SEPARATE OREXIGENIC HIPPOCAMPAL ENSEMBLES SHAPE DIETARY CHOICE BY ENHANCING CONTEXTUAL MEMORY AND MOTIVATION

Feeding behavior is orchestrated by a complex interplay of homeostatic, hedonic, and cognitive mechanisms. While much is known about the hypothalamic and brainstem circuits that regulate hunger and satiety, the contribution of higher-order brain regions—particularly the hippocampus(HPC)—to dietary decision-making has remained elusive. In this dissertation, I demonstrate that the HPC not only integrates spatial and episodic memory but also serves as a critical modulator of food-seeking behavior in response to post-ingestive nutrient signals. Using a combination of genetic, behavioral, and circuit-level approaches, I identify two spatially distinct, glutamatergic neuronal populations in the dorsal HPC that are selectively activated by either intragastric sugar or fat. These neurons form macronutrient-specific ensembles: sugar-responsive neurons encode spatial memory for sugar-paired environments, while fat-responsive neurons enhance motivation for fat-rich foods. Manipulating these neurons via chemogenetic stimulation or targeted ablation reveals that they are both necessary and sufficient to drive nutrient-specific food-seeking behavior and shape consumption patterns. Further, I show that these nutrient-responsive neurons receive input via vagal sensory pathways, establishing a functional gut-to-HPC axis. This highlights the hippocampus as a site of convergence between interoceptive and contextual signals, capable of forming long-lasting appetitive memories. Deletion of these circuits not only impairs nutrient-specific memory and motivation but also protects against diet-induced obesity by reducing intake of fat- and sugar-rich diets. Notably, these effects are specific to nutrient-related memory, leaving general spatial working memory and non-food object-context recognition intact. Together, these findings provide the first evidence for distinct orexigenic memory engrams in the hippocampus and establish memory as a third major driver of food intake, alongside homeostatic and hedonic mechanisms. This work challenges existing models of feeding control and opens new avenues for understanding the cognitive contributions to obesity and overeating in nutrient-rich environments.