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

项目摘要 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。 包括物质使用障碍和抑郁症在内的与认知和执行相关的疾病， 功能障碍。然而，额叶功能减退发展的潜在机制是对经验的反应， 仍然未知。神经元周网（perineuronalnets，PNNs）是由细胞外基质糖蛋白组成的，是一种调节异常的神经元网络 在药物成瘾和抑郁症中，已经成为突触可塑性的重要调节因子， 发育成熟的大脑。PNNs在小白蛋白阳性快速发放中间神经元（PV+ FSI）周围形成 倾向于增加PV+ FSI活性，这增强了神经元网络中的GABA能抑制，并提示 PNNs可能参与前额叶功能减退。我们的初步数据，使用大鼠前额叶皮层模型， (PFC)慢性甲基苯丙胺（METH）给药诱导的功能减退（即，前额功能减退）提示 慢性METH诱导PNN包围的PV+ FSI百分比增加，与 PV+ FSI兴奋性增加，对锥体神经元的抑制性传递增加，以及 出现认知缺陷。 这项建议的总体目标是研究PNNs在METH诱导的额叶功能减退和认知功能障碍中的作用。 赤字根据强有力的初步数据和文献，中心假设是， PNN的增加增强PFC中PV+ FSI的活性，并产生前额叶功能减退和认知缺陷。目的 1将评估慢性METH自我给药何时开始PNN密度、表达水平和 以及这些变化是否持久。目的2将研究PNNs在METH中的作用。 导致认知缺陷。目的3将评估PNNs在MET诱导的前额叶功能减退中的作用。 这项研究具有重要意义，因为它将填补与机制相关的知识空白 冰毒成瘾的潜在前额叶功能减退拟议研究的主要概念创新是 PNNs和hypofrontality之间的联系的调查。此外，从《公约》获得的知识 拟议的实验将有助于开发有效的治疗方法，以改善下额叶相关的症状， SUD和其他精神疾病，也可以提供新的见解的基本机制， 前额叶功能减退

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.