Study reveals distinct hippocampal neurons that regulate nutrient choice, memory, and intake, offering potential targets for combating obesity.
Study: Separate orexigenic hippocampal ensembles shape dietary choice by enhancing contextual memory and motivation. Image Credit: beats1/Shutterstock.com
In a recent study published in Nature Metabolism, researchers identified distinct neuronal populations in the hippocampus (HPC) responsive to sugars or fats.
Background
Survival depends upon sufficient food acquisition to meet metabolic demands. As such, the ability to build a cognitive map and navigate to a known food source confers a competitive advantage.
Repeatedly associating contextual or discrete cues with food in a way that predicts food consumption leads to a motivational state that elevates the desire to eat.
This adaptive behavior is overwhelmed in the current food environment characterized by the inundation of food-related cues and fat- and sugar-rich foods. Notably, associative-learning mechanisms associating food cues with the consumption of calorie-dense foods enhance susceptibility to obesity.
Therefore, unraveling mechanisms underlying memory formation about contextual cues related to sugar and fat intake could be promising to combat obesity.
The HPC is a neural substrate critical for forming episodic memories and cognitive mapping. Recent studies suggest that the HPC has a role in food intake regulation. HPC lesioning in rats has been reported to elevate food intake and body weight.
Disruption of HPC functions has been associated with obesity. Besides, 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, researchers investigated whether sugar and fat activate HPC neurons with orexigenic function. First, they assessed whether HPC activates in response to individual nutrients by measuring Fos immunofluorescence in mice in response to intragastric (IG) infusions of sugar, fat, or saline.
Fos levels increased in distinct neuronal populations within the dorsal HPC (dHPC) in fat or sugar recipients relative to saline recipients.
Next, the team quantified Fos expression in the dHPC following IG infusions in mice with sub-diaphragmatic vagotomy or sham surgery. Control mice with IG saline infusion had low dHPC Fos that increased in response to fat or sugar.
By contrast, nutrient-induced Fos expression was significantly lower in the dHPC in mice with vagotomy, suggesting that the vagus nerve was necessary to relay signals to the dHPC.
Further, a FosTRAP mouse was used to compare neuronal activity after infusions of sugar and fat in the same mouse. The team identified two populations of dHPC neurons differentially responsive 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.
By contrast, vGLUT1 is labeled extensively throughout the dHPC. Most sugar- and fat-responsive dHPC neurons colocalized with vGLUT1. Next, the team sought to evaluate the role of nutrient-responsive populations in food intake control.
To this end, the distinct populations activated by sugar or fat in FosTRAP mice were genetically targeted by selectively ablating them using a Cre-dependent virus expressing caspase or a control virus.
Mice were given a choice between bottles containing fat or sugar, and their intake was measured using a lickometer. Mice with ablated sugar-responsive neurons showed a 50% reduction in sugar intake relative to controls, with no effects on fat consumption. By contrast, those with ablated fat-responsive neurons had 40% reduced fat intake with no changes in sugar intake.
When bottles were presented one at a time, ablation of sugar-responsive neurons did not affect fat or sugar intake, while 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 intake.
A food-cup location memory task was adapted to investigate whether neurons retain contextual information about the location of sugars and fats. Mice were acclimated to a novel context with two empty Petri dishes; during training, one dish contained fat or sugar droplets, while the other contained water droplets. After training, empty dishes were used to test whether mice could recall the position of the nutrient-paired quadrant.
Control mice discriminated the sugar-paired quadrant in tests conducted one hour and 24 hours after the final training session. However, mice with ablated sugar-responsive dHPC neurons failed to distinguish the location of the sugar dish. In addition, a novel object-in-context task was performed to ascertain whether generalized spatial memory is affected.
The researchers noted that the ablation of sugar- or fat-responsive neurons had no impact on the time exploring the novel object, whereas control mice spent more time exploring it.
This suggested that the deletion of nutrient-responsive neurons influenced the contextual memory of nutrient location, and these neurons were food-specific with no effects on the contextual memory for objects unrelated to foods.
Further experiments confirmed that both sugar- and fat-responsive dHPC neurons were orexigenic, promoting the consumption of an obesogenic diet.
Mice expressing Cre-dependent caspase in sugar-responsive neurons were generated to assess the necessity of dHPC neurons in energy intake regulation. These mice were fed an HFHS diet for 10 days. Caspase-treated mice showed a decrease in HFHS intake, driven by a reduced meal frequency.
Moreover, caspase-treated mice maintained stable fat mass and body weight, while controls gained fat mass and weight. Fat mass was significantly lower in caspase-treated mice at four weeks than in controls. Likewise, caspase ablation of fat-responsive dHPC neurons significantly reduced the intake of a high-fat diet driven by smaller meal portions.
Conclusions
The findings illustrate the critical role of the dHPC in food intake control. The team identified distinct orexigenic populations of dHPC neurons that selectively respond to sugar or fat. While both nutrient-responsive neuronal populations are orexigenic, they have differential control over macronutrient choice, memory, and motivation.
Fat-responsive neurons primarily influence motivation, while sugar-responsive neurons affect spatial memory. Overall, the study established the dHPC as a vital brain region with multiple orexigenic populations, offering potential therapeutic targets for obesity.
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