Cazares, V. A. | bioRxiv Science

bioRxiv2026

Multiple-Context Training Enhances Generalization of Cued Fear Extinction and Requires the Dorsal Hippocampus

BACKGROUNDMultiple-session fear extinction (FE) models exposure therapy, which also occurs over many sessions. In humans, conducting extinction training across multiple contexts improves fear suppression as compared to a single context, but rodent work delineating boundary conditions and neural mechanisms remains sparse. METHODSWe compared single-context FE (SCFE) versus multiple-context FE (MCFE) in 129S1 and C57BL/6J mice, manipulating context familiarity (familiar vs novel FE contexts). Outcomes included FE acquisition and tests for fear relapse such as recent (2 d) and remote (30 d) recall in trained, extinction, and novel contexts, as well as reinstatement tests. We mapped extinction-related neural activity with dual Fos labeling (TRAPxFos immunofluorescence) and graph analyses of regional co-activation, and used chemogenetic inhibition to selectively silence dorsal (dHP) or ventral hippocampus (vHP) during extinction. RESULTSMCFE produced greater across-session reduction in freezing than SCFE. The MCFE advantage did not require contextual novelty. MCFE also enhanced short- (2 d) and long-term (30 d) recall in a novel context, but did not prevent recovery over time or US-induced reinstatement. Dual-labeling revealed that MCFE strengthened hippocampal-prefrontal co-activation (with relatively weaker prefrontal-amygdala coupling than SCFE). Chemogenetic silencing of dHP, but not vHP, selectively impaired between-session extinction under MCFE and abolished the MCFE benefit; hippocampal silencing did not improve SCFE. CONCLUSIONSConducting extinction across multiple contexts enhances acquisition and recall relative to SCFE, without requiring novelty, and engages distinct hippocampal-prefrontal circuit dynamics. dHP activity is necessary for the MCFE-specific improvement, highlighting a circuit mechanism in which distributing extinction across contexts augments fear reduction.

neuroscience↗

bioRxiv2024

A simple action reduces food intake and obesity in mice

Diets that are high in fat cause over-eating and weight gain in multiple species of animals, suggesting that high dietary fat is sufficient to cause obesity. However, high-fat diets are typically provided freely to animals in obesity experiments, so it remains unclear if high-fat diets would still cause obesity if they required more effort to obtain. We hypothesized that unrestricted and easy access is necessary for high-fat diet induced over-eating, and the corollary that requiring mice to perform small amounts of work to obtain high-fat diet would reduce high-fat diet intake and associated weight gain. To test this hypothesis, we developed a novel home-cage based feeding device that either provided high-fat diet freely, or after mice poked their noses into a port one time - a simple action that is easy for them to do. We tested the effect of this intervention for six weeks, with mice receiving all daily calories from high-fat diet, modifying only how they accessed it. Requiring mice to nose-poke to access high-fat diet reduced intake and nearly completely prevented the development of obesity. In follow up experiments, we observed a similar phenomenon in mice responding for low-fat grain-based pellets that do not induce obesity, suggesting a general mechanism whereby animals engage with and consume more food when it is freely available vs. when it requires a simple action to obtain. We conclude that unrestricted access to food promotes overeating, and that a simple action such as a nose-poke can reduce over-eating and weight gain in mice. This may have implications for why over-eating and obesity are common in modern food environments, which are often characterized by easy access to low-cost unhealthy foods.

animal behavior and cognition↗