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: 10618014
• 负责人: ANTONIETA LAVIN
• 金额: $ 11.7万
• 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/10618014
• 关键词: Acute; Attention; Bathing; Behavior; Biological Markers; Career Choice; Chronic; Cognitive; Cognitive deficits; Complement; Cues; Data; Disease; Dopamine D1 Receptor; Dopamine Receptor; Drug Addiction; Electrophysiology (science); Ensure; Equilibrium; Executive Dysfunction; Female; Fiber; Functional disorder; Genetic; Glutamates; Goals; Impaired cognition; Impulsivity; Interneurons; Knowledge; Laboratories; Latina; Literature; Maintenance; Mediating; Medical; Memory; Memory impairment; Mentorship; Methamphetamine; Methamphetamine dependence; N-Methylaspartate; Neurodevelopmental Disorder; Parents; Parvalbumins; Pathologic; Pathology; Performance; Pharmaceutical Preparations; Pharmacology; Photometry; Play; Positioning Attribute; Prefrontal Cortex; Preparation; Rattus; Reagent; Receptor Activation; Receptor Signaling; Research; Role; Scientist; Self Administration; Sex Differences; Short-Term Memory; Slice; South Carolina; Substance Use Disorder; Symptoms; Synapses; Synaptic Transmission; Technical Expertise; Techniques; Testing; Training; Training Programs; Training Support; Transgenic Organisms; Universities; Viral; Whole-Cell Recordings; Woman; addiction; antagonist; behavior test; cell type; cognitive disability; cognitive function; cognitive task; effective therapy; executive function; experimental study; frontal lobe; hippocampal pyramidal neuron; in vivo; insight; knock-down; male; methamphetamine abuse; methamphetamine effect; monserrat; neuropsychiatric disorder; neuropsychiatry; novel; novel therapeutic intervention; psychostimulant; receptor function; sensor; sex; skills; tenure track; tool; transmission process

SUMMARY This Diversity Supplement support is for Dr. Monserrat Armenta-Resendiz in the laboratory of Dr Antonieta Lavin at the Medical University of South Carolina with additional mentorship by Dr. Carmela Reichel and Tom Jhou. Dr. Armenta-Resendiz is a Latina woman whose goal is to become an independent scientist in a field that will intersect drug addiction, cognitive deficits and sex differences. Dr Armenta-Resendiz needs to acquire additional technical skills, enhance her professional skills, and develop an academic profile to ensure she is in a competitive position to apply for R type founding and tenure track academic positions. The objective of the parent R01 (DA 054589-01) is 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. To support the training of Dr Armenta-Resendiz, we have developed an additional aim that extends and complements the parent RO1. 1. She will implement fiber photometry assessments of DA and Glutamate sensors in the PFC of METH and SAL male and female rats during the performance of a cognitive task (Temporal Order Memory) in vivo. This training program will provide Dr Armenta-Resendiz with additional skills in fiber photometry, sex defenses and behavior. She will also receive additional mentorship from a diverse team and trainings to ensure she is fully equipped for her chosen career path.

总结 该多样性补充支持是为Antonieta Lavin博士实验室的Monserrat Armenta-Resendiz博士提供的 在南卡罗来纳州医科大学，由Carmela Reichel博士和Tom Jhou博士提供额外的指导。 博士Armenta-Resendiz是一名拉丁裔女性，她的目标是成为一名独立的科学家， 药物成瘾、认知缺陷和性别差异。Armenta-Resendiz博士需要 额外的技术技能，提高她的专业技能，并发展学术形象，以确保她是在一个 竞争力的立场，申请R型创始和终身制轨道学术职位。 母体R 01（DA 054589-01）的目的是确定METH-SA对 皮质小白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。的 中心假设-由强有力的初步数据和文献所告知-是METH治疗增强认知能力， 通过PV+ FSI的D1 R激活，PFC中GABA能突触传递增加导致的缺陷。的 该提案的基本原理是，实验将产生与理解相关的基础知识 的细胞和突触机制的基础hypofrontality引起的甲基，并将提供新的见解 前额叶皮层中控制E-I平衡的基本机制。我们将通过以下方式检验中心假设： 追求以下具体目标：目标1将确定PV+ FSI在METH诱导的认知中的作用 赤字目的2将确定PFC PV+ FSI中的D1 R信号传导是否是METH诱导的FSI所必需的。 增强GABA能传递。目标3将确定PFC PV+ FSI中的D1 R信号传导是否 METH SA诱导的认知缺陷和METH恢复所需。所提出的研究是有意义的 因为它将填补有关额叶功能减退机制的知识空白， METH成瘾和精神兴奋剂对皮质PV+ FSI活动的影响。而且 从拟议的实验中获得的知识将有助于开发有效的治疗方法，以改善药物， 相关的认知缺陷，并可以提供新的见解的基本机制， 其他神经精神疾病。 为了支持Armenta-Resendiz博士的培训，我们制定了一个额外的目标， 与父RO 1互补。1.她将实施DA和谷氨酸的纤维光度法评估 METH和SAL雄性和雌性大鼠在执行认知任务（时间）期间PFC中的传感器 Order Memory）in vivo.该培训计划将为Armenta-Resendiz博士提供纤维方面的额外技能 测光，性防御和行为。她还将获得来自多元化团队的额外指导， 培训，以确保她为自己选择的职业道路做好充分准备。