CalorieRL

The intricate details behind the formation of food preferences

How do we choose what we would like to eat? Revealing the factors that influence food selection has been a crucial question in the study of eating behaviour. Dr. Oliveira-Maia and his research team at the CalorieRL project are working on a more exact understanding of the mechanisms that drive and reinforce food-seeking behaviour.

Extensive research across several

species suggests that, in addition to sensory properties such as taste, smell, texture, appearance, as well as other environmental signals, regulation and selection of food are also influenced by the caloric content of the meal. Indeed, after being swallowed, i.e. during the post-ingestive phase, food is analyzed for its caloric and nutritional content, and this post-ingestive assessment is responsible for the formation of long-term food preferences. Specifically, many studies have shown, both in animal models and in humans, that learning associations between food cues and post-ingestive consequences will lead to development of preferences toward highcalorie foods that, in the long term, is thought to alter food-seeking behaviour.

Dr. Oliveira-Maia developed an interest in post-ingestive reinforcement during his Ph.D. “We had access to a transgenic mouse with a modification in a gene relevant for taste transduction in taste receptor cells. This mouse was engineered specifically to study taste, and it had been previously shown to be unable to sense sweetness, i.e., it was ‘sweet-blind’. We decided to study if the animal could detect the rewarding and reinforcing properties of calorie-rich sugar solutions, even though it was unable to sense their sweet taste. Indeed, we demonstrated that these animals were still capable of identifying the presence of sugar, since they would prefer solutions with sugar over water, namely when the different alternatives were left in the same place across several days” explains Dr. Oliveira-Maia. In this study, the research team further demonstrated that reward-related brain areas such as the ventral striatum and the orbitofrontal cortex were activated when the animals were consuming sugar, relative to consumption of a noncaloric sweetener, used as a control. They also demonstrated that dopamine was released in the ventral striatum, also when the animals were drinking sugar. “This revealed to us that a non-oral component of sugar could be identified by the organism, and this process of identification was somehow related to activation of reward circuits in the brain and to the release of dopamine. This was the first paper which proved that animals can identify the post-ingestive nutritional value of sugars, in a manner that is fully independent of any orosensory properties” says Dr. OliveiraMaia, who has continued to work in this area.

More recently, to identify how the metabolic reward coming from sugar induces learning, Dr. Oliveira-Maia and his team developed a protocol for conditioning lever-pressing behaviour in mice, using another method to bypass sweet taste and oral stimulation. In this task, whenever the animal pressed a lever, the researchers would inject solutions into its stomach via a surgically implanted catheter. Injecting solutions directly into the animal’s stomach bypasses the mouth, and eliminates the palatable effects of food. Once the animals had established lever-pressing behaviour to obtain only water, the researchers would change the rewards to either sugar or a non-caloric

sweetener, delivered directly into the stomach. While the non-caloric sweetener was not sufficient to stimulate continued lever-pressing, the animals receiving sugar persisted in lever pressing across many days, and could actually significantly increase these behaviours given certain conditions. “This gave us insight into the fact that post-ingestive metabolic signals were having an important impact on the maintenance of these learned behaviours across time, and we became quite interested in understanding how this could have a more global impact in terms of feeding behaviours” says Dr. Oliveira-Maia. In this paper, the researchers also demonstrated that injecting sugar into the stomach would increase the firing rate of subpopulations of midbrain dopaminergic neurons. Furthermore, in what Dr. Oliveira-Maia considers one of the most interesting findings from the paper, once the researchers cut the branch of the vagus nerve that carries information from the liver, the capacity of animals to learn from postingestive administration of sugar was severely impacted. This paper was the main inspiration for CalorieRL. It formed the hypothesis that behaviours conditioned by the nutrient value of sugar has a dopaminergic substrate associated with neural activity in brain reward circuits, resulting from sensory information transmitted through the vagus nerve.

This gave us insight into the fact that post-ingestive metabolic signals were having an important impact on the maintenance of these learned behaviours across

time, and we became quite interested in understanding how this can have a more global impact in terms of feeding behaviours.

