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.

项目摘要 高额叶对应于在几种神经精神病学中发现的额叶皮质活性降低的状态 疾病，包括使用障碍和抑郁症，与认知和执行 功能障碍。但是，响应经验的低尚发展的基础机制 仍然未知。会内神经元网（PNN）由细胞外基质糖蛋白组成，失调 在药物成瘾和抑郁症中，已经成为突触可塑性的重要调节剂 发育和成熟的大脑。 PNNS围绕白蛋白阳性阳性快速尖峰中间神经元（PV+FSIS）形成 倾向于增加PV+FSIS活性，从而增强了神经元网络中的GABA能抑制 PNNS在低调性中的潜在参与。我们的初步数据，使用前额叶皮层的大鼠模型 （PFC）慢性甲基苯丙胺（甲基苯丙胺）诱导的功能障碍（即低纤维性）表明 慢性甲基甲基苯丙胺引起了PNN包围的PV+FSI的百分比，与 PV+FSIS兴奋性的增加，抑制性传播到金字塔神经元的增加以及 认知缺陷的出现。 该提案的总体目的是研究PNN在甲基甲基诱导的低焦性和认知中的作用 缺陷。强有力的初步数据和文献所告知的中心假设是甲基苯丙胺诱导的 PNN的增加增强了PVC中PV+FSIS活性，并产生低焦性和认知缺陷。目的 1将评估慢性甲基自动化启动启动PNNS密度，表达水平和 堆肥以及这些变化是否长期。 AIM 2将研究PNN在甲基中的作用 诱发认知缺陷。 AIM 3将评估PNN在甲基甲基诱导的低处中的作用。 拟议的研究很重要，因为它将填补与机制有关的知识的基本差距 甲基化中心的潜在性低下。拟议研究的主要概念创新是 调查PNN与高额叶之间的联系。此外，从 拟议的实验将有助于开发有效的治疗方法，以改善与额外性相关的症状 SUD和其他精神科状况，还可以提供有关基本机制的新见解 高尚。