Short-chain fatty acids, microbiota-gut-brain axis & hippocampal neurogenesis: a vehicle to learn techniques of dietary modulation of brain plasticity

许多先前的研究已经确定，认知（即心理过程，如记忆，注意力和反应时间）受到饮食的影响。然而，饮食调节认知的神经机制还没有得到很好的理解。人类海马体是大脑中与学习和记忆有关的区域。海马是成人大脑中新生神经元形成的两个结构之一，称为成人海马神经发生（AHN）。成年人出生的海马神经元是功能性的，并整合到海马电路中。大脑中AHN的水平与学习和记忆直接相关。在整个生命周期中，AHN逐渐减少，伴随着学习和记忆能力受损。此外，AHN的减少见于与年龄相关的神经退行性疾病，如阿尔茨海默病和帕金森病，这两种疾病都伴有认知能力下降。虽然仍有许多有待解释的机制，有证据表明，饮食因素可以促进AHN。饮食可以通过热量摄入、进餐频率、膳食结构和膳食内容影响AHN。因此，饮食调节AHN可能是营养影响认知功能的神经机制。短链脂肪酸（SCFA）是由肠道中的膳食纤维发酵产生的细菌代谢产物，在肠道和大脑之间的通信回路（“微生物-肠道-大脑轴”）中发挥重要作用。然而，SCFAs影响认知的机制尚不清楚。最近的一项研究首次证明SCFA可以促进AHN（Yang et al. 2020）。目前对SCFAs对人AHN的调控机制知之甚少，而且这一领域的研究人员也不多，这使得相关知识和技能基础存在很大的空白。成人神经发生和心理健康实验室（伦敦国王学院;由Sandrine Thuret博士领导）是全球领先的AHN饮食调节研究小组，并使用了一种新的AHN体外模型。该奖项的目的是支持早期职业研究人员（ECR）完成体外细胞技术的集中和沉浸式培训，以调查饮食对AHN和认知的影响，并调查生理相关SCFA对AHN的影响。ECR目前是一名博士后研究员，她一直在研究饮食对儿童和青少年认知功能的影响，使用以学校为基础的饮食干预研究，她的工作跨越了学术界和食品工业。ECR将完成一个共同制定的、量身定制的10阶段培训计划，包括：1）基础细胞培养培训; 2）细胞实验设计培训; 3）海马祖细胞（HPC）培养培训; 4）细胞库制作培训; 5）HPC增殖培训; 6）HPC分化培训; 7）免疫细胞化学培训; 8）显微镜培训; 9）高内容成像训练和10）数据分析训练。该奖项将培养跨学科技能，并深入了解饮食可能影响认知的潜在神经机制。这将有助于完成该奖项以外的多学科研究，研究饮食对认知的影响，从而深入了解人类营养及其在人口认知健康中的作用。这项培训计划将加强教统局在实验室营养技术方面的知识和技能，以配合他们在人类饮食干预研究方面的实地培训。这一研究领域是新的，值得进一步关注，因为更好地了解营养影响认知健康的神经机制可能会导致新的饮食方法来对抗与年龄相关的认知衰退，神经退行性疾病，并促进健康的老龄化。

Numerous previous studies have firmly established that cognition (i.e. mental processes such as memory, attention, and reaction time) is influenced by diet. However, the neural mechanisms by which diet modulates cognition are not well understood. The human hippocampus is an area of the brain associated with learning and memory. The hippocampus is one of the two structures in the adult brain where the formation of newborn neurons, known as adult hippocampal neurogenesis (AHN) persists. Adult-born hippocampal neurons are functional and integrated into the hippocampal circuitry. The level of AHN in the brain has been linked directly to learning and memory. Across the lifespan, a progressive reduction of AHN and concomitant impaired learning and memory abilities occurs. Furthermore, a reduction in AHN is seen in age-related neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, both of which are accompanied by cognitive decline. Whilst much remains to be explained mechanistically, there is evidence that dietary factors can promote AHN. Diet can influence AHN through calorie intake, meal frequency, meal texture, and meal content. Therefore, modulation of AHN by diet is a possible neural mechanism by which nutrition impacts on cognitive function. Short-chain fatty acids (SCFAs) are bacterial metabolites produced by fermentation of dietary fibre in the gut that play an important role in the communication loop between the gut and the brain ('the microbiota-gut-brain axis'). However, the mechanisms through which SCFAs influence cognition are unclear. A recent study demonstrated for the first time that SCFAs can promote AHN (Yang et al. 2020). We know little about the modulatory mechanisms of human AHN via SCFAs and there are few skilled researchers in this field, which leaves a large gap in the knowledge and skill base. The Adult Neurogenesis and Mental Health laboratory (Kings College London; led by Dr Sandrine Thuret) are the leading research group globally on dietary modulation of AHN and use a novel in vitro model of AHN. The aim of this award is to support the completion of focussed and immersive training of an early career researcher (ECR) on the in vitro cellular techniques required to investigate the impact of diet on AHN and cognition and to investigate the impact of physiologically relevant SCFAs on AHN. The ECR is currently a postdoctoral researcher who has been working on the effects of diet on cognitive function in children and adolescents using school-based dietary intervention studies and her work has spanned both academia and the food industry. A co-produced, tailored, 10-stage training plan will be completed by the ECR including: 1) Basic cell culture training; 2) Cellular experimental design training; 3) Hippocampal progenitor cells (HPC) culture training; 4) training in making a cell bank; 5) HPC Proliferation training ; 6) HPC Differentiation training; 7) Immunocytochemistry training 8) Microscopy training; 9) High content imaging training and 10) Data analyses training. This award will develop cross-disciplinary skills and a deep understanding of the underlying neural mechanisms by which diet could influence cognition. This will enable to completion of multi-disciplinary research beyond this award on the effects of diet on cognition, which could lead to insights into human nutrition and its role in the cognitive health of the population. The training award will strengthen the ECR's knowledge and skills in lab-based nutrition techniques to complement their field-based training in human dietary intervention studies. This area of investigation is new and warrants further attention because a better understanding of the neurological mechanisms by which nutrition affects cognitive health may lead to novel dietary approaches to combat age-associated cognitive decline, neurodegenerative diseases, and promote healthy ageing.