Elucidation of the Mechanism Behind the Pro-Cognitive Effects of Intranasal Insulin

阐明鼻内胰岛素促认知作用背后的机制

基本信息

批准号：
10295131
负责人：
Jennifer Erichsen
金额：
$ 3.56万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-10 至 2022-08-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10295131
关键词：
Acetylcholine Acute Age Age-associated memory impairment Aging Alzheimer&apos s Disease Animals Attention Basic Science Behavior Behavioral Behavioral Assay Chronic Clinical Cognition Cognitive Communication Critical Thinking Data Deterioration Development Dose Functional disorder Funding Glare Goals Health High Pressure Liquid Chromatography Hospitals Human Immunoblot Analysis Impaired cognition Individual Insulin Insulin Receptor Insulin Resistance Intranasal Administration Investigation Laboratories Laboratory Research Lead Learning Measures Medial Mediating Memory Memory impairment Microdialysis Molecular Multi-Institutional Clinical Trial Neuraxis Older Population Performance Play Prefrontal Cortex Public Health Publications Rattus Receptor Signaling Recording of previous events Regimen Research Research Project Grants Rodent Saline Science South Carolina System Task Performances Techniques Testing Therapeutic Time Training Universities Writing aged cholinergic cognitive capacity executive function improved insight insulin signaling interest matriculation medical schools neurochemistry neurotransmission prisma programs skills transmission process

项目摘要

Project Summary/Abstract Age-related cognitive decline (ARCD) is one of the most dreaded aspects of growing old and a public health concern. Unfortunately, there is currently no treatment that effectively ameliorates ARCD. In recent decades, intranasal insulin (INI) has demonstrated promising memory enhancements for rodents and individuals with Alzheimer’s disease, both in basic science research laboratories and multi-center clinical trials. Other studies have shown INI improves memory and cognition in healthy rodents and humans, indicating that INI may hold promise as a successful ARCD therapeutic. However, there is a glaring lack of evidence regarding how INI produces these effects. The goal of this proposal is to begin to elucidate this underlying mechanism of action, as INI eventually could be used in a broader clinical setting to treat the cognitive dysfunction seen with aging. Further, fully understanding this mechanism could lead to the development of other successful treatments for ARCD that exploit the same mechanism. The overarching hypothesis of this proposal is that INI improves attentional behaviors, stimulates insulin receptor (IR) signaling, and augments cholinergic neurotransmission in the medial prefrontal cortex (mPFC). Examination of these functional relationships will ultimately lead to the elucidation of the mechanism underlying INI. I will test my central hypothesis and fulfill the goal of this proposal through the investigation of the effect of acute and chronic INI on: 1) performance on the PFC-mediated attentional set-shifting task, 2) IR signaling in the mPFC, and 3) acetylcholine efflux in the mPFC in both young and aged rats. To fulfill these aims, I will be trained on several new laboratory techniques, including behavioral assays, assessment of central insulin signaling, microdialysis, and HPLC under the guidance of Drs. Jim Fadel and Lawrence Reagan at the University of South Carolina School of Medicine. My co-sponsors are long-time collaborators with numerous co-author publications and a history of federal funding. This research project is an intersection of the research interests of the two laboratories. Other aspects of my graduate training, including developing my critical thinking, presentation, networking, and scientific writing skills, will be provided through my matriculation through the Biomedical Sciences doctoral program. Finally, access to the clinical setting will be provided through several avenues, including guidance from consultant Dr. Souvik Sen, regular communication with Mrs. Beckler, and proximity to the VA and Prisma Health Hospital Systems.

项目概要/摘要与年龄相关的认知能力下降（ARCD）是变老和公共卫生中最可怕的方面之一不幸的是，近几十年来，目前还没有有效缓解 ARCD 的治疗方法。鼻内胰岛素（INI）已被证明可以增强啮齿类动物和患有以下疾病的个体的记忆力：阿尔茨海默病，既有基础科学研究实验室，也有多中心临床试验。研究表明 INI 可以改善健康啮齿动物和人类的记忆和认知能力，这表明 INI 可能有效作为一种成功的 ARCD 治疗方法，INI 的作用明显缺乏证据。该提案的目标是开始阐明这种潜在的作用机制，因为 INI 最终可以在更广泛的临床环境中使用，以治疗随衰老而出现的认知功能障碍。此外，充分理解这一机制可能会导致其他成功治疗方法的开发利用相同机制的 ARCD 该提案的总体假设是 INI 改进。注意力行为、刺激胰岛素受体 (IR) 信号传导并增强胆碱能内侧前额皮质 (mPFC) 中的神经传递检查这些功能关系。最终将阐明 INI 背后的机制，我将检验我的中心假设并实现它。该提案的目标是通过调查急性和慢性 INI 对以下方面的影响：1) PFC 介导的注意力转移任务，2) mPFC 中的 IR 信号传导，以及 3) 中枢神经系统中的乙酰胆碱流出为了实现这些目标，我将接受几种新的实验室技术的培训，包括行为测定、中枢胰岛素信号传导评估、微透析和 HPLC 南卡罗来纳大学医学院 Jim Fadel 和 Lawrence Reagan 博士的指导。共同赞助者是长期合作者，拥有众多合著者出版物并拥有联邦资助的历史。这个研究项目是我两个实验室其他方面研究兴趣的交叉点。研究生培训，包括培养我的批判性思维、演讲、网络和科学写作技能，将通过我的生物医学科学博士课程的预科提供最后，访问。临床环境将通过多种途径提供，包括顾问 Souvik Sen 博士的指导，与 Beckler 夫人定期沟通，并靠近 VA 和 Prisma Health 医院系统。