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.

项目摘要/摘要与年龄相关的认知下降（ARCD）是增长旧和公共卫生的最令人恐惧的方面之一忧虑。不幸的是，目前尚无有效缓解ARCD的治疗方法。近几十年来鼻内胰岛素（INI）证明了对啮齿动物和患者的承诺记忆增强基础科学研究实验室和多中心临床试验，阿尔茨海默氏病。其他研究已经显示INI改善了健康啮齿动物和人类的记忆和认知，表明INI可能会持有承诺作为一种成功的ARCD疗法。但是，缺乏关于INI的证据产生这些影响。该提案的目的是开始阐明这种基本的行动机制，因为INI最终可以在更广泛的临床环境中使用，以治疗衰老的认知功能障碍。此外，完全了解这种机制可能会导致其他成功治疗的发展利用相同机制的ARCD。该提议的总体假设是INI改善了注意行为，刺激胰岛素受体（IR）信号传导并增强胆碱能介质前额叶皮层（MPFC）中的神经传递。检查这些功能关系最终将导致INI基础机制的阐明。我将检验我的中心假设并实现通过投资急性和慢性INI对：1）表现的目标 PFC介导的注意设置转移任务，2）MPFC中的IR信号和3）乙酰胆碱外排在 MPFC的年轻大鼠和年龄大鼠。为了实现这些目标，我将接受几种新的实验室技术的培训，包括行为评估，中央胰岛素信号传导，微透析和HPLC的评估 Drs的指导。南卡罗来纳大学医学院的吉姆·法德尔（Jim Fadel）和劳伦斯·里根（Lawrence Reagan）。我的共同发起人是长期合作者，拥有众多合着者出版物和联邦资助的历史。该研究项目是两个实验室的研究利益的交集。我的其他方面研究生培训，包括发展我的批判性思维，演示，网络和科学写作技巧，将通过我的矩阵通过生物医学博士学位课程提供。最后，访问临床环境将通过几种途径提供，包括顾问Souvik Sen博士的指导，定期与贝克勒夫人进行沟通，并靠近VA和Prisma Health医院系统。