
The hippocampus, especially the dorsal hippocampus (dHPC), plays a critical role in controlling food intake, influencing spatial memory, motivation, and preference for certain types of food. Stimulation of these neurons increased food intake, while their ablation prevented weight gain induced by diets high in fat and sugar. These findings represent a promising field for therapeutic interventions aimed at regulating food intake and combating excess weight.
The survival of any living being fundamentally depends on its ability to acquire enough food to meet its metabolic demands.
This means that animals need to consume enough energy and nutrients to maintain their bodily functions and daily activities.
To achieve this, it is crucial that they develop the ability to locate and return to known food sources in their environment. This ability to build a “cognitive map,” that is, a mental representation of the space around them, confers a significant advantage, as it allows them to navigate accurately to these food sources.

Animals learn to associate contextual cues, such as smells, colors, and sounds, with the nutritional value of the food they encounter. For example, if an animal discovers that a certain type of plant is nutritious, it can memorize the location where that plant grows and the surrounding cues so it can return to that location in the future.
This specific memory is called episodic memory because it is related to specific events and their spatial location. This behavior is amplified when animals repeatedly associate specific cues, such as a sound or smell, with the availability of food.
This association not only makes it easier to memorize the location, but also creates a motivational state that increases the desire to eat. This phenomenon is known as “cue-enhanced feeding” and refers to the increase in appetite triggered by the presence of food-related cues.
However, in our modern environment, which is full of easily accessible foods that are high in fats and sugars, these adaptive mechanisms can become detrimental.
Food cues are everywhere, from TV commercials to the smell of food in restaurants, and these constant cues can amplify susceptibility to weight gain and the development of obesity.

Studies show that the brain’s reactivity to these food cues can predict a person’s body mass index (BMI), their propensity to gain weight, and their future food choices.
The hippocampus (HPC), a region of the brain involved in memory formation and spatial navigation, plays an important role in controlling food intake. When animals are fasting, the hormone ghrelin, produced in the stomach, activates the hippocampus, increasing food intake and motivation to seek food rewards.
In humans, hippocampal activity also increases in response to images and smells of food, promoting arousal and the desire to eat, especially in individuals with obesity.
In human functional magnetic resonance imaging (fMRI) studies, hippocampal activity is increased in response to images of food and tastants.
Recent studies have identified a subregion of the hippocampus that plays a crucial role in encoding the appetitive value of foods high in fat and sugar. This subnetwork within the hippocampus is compromised in people with obesity, suggesting that changes in activity in this area may influence increased food intake.

However, it remains unclear whether there is a specific population of neurons in the hippocampus responsible for these orexigenic (appetite-increasing) effects.
Research has shown that the dorsal hippocampus (dHPC) is understudied, despite recent advances in molecular analysis techniques that have revealed a diversity of neuron types in this region.
Findings show that many neurons in the dHPC are activated by feeding, and some of these neurons, which express dopamine receptor type 2 (DRD2), have been shown to reduce food intake when inhibited.
Orexigenic appetitive processing relies on the integration of sensory, interoceptive, and hormonal signals to govern consummatory behaviors.

Dysregulation of this process leads to maladaptive eating behavior, such as binge eating, and is associated with obesity. This circuit, however, has been elusive in humans, until now. Image credit: Barbosa et al., doi: 10.1038/s41586-023-06459-w.
Researchers at the University of Pennsylvania hypothesized that foods high in fat and sugar could activate a subset of neurons in the hippocampus with orexigenic function. To do this, they used mice.
The study demonstrated that the neurons in the dorsal hippocampus (dHPC) that respond to sugar are part of an appetitive engram, which is a physical memory in the brain that encodes the location where sugar was found.
Using genetic manipulation techniques, they were able to artificially activate or erase these memories.
This means that they could make the animals remember or forget where the sugar was located, demonstrating that these neurons are crucial for storing this information.
On the other hand, dHPC neurons that respond to fat have a different role. They are more involved in increasing motivation to seek fat and in strengthening associations between environmental cues and fat after ingestion.

These neurons help create an internal model of the environment that tells mice where to find high-fat foods and also modulate the desire to obtain them.
To investigate this, the researchers conducted experiments in which they exposed mice to different high-sugar and high-fat foods while monitoring the activity of dHPC neurons.
They found that sugar-responsive neurons were specifically activated when the mice sought out locations where they had previously found sugar, indicating that these neurons store spatial memories of where sugar is located.
Fat-responsive neurons, on the other hand, increased their activity when the mice were motivated to seek out fat, even without clear cues, indicating their role in internal motivation.
In our current food environment, which is full of obesogenic foods high in fat and sugar, these orexigenic (appetite-stimulating) neurons can have a devastating impact by increasing consumption driven by environmental cues.

This means that constant exposure to food cues can exacerbate uncontrolled eating behavior, contributing to the development of obesity.
By better understanding the neural mechanisms that control the consumption of specific nutrients, these findings pave the way for the development of strategies that may help counteract the impact of this obesogenic environment.
In summary, the hippocampus, especially the dorsal hippocampus (dHPC), plays a critical role in controlling food intake, influencing spatial memory, motivation, and preference for certain types of food.
Recent findings highlight distinct neuronal populations in the dHPC that respond selectively to fats or sugars, offering new targets for potential treatments of obesity.
These orexigenic neuronal populations represent a promising field for therapeutic interventions aimed at regulating food intake and combating excess weight.
READ MORE:
Separate orexigenic hippocampal ensembles shape dietary choice by enhancing contextual memory and motivation
Mingxin Yang, Arashdeep Singh, Alan de Araujo, Molly McDougle, Hillary Ellis, Léa Décarie-Spain, Scott E. Kanoski & Guillaume de Lartigue
Nature Metabolism (2025)
Abstract:
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.
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