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

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.

The human hippocampus retains its ability to generate neurons throughout life. This is known as adult hippocampal neurogenesis (AHN) and is important in normal hippocampal-dependent learning and memory. Furthermore, AHN contributes to neural reserve, which facilitates compensation in situations of neuron depletion such as ageing. Nutrition can significantly modulate AHN. Short-chain fatty acids (SCFAs) are predominantly produced during the fermentation of dietary fibres by the gut microbiota. SCFAs play an important role in the microbiota-gut-brain axis, regulating central nervous system processes. In 2020, Yang et al. demonstrated for the first time that SCFAs promote proliferation and mitosis of human early neural progenitor cells. However, due to the inherent difficulties in studying AHN in humans, much of what we know about dietary modulation of AHN, including how SCFAs impact AHN, is from animal studies. Thus, we know little about the mechanisms of human AHN via SCFAs or other dietary constituents and there are few highly skilled experts in this field. The aim of this award is to support immersive training of an early career researcher (ECR) on in vitro cellular techniques required to investigate the impact of diet on AHN and cognition using hippocampal progenitor cells (HPC). This will involve pilot work to investigate the impact of SCFAs on HPCs and neurogenesis. This Award will upskill the ECR in cell culture of human HPCs using biologically relevant concentrations of SCFAs, immunocytochemistry and high-throughput analysis to quantify markers determining cell fate after HPCs are either maintained in a proliferative state or allowed to differentiate in the presence of SCFAs. The co-produced, tailored, 10-stage training plan completed by the ECR will develop her advanced cross-disciplinary skills and imbue her with a deep understanding of the underlying neural mechanisms by which diet can influence cognition.

In the short-term, the Travelling Skills Award will have a significant positive impact on the Early Career Researcher (ECR). Firstly, it will have a positive impact by upskilling the ECR in new lab-based in vitro techniques of dietary modulation of brain plasticity via the Microbiota-Gut-Brain Axis. Currently, the ECR has experience in field-based human dietary intervention studies examining cognitive outcomes in children and adolescents. She has collected data on large samples of schoolchildren on using anthropometric, dietary, socio-demographic, and cognitive function measures. The Travelling Skills award will enable the ECR to become scientifically bi-lingual. She will gain unique knowledge allowing her to be proficient in both lab and field based techniques in the field of diet and cognition. Furthermore, the new knowledge of the cellular and molecular mechanisms underlying dietary modulation of brain plasticity combined with her existing knowledge of the effects of diet on cognition will give the ECR a unique blend of skills which will fill a gap in global expertise and allow the ECR to develop a specific research niche in this field. These new multidisciplinary skills and knowledge obtained during the Travelling Skills Award will have both an immediate and long-term impact by accelerating the career trajectory of the ECR. It will enable her to develop multidisciplinary collaborative research funding applications between her home and host institutions to better understand the mechanisms by which nutrition can affect cognition across the lifespan. The opportunities that the travelling award provides; to connect with ECRs, senior researchers, and Directors beyond the ECR's host institution and join part of a larger, supportive community from a different field will have significant impact. For example, the collaborative, cross-sectoral nature of the award will facilitate the formation of new collaborations and research ideas for future collaborative projects that could form the basis of future proposals for follow-on funding (e.g. New Investigator Award or Future Leaders Fellowship).

In the longer-term, it will have impact by accelerating progress in nutrition-related research by fully supporting multidisciplinary research in the field of nutrition and cognitive function. We know that cognition is influenced by diet as evidenced by numerous previous studies. However, the neural mechanisms by which diet modulates cognition are not well understood. Future research will lead to a better understanding of the neurological mechanisms by which nutrition affects cognitive health and may lead to novel dietary approaches for age-associated cognitive decline, healthier ageing, and neurodegenerative diseases. Ultimately, we hope that the accelerated scientific progress that the award will facilitate could lead to feasible evidence based dietary recommendations which are tailored to specific groups across the lifespan.