Food is vital to survival, and animals have developed strong physiological mechanisms that control feeding behavior and the search for food. Scientists at Rockefeller University have now identified a set of neurons in the hippocampus of mice that can hold back the drive to eat, but which also play a role in regulating food-related memory.

Findings by Rockefeller University hint that with training, people may be able to learn to change their relationship to food. “These cells keep an animal from overeating,” commented lead author Estafania Azevedo, PhD. “They appear to make eating less rewarding and, in that sense, are tuning the animal’s relationship to food … Our study shows that brain areas involved in cognitive processing and memory formation affect feeding behavior. So it is possible that, with training, people may be able to learn to change their relationship to food.”

Azevedo and colleagues, working in the laboratory of corresponding author Jeffrey M. Friedman, PhD, reported their findings in a paper titled, “A role of Drd2 hippocampal neurons in context-dependent food intake.”

Scientists have historically considered feeding to be an instinctive process tied to survival, but continued research indicates that the brain may instruct the animal whether to eat or refuse a meal dependent on its physiological needs. “Specific populations of neurons in the brain control food intake and energy balance by integrating a panoply of relevant sensory and hormonal signals, thus orchestrating an adaptive behavioral response.”

We know that humans can consciously decide not to eat even if they are hungry, say, for example, to save their appetite before meeting friends for a meal. Research suggests that animals may also employ cognitive processes in their feeding behavior, and studies have found that changes to neurons in the hippocampus, a brain region involved in memory, can alter feeding behavior. “Recently, several groups have also shown that hippocampal dysfunction can alter feeding behavior,” the authors wrote.

It’s thus possible that past experiences may influence an animal’s drive to eat, and that this may be controlled by the hippocampus. However, as the Rockefeller University team further pointed out, “the neural processes by which these and other brain regions integrate relevant, previous experiences and environmental cues to regulate feeding and enabling an animal to efficiently locate food are largely unknown … our knowledge of the neural mechanisms responsible for the modulation of feeding by the hippocampus is incomplete, and the role of specific neural populations in these processes has not been fully elucidated.”

The authors devised a series of studies in mice to determine whether the presentation of a meal could activate specific sets of hippocampal neurons, and if so, then evaluate whether those neurons play a role in feeding behavior and memory. “We hypothesized that the appetitive characteristics of food (appearance, taste, odor, or calories) might activate hippocampal neurons and construct a memory of that meal.”

Using methods including a technique known as PhosphoTrap, which can enable molecular profiling of gene expression based on a change in the activation state of specific neural populations, they found that food cues activated a specific subpopulation of hippocampal neurons that expressed the dopamine receptor 2 (D2R). These initial results indicated that the hD2R neurons were activated by visual cues and possibly olfactory cues associated with the presence of food.

“Our findings that the state of activation of hD2R neurons is altered by sensory cues associated with food and that these neurons can regulate food intake raised the possibility that these neurons might play a role in the encoding of a memory that links food to a specific context,” the scientists wrote. “These data prompted us to evaluate whether these neurons could, in turn, modulate food intake and possibly modulate the association of sensory cues to food location. To investigate this, we tested whether manipulating the activity of hD2R neurons during the encoding of a memory associating food and spatial location could modulate a subsequent behavior (indicative of an effect on the formation of that memory).”

Their experiments in the mouse models found that inhibiting the hD2R neurons increased food intake, whereas stimulating the neurons resulted in the animals eating less. “These cells keep an animal from overeating,” Azevedo said. “They appear to make eating less rewarding and, in that sense, are tuning the animal’s relationship to food.”

Knowing where to find food is important for wild animals, and the brain is, fortunately, very effective in remembering the location of past food sources. In a subsequent set of tests the researchers investigated whether the hD2R neurons also played a role in positional food memory. They found that when they stimulated the hD2R neurons while the mice were moving around a food-containing environment, the animals were then less likely to return subsequently to the area in which the food had previously been located. Stimulating the neurons had somehow reduced the animals’ memory of prior food location.

“Mental connections between food and location are important for survival, and the strength of these connections is regulated by how rewarding an experience is,” Azevedo commented. “Because hD2R neurons affect an animal’s relationship with food, it also ends up affecting these connections.”

Further tests demonstrated that the hD2R neurons received their input from the entorhinal cortex (LEC), a region of the brain that processes sensory information, and then sent the information on to the septal area (SA), which is involved in feeding. The combined data “suggest that hD2R neurons can reduce food intake in hungry animals via projections to the SA,” the researchers noted.

“In summary, we show that hD2R neurons are an important cellular component of an LEC > hD2R > septal circuit regulating food intake,” they concluded. “hD2R cells sense nutritional state and regulate feeding behavior as well as a memory associating food with a specific location.”

An animal’s ability to generate a durable memory of food location has important adaptive implications because a stronger memory would increase the chances of successful foraging in areas where food has been previously found, and so reduce wasted energy expenditure associated with unnecessary foraging, the team concludes. “Our data suggest the novel finding that the activation of hD2R neurons is associated with a decrease of the strength of this memory. This further suggests that, while hD2R neurons diminish this association, other pathways must reinforce it.”

They also acknowledge that the mechanisms used by the hD2R neurons and their connections to encode food-place associations aren’t yet known, and might relate to motivational state, learning or reward preferences, or to spatial navigation. “One interesting possibility is that these hippocampal ensembles form a network that can couple the regulation of food intake to a food-place memory as part of a system that enables animals to embark on a particular behavior,” they suggested “ … possible changes in motivation might influence memory recall, and these possible effects on motivation and memory recall will be the subject of future studies.”

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