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.

项目概要/摘要全球肥胖和代谢疾病的增加对公共健康产生了可怕的后果。与这种增长相伴随的是饮食的变化，值得注意的是，食用高含量的美味食品。饱和脂肪和精制碳水化合物——统称为西方饮食（WD）——有所增加全球范围内 1,2 因为儿童正处于发育的关键阶段，据报道他们获得了约 65% 的能量。摄入此类高脂肪、高糖食物3后，他们特别容易受到WD 4,5的影响。此外，新出现的证据表明，食用 WD 会损害神经认知过程，特别是当在生命早期发育阶段食用时，这些负面结果可能独立于以下因素而发生：肥胖和代谢功能障碍，以及生命早期的 WD 消耗优先扰乱记忆过程依赖于海马体 8,9，这是一个传统上与学习和记忆功能相关的大脑区域，最近进行了食物摄入控制 10。然而，这种饮食暴露的关键时机和持续时间此外，人们对儿童期和青春期的神经生物学机制知之甚少。与早期生活相关的海马功能障碍的发生仍然难以捉摸。微生物组可能在功能上涉及，因为微生物类群先前已被证明与以下因素存在因果关系：与生命早期摄入添加糖相关的记忆障碍 11. 另一个假设是 WD 引起的海马功能障碍可能部分是由乙酰胆碱系统损伤引起的，鉴于先前已证明促进肥胖的食物会改变这些系统 7,12,13 并且乙酰胆碱与新颖性和基于情境的记忆过程有关，这些过程尤其重要容易受到 WD 相关损伤的影响 14. 因此，该提案以我们的初步结果为基础 Aim 结果揭示了生命早期摄入 WD 损害海马功能的机制。 1 将确定是否可以查明与早年 WD 消耗相关的记忆障碍到较大的青少年时期（早期、中期、晚期或整个时期）内的特定发展时期目标 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最后，根据初步数据，Aim 3 实验。将利用两种互补的体内方法（行为神经药理学和体内纤维光度测定）揭示乙酰胆碱信号传导是否与早期生命有功能相关 WD- 总的来说，所提出的实验将在识别海马功能障碍方面取得进展。关键发育时期和生命早期 WD 摄入赋予持久作用的机制海马功能障碍。