stability; Exposure to; Extracellular Matrix; Glycoproteins; Goals; Human; Hyperactivity; Impulsivity; Individual; Interneurons; Investigation; Ion Channel; Knowledge; Label; Link; Literature; Medial; Memory; Memory impairment; Mental Depression; Methamphetamine; Methamphetamine dependence; Modeling; Neuronal Plasticity; Neurons; Parvalbumins; Pathologic; Prefrontal Cortex; Quality of life; Rattus; Regulation; Research; Role; Self Administration; Short-Term Memory; Substance Use Disorder; Symptoms; Synapses; Synaptic Receptors; Synaptic plasticity; Techniques; Testing; Time; Viral; Whole-Cell Recordings; addiction; cognitive disability; density; disability; effective therapy; executive function; experience; experimental study; frontal lobe; hippocampal pyramidal neuron; innovation; insight; methamphetamine exposure; neuronal cell body; neuropsychiatric disorder; neuropsychiatry; novel; novel therapeutic intervention; relapse risk; response; transmission process

PROJECT SUMMARY Hypofrontality corresponds to a state of reduced frontal cortex activity found in several neuropsychiatric disorders, including substance use disorders and depression, that correlates with cognition and executive function disabilities. However, the mechanisms underlying hypofrontality development in response to experience remain unknown. Perineuronal nets (PNNs) are composed of extracellular matrix glycoproteins, are dysregulated in drug addiction and depression, and have emerged as important regulators of synaptic plasticity in the developing and mature brain. PNNs formation around parvalbumin-positive fast spiking interneurons (PV+FSIs) tends to increase PV+FSIs activity, which enhances GABAergic inhibition in neuronal networks and suggests the potential involvement of PNNs in hypofrontality. Our preliminary data, using a rat model of prefrontal cortex (PFC) hypofunction (i.e. hypofrontality) induced by chronic methamphetamine (METH) administration, suggest that chronic METH induces an increase in the percentage of PV+FSIs surrounded by PNNs, associated with an increase in PV+FSIs excitability, an increase in inhibitory transmission onto pyramidal neurons, as well as the emergence of cognitive deficits. The overall objective of this proposal is to study the role of PNNs in METH-induced hypofrontality and cognitive deficits. The central hypothesis- informed by strong preliminary data and literature- is that METH-induced increase in PNNs enhances PV+FSIs activity in the PFC and produces hypofrontality and cognitive deficits. Aim 1 will assess when chronic METH self-admnistration initaites changes in PNNs density, expression level and compostion and whether these changes are long-lasting. Aim 2 will investigate the role of PNNs in METH- induced cognitive deficits. Aim 3 will assess the role of PNNs in METH-induced hypofrontality. The proposed research is significant because it will fill fundamental gap in knowledge related to the mechanisms underlying hypofrontality in METH-addiction. The main conceptual innovation of the proposed study is the investigation of the link between PNNs and hypofrontality. Furthermore, the knowledge obtained from the proposed experiments will help to develop effective treatments to ameliorate hypofrontality-related symptoms in SUD and other psychiatric conditions and can also provide new insights into the basic mechanisms underlying hypofrontality.

项目概要 额叶功能减退对应于在几种神经精神疾病中发现的额叶皮层活动减少的状态 与认知和执行能力相关的疾病，包括物质使用障碍和抑郁症 功能障碍。然而，对经验做出反应的额叶发育的潜在机制 仍然未知。神经周围网 (PNN) 由细胞外基质糖蛋白组成，失调 在药物成瘾和抑郁症中，并已成为突触可塑性的重要调节因子 发育和成熟的大脑。 PNN 围绕小清蛋白阳性快速尖峰中间神经元形成 (PV+FSIs) 倾向于增加 PV+FSI 活性，从而增强神经元网络中的 GABA 抑制，并表明 PNN 可能参与下额功能。我们的初步数据，使用前额皮质大鼠模型 长期使用甲基苯丙胺 (METH) 引起的 (PFC) 功能减退（即额叶功能减退），表明 慢性 METH 会导致被 PNN 包围的 PV+FSI 的百分比增加，这与 PV+FSIs 兴奋性增加，锥体神经元抑制性传递增加，以及 认知缺陷的出现。 该提案的总体目标是研究 PNN 在 METH 引起的额叶功能减退和认知方面的作用 赤字。中心假设——基于强有力的初步数据和文献——是 METH 引起的 PNN 的增加会增强 PFC 中的 PV+FSI 活动，并产生额叶功能减退和认知缺陷。目的 1 将评估慢性 METH 自我给药何时引发 PNN 密度、表达水平和 成分以及这些变化是否持久。目标 2 将研究 PNN 在 METH- 中的作用 诱发的认知缺陷。目标 3 将评估 PNN 在 METH 引起的额叶功能减退中的作用。 拟议的研究意义重大，因为它将填补与机制相关的知识的基本空白 冰毒成瘾中潜在的额叶功能低下。本研究的主要概念创新在于 PNN 与额叶下质之间联系的调查。此外，从所获得的知识 拟议的实验将有助于开发有效的治疗方法，以改善额叶下垂相关的症状 SUD 和其他精神疾病，也可以为潜在的基本机制提供新的见解 额叶不足。