Mechanistic Study On Reconsolidation Of A Post-ingestive Nutrient Memory

The global epidemic of obesity is largely due to the increasing ease of food access,where high-energy and tasty foods promote non-starvation eating behaviors and guide subsequent dietary choice through its reinforcing effects.Binge eating disorder allows the body to consume surplus energy than is required for metabolism homeostasis,ultimately leading to fat accumulation and obesity.Based on the prevalence of obesity caused by maladaptive feeding behaviors,we focused our study on the central regulation of feeding behaviors.The regulation of feeding behavior by brain regions and circuits such as the limbic reward system and the feeding center hypothalamus is influenced by both the metabolic demands(maintenance of body weight and functional homeostasis of energy metabolism)and the hedonistic value of food(sensory pleasure during feeding),and the palatability and energy of food can produce rewarding effects through different neural circuits to promote feeding.Previous studies have found that animals can produce food preferences and form memories through associative learning of particular flavors and post-ingestive nutrient valence,but the dynamic control mechanisms(e.g.,memory retrieval,reconsolidation)of such post-ingestive nutrient memory after formation are still unclear,and whether new strategies for effective feeding behavior interventions can be developed to address the dynamic control mechanisms of such novel types memories are worth further investigation.Based on the conditioned flavor preference(CFP)paradigm driven by the post-ingestive nutrient valence,this study investigated the mechanisms of reconsolidation of post-ingestive nutrient memory by using pharmacological,behavioral,molecular biological,and immunohistochemical approaches.1)We took advantage of a novel paradigm of conditioned flavor preference in which a feeding catheter extending to the back of the neck was implanted in the stomach of mice and trained with oral administration of different flavored drinks that do not contain substances metabolizable to energy as a conditioned stimulus(CS)and feeding catheter injection of either glucose or water as an unconditioned stimulus(US),allowing mice to generate post-ingestive nutrient memory through associative learning.2)Retrieval of post-ingestive nutrient memory activated the central amygdala(CeA),Nucleus Accumbens(NAc),and lateral septum.As a control,mice subjected to the CS only,neuronal activation of CeA failed to be induced,but activation of NAc and LS persisted.Moreover,neuronal activation was induced in the NAc but not in the lateral septum and CeA on animals subjected to the US only training.3)Inhibition of mTORC1 in the CeA or systemically during reconsolidation erased the post-ingestive nutrient memory in mice and prevented reinstatement after the application of the US reminder.4)Memory reactivation increased the amounts of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR)subunits G1uA1 and GluA2,in addition to that of N-methyl-D-aspartic acid receptor(NMDAR)subunits GluN1,GluN2A,and G1uN2B,and the increase in the amount of these synaptic proteins induced by memory reactivation was abolished by rapamycin.5)The effect of rapamycin on the reconsolidation of feeding-associated post-ingestive nutrient memory was retrieval-dependent and temporally specific.Preventing mTORC1 activity by rapamycin in the CeA had no effect on the subsequent expression of CFP in the absence of memory retrieval or 6 h after retrieval on the expression of intra-gastric glucose-induced CFP memory.Taken together,our study established mTORC1 signaling in the CeA as a molecular and cellular mechanism for reconsolidation of an understudied form of post-ingestive nutrient memory,which is critical for the central control of feeding behavior.Moreover,this study provides a promising target for treating eating disorders,in addition to systemic nutritional and metabolic diseases,through a mechanism that interrupts the vicious cycle from eating to post-ingestive reward processing that commonly leads to incessant maladaptive eating behaviors.