Control of non-homeostatic feeding in sated mice using associative learning of contextual food cues

Molecular Psychiatry, Jun 2018

Feeding is a complex motivated behavior controlled by a distributed neural network that processes sensory information to generate adaptive behavioral responses. Accordingly, studies using appetitive Pavlovian conditioning confirm that environmental cues that are associated with food availability can induce feeding even in satiated subjects. However, in mice, appetitive conditioning generally requires intensive training and thus can impede molecular studies that often require large numbers of animals. To address this, we developed and validated a simple and rapid context-induced feeding (Ctx-IF) task in which cues associated with food availability can later lead to increased food consumption in sated mice. We show that the associated increase in food consumption is driven by both positive and negative reinforcement and that spaced training is more effective than massed training. Ctx-IF can be completed in ~1 week and provides an opportunity to study the molecular mechanisms and circuitry underlying non-homeostatic eating. We have used this paradigm to map brain regions that are activated during Ctx-IF with cFos immunohistochemistry and found that the insular cortex, and other regions, are activated following exposure to cues denoting the availability of food. Finally, we show that inhibition of the insular cortex using GABA agonists impairs performance of the task. Our findings provide a novel assay in mice for defining the functional neuroanatomy of appetitive conditioning and identify specific brain regions that are activated during the development of learned behaviors that impact food consumption.

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Control of non-homeostatic feeding in sated mice using associative learning of contextual food cues

Abstract Feeding is a complex motivated behavior controlled by a distributed neural network that processes sensory information to generate adaptive behavioral responses. Accordingly, studies using appetitive Pavlovian conditioning confirm that environmental cues that are associated with food availability can induce feeding even in satiated subjects. However, in mice, appetitive conditioning generally requires intensive training and thus can impede molecular studies that often require large numbers of animals. To address this, we developed and validated a simple and rapid context-induced feeding (Ctx-IF) task in which cues associated with food availability can later lead to increased food consumption in sated mice. We show that the associated increase in food consumption is driven by both positive and negative reinforcement and that spaced training is more effective than massed training. Ctx-IF can be completed in ~1 week and provides an opportunity to study the molecular mechanisms and circuitry underlying non-homeostatic eating. We have used this paradigm to map brain regions that are activated during Ctx-IF with cFos immunohistochemistry and found that the insular cortex, and other regions, are activated following exposure to cues denoting the availability of food. Finally, we show that inhibition of the insular cortex using GABA agonists impairs performance of the task. Our findings provide a novel assay in mice for defining the functional neuroanatomy of appetitive conditioning and identify specific brain regions that are activated during the development of learned behaviors that impact food consumption. Introduction Associative learning is a fundamental process that enables organisms to make adaptive decisions based on prior outcomes. However, in some cases, associative learning may also lead to maladaptive decisions, as in the case of drug addiction and obesity [1]. Obesity is a growing problem in the developed world, as 30% of adult Americans are currently classified as overweight or obese [2, 3]. Though decades of research have elucidated numerous genetic factors underlying obesity, monogenetic disorders do not account for the majority of cases [4]. Furthermore, environmental factors can also play an important role in overeating and weight gain. Thus, external motivating factors, including easy access to high-energy food, as well as cognitive and emotional cues, can lead to overeating and even binge eating [5,6,7,8]. Consistent with this, it has been demonstrated in both humans and rodents that environmental cues that are paired with food delivery can augment subsequent feeding responses. For example, Weingarten used a Pavlovian conditioning paradigm to show that a cue paired with food delivery when rats were hungry could later be used to decrease the latency to eat even when rats were sated [9]. In contrast, an unpaired cue did not affect the latency to eat. More recently, it has been demonstrated in both rats [10] and mice [11] that visual and auditory cues can also be used to elicit overeating in sated animals after Pavlovian training. Pavlovian conditioning is an extremely well-studied paradigm and has been used to study many behaviors, in particular feeding and fear [12, 13]. Indeed, Pavlov’s original studies paired food and a sound in dogs [14], highlighting the powerful motivation of food as a reinforcer. Conditioning experiments can be further subcategorized as either cued or contextual conditioning depending on the type of sensory stimulus that is provided. For example, cued fear conditioning, which measures the freezing response after pairing discrete visual or auditory cues with footshocks, can be demonstrated in as little as one training session [15]. In contrast, conditioning animals to eat even when sated using an analogous cue-induced feeding task with visual or auditory cues requires more extensive training in chronically underfed animals, and it can take as long as 1 month to fully train an animal [11]. As an alternative, contextual training has also been used to link associative cues to a response. In previous studies of fear conditioning, a specific context (e.g., a behavioral chamber which provides a variety of different sensory cues) can serve as the conditioned stimulus. For example, it has been shown that placing animals in a novel context paired to a specific stimulus (e.g., footshocks) can induce the subsequent conditioned response (CR) of increased freezing in a single trial [15]. The contextual cues serve as a general predictive environment for a specific outcome rather than the onset of the single sensory input such as an auditory or visual cue as employed in cued Pavlovian conditioning [16]. While context-induced feeding (Ctx-IF) has been used to potentiate food intake in sated rats [17], this paradigm has not been evaluated in mice. In this report we tested whether context, rather than discrete cues, could be used to induce a conditioned response of overeating (...truncated)


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Sarah A. Stern, Katherine R. Doerig, Estefania P. Azevedo, Elina Stoffel, Jeffrey M. Friedman. Control of non-homeostatic feeding in sated mice using associative learning of contextual food cues, Molecular Psychiatry, 2018, DOI: 10.1038/s41380-018-0072-y