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: 10303903
• 负责人: ANTONIETA LAVIN
• 金额: $ 34.03万
• 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/10303903
• 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; 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.

项目摘要 神经精神障碍是一个非常严重的医学和社会问题，有许多不同的起源， 然而，在这些疾病中发现的常见和普遍的缺陷是前额叶功能减退。新兴理论 前额叶功能减退（兴奋性（E）和抑制性（I）突触传递比例的改变）是 精神分裂症、焦虑症、成瘾、自闭症谱系障碍和抑郁症。 甲基苯丙胺（METH）成瘾者经常出现前额叶功能减退和工作记忆缺陷 (WM)注意力和冲动。同样，在啮齿类动物中，重复精神兴奋剂给药或自我- 管理elevated hypofrontality，WM缺陷，精神病样行为，减少对外部的兴趣 刺激和环境，以及社会功能下降，这表明精神兴奋剂的管理， 在啮齿类动物中，这是一个强大的，面部有效的模型，用于研究基本的大脑机制， METH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对皮质神经元活动的影响。 小清蛋白阳性快速尖峰中间神经元（PV+ FSI）和由此产生的E-I比率的变化。 中心假设-由强有力的初步数据和文献所告知-是METH治疗有助于 认知缺陷，由于增加GABA能突触传递PFC通过D1 R激活 PV+ FSI。该提案的基本原理是，实验将产生与 理解METH和意志诱导的额叶功能减退的细胞和突触机制 提供了新的见解的基本机制，管理E-I平衡在前额叶皮层。我们将测试 目标1将确定PV+ FSI在方法中的作用， 导致认知缺陷。目标2将确定PFC PV+ FSI中的D1 R信号传导是否需要METH- 诱导GABA能传递的增强。目标3将确定PFC中的D1 R信号传导是否 METH SA诱导的认知缺陷和METH恢复需要PV+ FSI。 拟议的研究是重要的，因为它将填补有关知识的基本空白， 甲基苯丙胺成瘾性前额叶功能减退的机制及精神兴奋剂的作用 皮质PV+ FSI。此外，从拟议的实验中获得的知识将有助于开发 有效的治疗，以改善药物相关的认知缺陷，并可以提供新的见解的基本 在其他神经精神疾病中的潜在机制。