Central Metabolic Learning And Memory Formation And Systemic Metabolic Homeostasis

Metabolic syndrome is a group of complicated metabolic disorders, which mainly consists of waist circumference increase, glucose and lipid disorders, and high blood pressure. With the development of society, the incidence of metabolic syndrome increases every year, which has become a challenge to global public health and clinical areas. Chronic inflammation is an important pathological basis of the metabolic syndrome, in which the inflammatory pathway NF-κB activation plays a key role. In addition, long-term metabolic disorders influence the body’s metabolic microenvironment leading to a kind of metabolic memory. And even if metabolic disorders are corrected, this metabolic memory still exists and continues to impact local tissues and organs, activate inflammatory pathways, and produce microcirculation stress. However, whether this metabolic memory exists at a central level, how it regulates the systemic metabolism and which brain region is responsible for its regulation, are still unknown. Drosophila is awidely used insect model, which has well-established methods in analyzing learning and memory, and intensive understanding on learning and memory related genes and brain regions. Based on this, we focused on four themes in this paper, which included metabolic learning and memory in drosophila and the relevantphysiological changes, regulation of genes and brain regions associated with metabolic learning and memory, central inflammation metabolic pathway’seffects on drosophila learning and memory, relationships between metabolic learning and memory and obesity susceptibility in different strains in mice.The first part is to verify the presence of metabolic learning and memory. We used the classic Pavlovianolfactory conditioned training to detect the metabolic learning and memory in Drosophila. The "tasteless" sorbitol was used as carbohydrate food source, thereby creating almost the same taste as two foods: normal calorie food and high-calorie food. Through continuous testing and verification, we found that indeed there was a post-digestive memory, which helped fliesto distinguishdifferent calorie foods, and guided the formation of preference to normal calorie food. This kind of memory was not affected by the training odor, food training orders and so on. And thismemory coulddecrease over time because of the high-calorie food intake accumulation. We also examined the effect of long-term high-calorie foods to flies, and found that compared to normal-calorie food, high-calorie food would lead to shortened lifespan and fertility, glucose and lipid disorders, insulin-like peptide genes increase, and learning and memory genes decrease. Therefore, we suggested that the metabolic memory was a "positive" memory, protecting against damages from high-calorie foods. However, this memory was vulnerable to the interference of high-calorie food. When high-calorie food accumulated to a certain extent, it would drop quickly.The second part was focused on learning and memory regulatory factors. In Drosophila, the level of learning and memory is largely determined by c AMP/PKA pathway, such as rut, dnc, tequila. Using rut, dnc, tequila mutant flies, we found that these flies had significantly decreasedmetabolic memory levels, accompanied with glucose and lipid metabolic disorders. Then we usedthe UAS-GAL4 system, rescuing the rut gene expression in pan-neuron system with background of rut mutant flies and found that the metabolic memory was restored. Therefore, rut, dnc, tequilagenes play an important regulatory role in metabolic memory. In addition, we found that mushroom body(similar to the mammalian hippocampus) and pars intercerebralis(similar mammalian hypothalamus) is important for the formation of metabolic memory, disruption of c AMP/PKA pathway genes in these two regions would cause a metabolic memory decrease.The third part focused on the relationship between inflammation pathways and the metabolic learning and memory. Firstly, we examined the changes of the inflammation-related gene expression levels in flies consuming high-calorie food, and found that compared toflies fed with normal calorie food, the inflammatory pathways were activated in the brains of flies feeding with high-calorie food. Secondly, we focused on the NF-k B pathway-related genes. Using the techniques of UAS-GAL4 system, we generated flies with brain-specific or pars intercerebralis-specific activation of NF-k B pathway flies, and placed them in metabolic learning and memory test system. The results showedthese flies’ metabolic learning and memory were significantly impaired, accompanying with lipid and glucose disorders. However, pars intercerebralis-specific inhibiting NF-k B pathway flies showed a protection from the impaired learning and memory from high-calorie foods, and restored lipid and glucose disorders caused by the long-term accumulation of high-calorie food.The fourth part was based on the findings of fruit flies, and extended them into exploring the relationships between obesity susceptibilities and metabolic learning and memory in mice. Based on the conditionalplace preference model, we tested the preferences of mice with different obesity susceptibilities to normal calorie food and high calorie(high-fat) food, and found the obesity resistant strain(A/J) mice and the obesity susceptible strain(C57BL/6J) mice had different preferences in the two kinds of food: A/J mice preferred to normal-calorie foods when compared with C57BL/6J mice. We also measured food intake, body weight gain, body composition and glucose and lipid metabolism in these two strains of mice during training, and found that A/J mice had more normal food intake when compared with C57BL/6J mice, subsequently accompanying with lower body weight gain, less increased body fat content, and milder glucose and lipid disorder changes. At the same time, we also did a preliminary screening, and found that the two strains of mice have different learning and memory gene profiles and the hypothalamus may be involved in early formation of metabolic learning and memory.In summary, by adopting drosophila model, we initially proposed the concept of metabolic learning and memory, and proved the existence of metabolic learning and memory model. At the same time, the study revealed the molecular and the anatomical mechanism of metabolic learning memory, and proposed an important role of NF-k B inflammatory pathways during this process, which potentially have clinical significance. Finally, we tested mice to see whether metabolic learning and memory could be involved in the different obesity susceptibility of mice, and suggested that the hypothalamus might play an important role during this process, which established a good foundation for the clinical application of metabolic learning and memory research.