Neurobiological mechanisms of Western diet-induced cognitive dysfunction

西方饮食诱发认知功能障碍的神经生物学机制

基本信息

批准号：
10730548
负责人：
Anna Marie Rose Hayes
金额：
$ 6.95万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-25 至 2025-08-24
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730548
关键词：
Acetylcholine Adolescence Adolescent Adult Behavioral Binding Brain region Carbohydrates Child Childhood Cognition Consumption Data Development Diet Dietary Factors Dietary Intervention Eating Energy Intake Episodic memory Fatty acid glycerol esters Fiber Food Functional disorder Genomics Hippocampus Human Impaired cognition Impairment Learning Life Link Mediating Memory Memory impairment Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Modernization Neurocognitive Neurocognitive Deficit Neuropharmacology Neurotransmitters Obesity Outcome Performance Pharmacotherapy Phase Photometry Population Prevalence Process Public Health Rattus Reporting Research Rodent Model Role Signal Pathway Signal Transduction Structure Study models System Testing Toddler Western Blotting access restrictions bacterial genome sequencing behavior test cholinergic critical developmental period design dietary experimental study fecal transplantation food environment gut microbiome human model in vivo long term memory memory process microbial microbiome microbiota transplantation neurobiological mechanism novel pharmacologic postnatal saturated fat sensor sugar western diet

项目摘要

Project Summary/Abstract The rise in obesity and metabolic diseases worldwide has dire consequences on public health. Concomitant with this rise are changes in diet. Notably, consumption of highly palatable foods that are high in saturated fat and refined carbohydrates – collectively referred to as the Western diet (WD) – has increased globally 1,2. Because children are in key stages of development and reportedly obtain ~65% of their total energy intake from such high-fat, high-sugar foods 3, they are especially vulnerable to the impacts of the WD 4,5. Furthermore, emerging evidence reveals that WD consumption impairs neurocognitive processes, particularly when consumed during early life developmental periods 6,7. These negative outcomes can occur independent of obesity and metabolic dysfunction, and early life WD consumption preferentially disrupts memory processes that rely on the hippocampus 8,9, a brain region classically associated with learning and memory function and more recently with food intake control 10. However, the critical timing and duration of such dietary exposure during childhood and adolescence are poorly understood. Further, the neurobiological mechanisms that give rise to early life WD-associated hippocampal dysfunction remain elusive. One hypothesis is that the microbiome may be functionally involved, as microbial taxa were previously shown to be causally related to memory impairments associated with early life consumption of added sugars 11. An additional hypothesis is that WD-induced hippocampal dysfunction may be caused, in part, by impairments in the acetylcholine system, given that obesity-promoting foods have previously been shown to alter these systems 7,12,13 and that acetylcholine has been implicated in novelty and contextual-based memory processes that are particularly vulnerable to WD-associated impairments 14. Accordingly, this proposal builds off our preliminary results to unravel the mechanisms by which early life WD consumption impairs hippocampal function. Results from Aim 1 will determine whether memory impairments associated with early life WD consumption can be pinpointed to specific developmental epochs within the larger juvenile-adolescent period (early, mid, late, or the entire juvenile-adolescent period). Aim 2 experiments will utilize bacterial genome sequencing analyses and microbiome transplant approaches to determine whether the microbiome is functionally related to hippocampal deficits from early life WD consumption. Finally, based off preliminary data, Aim 3 experiments will utilize two complementary in vivo approaches (behavioral neuropharmacology and in vivo fiber photometry) to reveal whether altered acetylcholine signaling is functionally implicated in early life WD- induced hippocampal dysfunction. Collectively, the proposed experiments will make strides in identifying the critical developmental periods and mechanisms by which early life WD consumption imparts long-lasting hippocampal dysfunction.

项目摘要/摘要全球肥胖和代谢疾病的增长对公共卫生产生了可怕的影响。饮食的变化随着这种兴起的伴随。值得注意的是，食用高度可口的食物饱和脂肪和精制的碳水（统称为西部饮食（WD））增加了全球1,2。因为儿童处于发展的关键阶段，据报道获得约65％的总能量从这种高脂，高糖食品3的摄入量3，它们尤其容易受到WD 4,5的影响。此外，新兴的证据表明，WD消耗会损害神经认知过程，特别是早期发育期在6,7的早期发育期间食用时。这些负面结果可以独立于肥胖和代谢功能障碍，以及早期的生命WD消费优先破坏记忆过程依赖于海马8,9，这是一个与学习和记忆功能相关的大脑区域，最近使用食物摄入控制10。但是，这种饮食暴露的关键时机和持续时间在儿童期和青少年期间，人们对此很了解。此外，具有赋予的神经生物学机制与WD相关的海马功能障碍的早期生命崛起仍然难以捉摸。一个假设是微生物组可能涉及功能，因为先前显示微生物分类群与与添加糖的早期寿命相关的记忆障碍11.另一个假设是 WD诱导的海马功能障碍可能部分由乙酰胆碱系统损伤引起鉴于以前已显示出促进肥胖食品可以改变这些系统7,12,13，并且乙酰胆碱已在新颖性和基于上下文的记忆过程中隐含容易受到WD相关的损害14。根据该提议，我们的初步结果建立了揭示早期寿命消耗损害海马功能的机制。 AIM的结果 1将确定是否可以确定与早期生命WD消耗相关的记忆障碍在较大的少年 - 青春期（早期，中期，晚期或整个）中的特定发育时期青少年 - 青年时期）。 AIM 2实验将利用细菌基因组测序分析和微生物组移植方法，以确定微生物组是否在功能上与海马从早期的WD消耗中定义。最后，基于初步数据，目标3实验将在体内使用两种完整性（行为神经药理和体内纤维光度法）揭示乙酰胆碱信号改变是否在功能上与早期生命有关诱导海马功能障碍。总的来说，拟议的实验将在识别重要的发育时期和机制早期消耗wd消费量长期持久海马功能障碍。