Neurobiological mechanisms of Western diet-induced cognitive dysfunction

项目概要/摘要 世界范围内肥胖症和代谢性疾病的增加对公众健康造成了可怕的后果。 与这种增长相伴随的是饮食的变化。值得注意的是，食用美味的食物， 饱和脂肪和精制碳水化合物-统称为西方饮食（WD）-增加了 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%。 由于这些高脂肪、高糖食物的摄入量3，它们特别容易受到WD的影响4，5。 此外，新出现的证据表明，WD消费损害神经认知过程，特别是 在生命早期发育阶段食用时6，7.这些负面结果可能独立于 肥胖和代谢功能障碍，以及早期生活WD消费优先破坏记忆过程 它依赖于海马体8、9，这是一个典型的与学习和记忆功能相关的大脑区域， 最近的食物摄入控制10.然而，这种饮食接触的关键时间和持续时间 儿童和青少年时期的知识很少。此外，神经生物学机制， 早期生活中与WD相关的海马功能障碍的发生仍然是难以捉摸的。一种假设是， 微生物组可能在功能上参与，因为微生物分类群先前被证明与 与早年食用添加糖有关的记忆障碍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的损伤引起， 鉴于促肥胖食物先前已被证明会改变这些系统7，12，13， 乙酰胆碱与新奇和基于背景的记忆过程有关， 易受与WD相关的损害14.因此，本建议以我们的初步结果为基础， 揭示早期生活WD消耗损害海马功能的机制。Aim的结果 1将确定是否可以查明与早期生活WD消耗相关的记忆损伤 在更大的青少年时期内的特定发育时期（早期，中期，晚期或整个 青少年时期）。目标2实验将利用细菌基因组测序分析， 微生物组移植方法，以确定微生物组是否在功能上与 海马缺陷的早期生活WD消费。最后，根据初步数据，目标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 光度法），以揭示改变的乙酰胆碱信号传导是否在功能上与早期生命WD有关。 诱发海马功能障碍。总的来说，拟议的实验将在确定 关键的发展时期和机制，其中早期生活WD消费赋予持久的 海马功能障碍

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.