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The hippocampus (HPC) has emerged as a critical player in the control of food intake, beyond its well-known role in memory. While previous studies have primarily associated the HPC with food intake inhibition, recent research suggests a role in appetitive processes. Here we identified spatially distinct neuronal populations within the dorsal HPC (dHPC) that respond to either fats or sugars, potent natural reinforcers that contribute to obesity development. Using activity-dependent genetic capture of nutrient-responsive dHPC neurons, we demonstrate a causal role of both populations in promoting nutrient-specific intake through different mechanisms. Sugar-responsive neurons encoded spatial memory for sugar location, whereas fat-responsive neurons selectively enhanced the preference and motivation for fat intake. Importantly, stimulation of either nutrient-responsive dHPC neurons increased food intake, while ablation differentially impacted obesogenic diet consumption and prevented diet-induced weight gain. Collectively, these findings uncover previously unknown orexigenic circuits underlying macronutrient-specific consumption and provide a foundation for developing potential obesity treatments., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Pharmacotherapies targeting motivational aspects of feeding and palatable food reward, while sparing mood and cognitive function, represent an alluring approach to reverse obesity and maintain weight loss in an obesogenic environment. A novel glucagon-like peptide-1/dexamethasone (GLP-1/Dexa) conjugate, developed to selectively activate glucocorticoid receptors in GLP-1 receptor-expressing cells was shown to decrease food intake and lower body weight in obese mice. Here, we investigate if this novel drug candidate modulates the rewarding properties of food and if it affects behavioral indices of mood and memory., Methods: C57Bl6 mice treated with the GLP-1/Dexa conjugate, GLP-1 or vehicle lever-pressed for high-fat, high sugar (HFHS) food rewards in an operant task. Alterations in food-motivated behavior were also assessed following a HFHS diet withdrawal manipulation (switch to chow). The effects of repeated GLP-1/Dexa conjugate, GLP-1 or vehicle on free-feeding intake, body weight, anxiodepressive behaviors (elevated-plus maze, open field test & forced swim test), memory (novel object recognition) and mRNA expression of reward-relevant markers in the nucleus accumbens were also evaluated in mice fed a HFHS diet for 12 weeks., Results: Mice treated with a GLP-1 analogue displayed a transient (4 h) reduction in their motivation to lever press for HFHS reward, whereas treatment with equimolar doses of GLP-1/Dexa delivered a superior and sustained (20 h) suppression of food-motivated behavior. GLP-1/Dexa also inhibited food reward following withdrawal from the HFHS diet. These benefits coincided with related transcriptional changes of dopaminergic markers in the nucleus accumbens. Importantly, repeated GLP-1/Dexa treatment during a HFHS diet caused weight loss without affecting anxiodepressive behavior and memory., Conclusion: Via its actions to blunt the rewarding effects of palatable food without affecting mood and recognition memory, GLP-1-directed targeting of dexamethasone may serve as a promising and safe anti-obesity strategy., (Copyright © 2019. Published by Elsevier Ltd.)

Survival requires the integration of external information and interoceptive cues to effectively guide advantageous behaviors, particularly foraging and other behaviors that promote energy acquisition and consumption. The vagus nerve acts as a critical relay between the abdominal viscera and the brain to convey metabolic signals. This review synthesizes recent findings from rodent models and humans revealing the impact of vagus nerve signaling from the gut on the control of higher-order neurocognitive domains, including anxiety, depression, reward motivation, and learning and memory. We propose a framework where meal consumption engages gastrointestinal tract-originating vagal afferent signaling that functions to alleviate anxiety and depressive-like states, while also promoting motivational and memory functions. These concurrent processes serve to favor the encoding of meal-relevant information into memory storage, thus facilitating future foraging behaviors. Modulation of these neurocognitive domains by vagal tone is also discussed in the context of pathological conditions, including the use of transcutaneous vagus nerve stimulation for the treatment of anxiety disorders, major depressive disorder, and dementia-associated memory impairments. Collectively, these findings highlight the contributions of gastrointestinal vagus nerve signaling to the regulation of neurocognitive processes that shape various adaptive behavioral responses. [ABSTRACT FROM AUTHOR]

Remembering the location of a food or water source is essential for survival. Here, we reveal that spatial memory for food location is reflected in ventral hippocampus (HPCv) neuron activity and is impaired by HPCv lesion. HPCv mediation of foraging-related memory involves communication to the lateral septum (LS), as either reversible or chronic disconnection of HPCv-to-LS signaling impairs spatial memory retention for food or water location. This neural pathway selectively encodes appetitive spatial memory, as HPCv-LS disconnection does not affect spatial memory for escape location in a negative reinforcement procedure, food intake, or social and olfactory-based appetitive learning. Neural pathway tracing and functional mapping analyses reveal that LS neurons recruited during the appetitive spatial memory procedure are primarily GABAergic neurons that project to the lateral hypothalamus. Collective results emphasize that the neural substrates controlling spatial memory are outcome specific based on reinforcer modality. [Display omitted] • Ventral hippocampus activity increases during memory retrieval for food location • Ventral CA1-lateral septum circuitry encodes food- and water-based spatial memory • This circuitry does not regulate spatial memory in an escape-based procedure • Ventral CA1-lateral septum foraging circuitry targets the lateral hypothalamus How do hungry or thirsty animals find food or water? Décarie-Spain et al. identify a ventral hippocampus to lateral septum circuit that selectively promotes spatial memory for appetitive-based (food or water) but not aversive-based (escape) reinforcement. These findings identify a neural pathway that selectively encodes foraging-related memory. [ABSTRACT FROM AUTHOR]