Study reveals distinct hippocampal neurons that regulate nutrient selection, memory and intake, offering potential targets for fighting obesity.
Study: Distinct hippocampal orexigenic ensembles modulate food choice by enhancing associative memory and motivation. Image credit: beats1/Shutterstock.com
In a recent study published in Metabolism of Natureresearchers identified distinct neuronal populations in the hippocampus (HPC) that respond to sugars or fats.
Background
Survival depends on adequate food intake to meet metabolic demands. Therefore, the ability to create a cognitive map and navigate to a known food source provides a competitive advantage.
Repeatedly associating contextual or discrete cues with food in a way that predicts food consumption leads to a motivational state that increases the desire to eat.
This adaptive behavior is overwhelmed in the current nutritional environment characterized by the deluge of food-related cues and foods high in fat and sugar. In particular, associative learning mechanisms that associate food cues with the consumption of high-calorie foods enhance susceptibility to obesity.
Therefore, uncovering mechanisms that govern the formation of contextual memory related to sugar and fat intake could hold great promise in the fight against obesity.
The HPC is a neural substrate critical for the formation of episodic memories and cognitive mapping. Recent studies suggest that the HPC plays a role in regulating food intake. HPC lesion in rats has been reported to increase food intake and body weight.
Impaired HPC functions have been associated with obesity. Furthermore, a high-fat, high-sugar (HFHS) diet impairs HPC-dependent episodic memory and spatial learning tasks in rats.
The study and findings
In the present study, the researchers investigated whether sugar and fat activate HPC neurons with an orexigenic function. First, they assessed whether the HPC is activated in response to individual nutrients by measuring Fos immunofluorescence in mice in response to intragastric (IG) infusions of sugar, fat, or saline.
Fos levels were increased in distinct neuronal populations within the dorsal HPC (dHPC) in fat or sugar recipients relative to saline recipients.
The team then quantified Fos expression in the dHPC after IG injections in mice with subdiaphragmatic vagotomy or sham surgery. IG saline-infused control mice had low dHPC Fos that increased in response to fat or sugar.
In contrast, nutrient-induced Fos expression was significantly lower in the dHPC in vagotomy mice, suggesting that the vagus nerve was necessary for signaling to the dHPC.
Further, a LightTRAP mouse was used to compare neuronal activity after injections of sugar and fat in the same mouse. The team identified two populations of dHPC neurons that respond differently to sugars and fats.
To characterize these neurons, neurotransmitter phenotypes were examined for gamma-aminobutyric acid (GABA) and vesicular glutamate transporter 1 (vGLUT1). GABA expression was detected in < 5% of sugar- or fat-responsive dHPC neurons.
In contrast, vGLUT1 is extensively labeled throughout the dHPC. Most sugar- and fat-responsive dHPC neurons colocalize with vGLUT1. Next, the team sought to assess the role of nutrient-responsive populations in controlling food intake.
To this end, distinct populations are activated by sugar or fat in FosTRAP Mice were genetically targeted by their selective ablation using a Cre-dependent caspase-expressing virus or a control virus.
Mice were given a choice between bottles containing fat or sugar and their intake was measured using a dipstick. Mice with sugar-responsive neurons showed a 50% reduction in sugar intake relative to controls, with no effect on fat consumption. In contrast, those with neurons responsive to fat removal had a 40% reduction in fat intake with no changes in sugar intake.
When the bottles were presented one at a time, removal of sugar-responsive neurons did not affect fat or sugar intake, whereas ablation of fat-responsive neurons reduced fat intake but not sugar intake.
This indicated that sugar-responsive neurons influenced choice, while fat-responsive neurons influenced both choice and intake. Next, the researchers examined the mechanisms by which dHPC neurons control nutrient-specific uptake.
A food location memory task was adapted to investigate whether neurons retain information about the location of sugars and fats. Mice were acclimated to a new context with two empty Petri dishes. during training, one dish contained drops of fat or sugar, while the other contained drops of water. After training, empty dishes were used to test whether mice could recall the location of the quadrant paired with nutrients.
Control mice discriminated the paired sugar quadrant in tests conducted one hour and 24 hours after the final training session. However, mice with sugar withdrawal-responsive dHPC neurons failed to discriminate the location of the sugar dish. In addition, a new object-in-context task was performed to ascertain whether generalized spatial memory is affected.
The researchers observed that removing neurons that respond to sugar or fat had no effect on the time it took to explore the novel object, while control mice spent more time exploring it.
This suggests that deletion of nutrient-responsive neurons affected contextual memory of nutrient location, and these neurons were food-specific with no effects on contextual memory for non-food items.
Further experiments confirmed that both sugar- and fat-responsive dHPC neurons were orexigenic, promoting consumption of an obesogenic diet.
Mice expressing Cre-dependent caspase in sugar-responsive neurons were generated to assess the necessity of dHPC neurons in the regulation of energy intake. These mice were fed a HFHS diet for 10 days. Caspase-treated mice showed a reduction in HFHS intake, due to reduced meal frequency.
Furthermore, caspase-treated mice maintained stable fat mass and body weight, while controls gained fat mass and weight. Fat mass was significantly lower in the caspase-treated mice at four weeks than in controls. Similarly, caspase ablation of fat-responsive dHPC neurons significantly reduced intake of a high-fat diet driven by smaller meal portions.
conclusions
The findings illustrate the critical role of the dHPC in the control of food intake. The team identified distinct orexigenic populations of dHPC neurons that respond selectively to sugar or fat. While both nutrient-responsive neuronal populations are orexigenic, they have different control over macronutrient selection, memory, and motivation.
Fat-responsive neurons primarily influence motivation, while sugar-responsive neurons influence spatial memory. Overall, the study established the dHPC as a vital brain region with multiple orexigenic populations, offering potential therapeutic targets for obesity.