The idea of CalorieRL is transferring what has been found in mice, into humans. According to Dr. Oliveira-Maia, the main goals are to develop methods for a very well-defined measurement of post-ingestive reinforcement in humans and to understand the impact of the innervation of the liver, namely by the vagus nerve, on this behaviour. The researchers are recruiting healthy volunteers, as well as patients who have surgical lesions of the vagus nerve innervating the liver, and then understand how behaviour and neural activation from post-ingestive reinforcement are relevant in the context of obesity. “There are two possible approaches that would allow us to understand the impact of hepatic innervation. One is with patients who have received a liver transplant, since after a liver transplant one does not have any neural connections between the liver and the central nervous system. The other alternative is with patients that need to remove part of the liver, for many reasons such as the presence of a tumor. Depending on the part of the liver that is being removed, this will require cutting a part of the innervation during surgery. However, some patients will also have conserved innervation of the liver, and that will allow for a comparison with those that have nerve lesions” explains Dr. Oliveira-Maia. The researchers will use functional magnetic resonance imaging to measure neural activation, with brain activity measured while the patient is in the scanner performing the post-ingestive task. Dr. Oliveira-Maia and his team plan to identify the computations that the person is doing within the task, to extract parameters that are significant in terms of decision making and correlate them with brain activity. If relevant parameters of the computational model of the behaviour are reflected in the neural activity during the task, it is assumed that a similar computation is happening with a similar time course in a specific area of the brain. In parallel, the researchers will also assess neurochemical activation using a molecular imaging approach. Using a radioactive marker for dopamine receptors, the researchers can observe changes in radioactivity intensity that occur following consumption of food in areas of the brain that are rich in dopamine

receptors, and that reflect the concentration and release of dopamine in the synapse.

Dr. Oliveira-Maia is also a practicing psychiatrist and, naturally, one of the research team’s interests is also to uncover to what degree post-ingestive reinforcement is modified in individuals with disorders of eating behaviour. Their specific interest is in obesity. Obesity has become a problem of epidemic proportions with over 4 million people dying each year due to being overweight or obese. Patients with severe forms of obesity may require invasive bariatric surgery for long-term treatment and weight loss. “If we better understand the impact of the autonomic nervous system and gutbrain communication, this could provide opportunities for treatments that are less invasive, or treatments for those patients that do not respond or cannot access currently available options, like bariatric surgery” explains Dr. Oliveira-Maia.

Reinforcement learning from postingestive calories: from body to brain in health and disease

Project Objectives

Reinforcement learning from post-ingestive calories: from body to brain in health and disease. In CalorieRL, computational reinforcement models and brain functional imaging will be applied to instrumental conditioning in healthy volunteers and liver patients with and without surgically induced lesion of the hepatic branch of the vagus nerve. Our aim is to explore post-ingestive reinforcement of food-seeking behavior and the contribution of vagus nerve signalling for post-ingestive conditioning in humans.

Project Funding

Funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement Nº950357.

Project Partners

• Dr. Hugo Pinto Marques • Dr. Eric J. DeWitt • Dr. Durval C. Costa • Dr. Francisco P. M. Oliveira

Contact Details

Albino Jorge Oliveira-Maia, MD, MPH, PhD Group Leader @ Champalimaud Research Neuropsychiatry Director @ Champalimaud Clinical Centre Champalimaud Foundation Av. Brasilia, Doca de Pedrouços 1400-038 Lisbon, Portugal T: (00351) 21 0480 115 E: albino.maia@neuro.fchampalimaud.org W: https://www.fchampalimaud.org/ researchfc/groups/grupo-neuropsychiatry

Albino J. Oliveira Maia is the director of the Neuropsychiatry Unit at the Champalimaud Foundation. In addition to being a physician he holds a master’s degree in public health and a doctorate in neuroscience, and was trained at Porto, Duke and Harvard Universities. He is currently a practicing psychiatrist at the Champalimaud Clinical Centre, group leader at Champalimaud Research and Professor of Psychiatry and Neuroscience at NOVA Medical School.

Albino J. Oliveira Maia