FROM THE VAGUS NERVE TO THE VENTRAL TEGMENTAL AREA: A PATHWAY FOR POST-INGESTIVE FOOD REINFORCEMENT IN THE DEVELOPMENT AND TREATMENT OF OBESITY

Obesity has become of the one of the greatest threats to public health in the developed world, and currently there is no evidence that we close to understand the underlying mechanisms in the control of feeding behaviors. Several lines of evidence indicate that dopaminergic neuronal signals are related to compulsive food intake and weight gain. One of the proposed mechanisms is that dopamine signaling leads to overeating as a means to compensate for decreased activation of reward circuits. However, due to limitations in measuring neuronal activity in deep brain areas, such as the ventral tegmental area VTA, where dopamine neuron cell bodies are found, causal correlations between dopamine synthesis and the onset and development of obesity are unknown. Taking advantage of a novel in vivo imaging technique that allows for observation of activity, of well-defined neuronal populations, in deep brain structures, it is possible to measure, for the first time, the level of activation of dopamine-producing neurons during consumption of food.

Feeding behavior is characterized by an orosensorial component and a second component associated to the caloric content of food post-ingestive mechanisms. Both stimuli modulate feeding behavior, however there?s no clear evidence that these mechanisms cause an increase in VTA dopaminergic neurons activity. Our main interest is to understand how activity of dopamine producing-neurons is modulated during food consumption and how dopmaibergic activity change during the development of obesity. We will measure dopaminergic-activity during oral consumption of a non-caloric sweetener, to isolate stimulation from palatability, or intragastric injection of a calorie-containing sugar, to isolate postingestive stimulation. Dopaminergic neuron activity under these conditions will be repeatedly measured before and after exposure to hypercaloric food, and also while mice recover from obesity. In animals with diet-induced obesity, weight loss will be induced using gastric bypass, and measurements of VTA dopaminergic neurons will be performed after this surgical procedure

We hypothesize that dopaminergic activity during food consumption will increase as a factor of the consumption rate of the hypercaloric diety and the development of obesity. We further predict that postingestive stimulation occurring through the hepatic branch of the vagus nerve, that we have found is relevant in the modulation of postingestive-dependent feeding behaviour, contributes significantly to the increase of dopaminergic activity, and that both vagus nerve stimulation and VTA dopaminergic activity are required for development of obesity.

With the development of this project we expect to make a significant contribution to understand neuronal mechanisms underlying feeding behavior control with potential impact for future advances in the treatment and prevention of obesity.