Neurobiological mechanisms of Western diet-induced cognitive dysfunction

项目摘要/摘要 全球肥胖和代谢性疾病的增加对公共健康造成了可怕的后果。 随之而来的是饮食的变化。值得注意的是，食用高含量的可口食物 饱和脂肪和精制碳水化合物--统称为西方饮食(WD)--已经增加 全球1，2.因为儿童正处于发育的关键阶段，据报道，他们获得了总能量的65% 从这种高脂肪、高糖的食物中摄取3，他们特别容易受到WD 4，5的影响。 此外，新出现的证据显示，服用WD会损害神经认知过程，尤其是 在生命早期发育阶段摄入6，7。这些负面结果可能独立于 肥胖和代谢功能障碍，早期摄入WD优先扰乱记忆过程 它依赖于海马体8，9，一个经典的与学习和记忆功能有关的大脑区域 最近开始控制食物摄入量10。然而，这种饮食暴露的关键时间和持续时间 在童年和青春期，人们对此知之甚少。此外，神经生物学机制使 WD相关的海马区功能障碍仍难以捉摸。一种假设是， 微生物组可能在功能上参与其中，因为微生物分类群以前被证明与 与早年摄入添加糖有关的记忆障碍11.另一种假设是 WD诱导的海马区功能障碍可能部分是由乙酰胆碱系统的损伤引起的， 鉴于之前已经证明促进肥胖的食物会改变这些系统，7，12，13 乙酰胆碱与新奇和基于背景的记忆过程有关，尤其是 易受与WD相关的损害14.因此，这项建议建立在我们的初步结果基础上，以 揭示早期WD摄入损害海马体功能的机制。来自AIM的结果 1将确定与早期WD消费相关的记忆损害是否可以被精确定位 到较大的青少年时期(早期、中期、晚期或整个)内的特定发育时期 青少年时期)。Aim 2实验将利用细菌基因组测序分析和 确定微生物组是否与功能相关的微生物组移植方法 因早期服用WD而导致的海马区缺陷。最后，在初步数据的基础上，进行了三个实验 将利用两种互补的体内方法(行为神经药理学和体内纤维 以揭示乙酰胆碱信号的改变是否在功能上与早期WD有关- 诱导的海马区功能障碍。总的来说，拟议的实验将在识别 早期生活WD消费带来持久的关键发育时期和机制 海马区功能障碍。

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.