Methamphetamine Effects on Prefrontal Cortical PV+ Interneurons and Resulting Cognitive Deficits

甲基苯丙胺对前额皮质 PV 中间神经元的影响及由此产生的认知缺陷

• 批准号: 10473737
• 负责人: ANTONIETA LAVIN
• 金额: $ 35.86万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473737
• 关键词: Acute; Anxiety; Attention; Bathing; Behavior; Biological Markers; Brain; Chronic; Cognitive; Cognitive deficits; Cues; Data; Disease; Dopamine D1 Receptor; Dopamine Receptor; Electrophysiology (science); Equilibrium; Executive Dysfunction; Face; Functional disorder; Genetic; Goals; Impaired cognition; Impulsivity; Interneurons; Knowledge; Literature; Maintenance; Mediating; Medical; Memory impairment; Mental Depression; Methamphetamine; Methamphetamine dependence; N-Methylaspartate; Neurodevelopmental Disorder; Parvalbumins; Pathologic; Pathology; Pharmaceutical Preparations; Pharmacology; Play; Prefrontal Cortex; Preparation; Psychoses; Rattus; Reagent; Receptor Activation; Receptor Signaling; Research; Rodent; Role; Schizophrenia; Self Administration; Short-Term Memory; Slice; Social Functioning; Stimulus; Study models; Substance Use Disorder; Symptoms; Synapses; Synaptic Transmission; Techniques; Testing; Transgenic Organisms; Viral; Whole-Cell Recordings; addiction; antagonist; autism spectrum disorder; behavior test; cell type; cognitive disability; cognitive function; effective therapy; executive function; experimental study; frontal lobe; hippocampal pyramidal neuron; insight; interest; knock-down; methamphetamine abuse; methamphetamine effect; neuropsychiatric disorder; neuropsychiatry; novel; novel therapeutic intervention; psychostimulant; receptor function; theories; tool; transmission process

Project Summary Neuropsychiatric disorders are a very serious medical and societal problem with many different origins, however, a common and prevalent deficit found in these disorders is hypofrontality. Emerging theories posit that hypofrontality [alterations in the ratio of excitatory (E) and inhibitory (I) synaptic transmission] underlie schizophrenia, anxiety, addiction, autism spectrum disorders and depression. Methamphetamine (METH) addicts frequently develop hypofrontality and deficits in working memory (WM), attention, and impulsivity. Similarly, in rodents, repeated psychostimulant administration or self- administration elicits hypofrontality, WM deficits, psychosis-like behaviors, decreased interest in external stimuli and surroundings, and decreased social functioning, suggesting that psychostimulant administration in rodents represents a strong, face-valid model for studying the basic brain mechanisms that underlie hypofrontality and cognitive disabilities in METH addiction. The overall objective of the proposed studies is to identify the effects of METH-SA on the activity of cortical parvalbumin positive fast spiking interneurons (PV+FSIs) and the resulting changes in E-I ratio. The central hypothesis- informed by strong preliminary data and literature- is that METH treatment elicits cognitive deficits due to an increase in GABAergic synaptic transmission in the PFC via D1R activation of PV+FSIs. The proposal’s rationale is that the experiments will yield fundamental knowledge pertaining to the understanding of the cellular and synaptic mechanisms underlying hypofrontality induced by METH and will provide new insights into the basic mechanisms governing E-I balance in the prefrontal cortex. We will test the central hypothesis by pursuing the following specific aims: Aim 1 will determine the role of PV+FSIs in METH- induced cognitive deficits. Aim 2 will determine whether D1R signaling in PFC PV+FSIs is required for METH- induced enhancements of GABAergic transmission. Aim 3 will determine whether D1R signaling in PFC PV+FSIs is required for METH SA-induced cognitive deficits and METH reinstatement. The proposed research is significant because it will fill a fundamental gap in knowledge pertaining to the mechanisms underlying hypofrontality in METH-addiction and the effects of the psychostimulant in the activity of cortical PV+FSIs. Furthermore, the knowledge obtained from the proposed experiments will help to develop effective treatments to ameliorate drug-related cognitive deficits and can provide new insights into the basic mechanisms underlying hypofrontality in other neuropsychiatric conditions.

项目概要 神经精神疾病是一个非常严重的医学和社会问题，有许多不同的根源， 然而，新兴理论认为这些疾病中常见且普遍存在的缺陷是额叶功能低下。 额叶功能低下[兴奋性 (E) 和抑制性 (I) 突触传递比例的改变]是其基础 精神分裂症、焦虑症、成瘾症、自闭症谱系障碍和抑郁症。 甲基苯丙胺 (METH) 成瘾者经常出现额叶功能减退和工作记忆缺陷 （WM），注意力和冲动类似，在啮齿类动物中，重复的精神兴奋剂给药或自我调节。 管理引起额叶功能减退、WM 缺陷、精神病样行为、对外部事物的兴趣下降 刺激和周围环境，以及社会功能下降，表明精神兴奋剂给药 在啮齿类动物中代表了一个强大的、表面有效的模型，用于研究背后的基本大脑机制 冰毒成瘾中的额叶功能减退和认知障碍。 拟议研究的总体目标是确定 METH-SA 对皮质活动的影响 小白蛋白阳性快速尖峰中间神经元 (PV+FSIs) 以及由此产生的 E-I 比值变化。 核心假设——基于强有力的初步数据和文献——是冰毒治疗引起 认知缺陷是由于 D1R 激活导致 PFC 中 GABA 突触传递的增加 PV+FSI 该提案的基本原理是实验将产生有关的基础知识。 了解 METH 引起的额叶下垂的细胞和突触机制，并将 为控制前额皮质 E-I 平衡的基本机制提供新的见解。 通过追求以下具体目标来实现中心假设：目标 1 将确定 PV+FSI 在 METH- 中的作用 目标 2 将确定 METH- 是否需要 PFC PV+FSI 中的 D1R 信令 目标 3 将确定 PFC 中的 D1R 信号是否有效 PV+FSIs 是 METH SA 引起的认知缺陷和 METH 恢复所必需的。 拟议的研究意义重大，因为它将填补有关知识的根本空白 冰毒成瘾中额叶功能低下的机制以及精神兴奋剂在活动中的作用 此外，从所提出的实验中获得的知识将有助于开发。 有效的治疗方法可以改善与药物相关的认知缺陷，并可以为基本认知障碍提供新的见解 其他神经精神疾病中额叶功能减退的潜在机制。