Grant: Discovery Grants Program - Individual

Energy regulation is essential for life and balances the energy demands of an organism with food availability. Prolonged periods where energy demands exceed food intake would lead to starvation and eventually death. Paradoxically, while energy balance is needed for survival, it is also dependent on motivated actions like going to look for food and then moving towards the food source. This locomotor or activity aspect of energy balance is considerably less studied than feeding. This Discovery Grant aims to investigate the brain processes that regulate motivated activity to regulate energy balance. Melanin-concentrating hormone (MCH) is one important peptide hormone whose actions promote energy storage. Our recent work showed that mice that have lost MCH signaling are hyperactive, burn more energy, and are lean, but there was no effect on how much food they eat. Interestingly, this hyperactive state is attributed to an increase in dopamine functioning. Dopamine, especially when released by the ventral tegmental area (VTA), is a well-known chemical messenger synonymous with motivated behavior. We found that MCH can suppress dopamine release, and consistent with this, the loss of MCH signaling increases the availability of dopamine. We recently showed that MCH can directly inhibit dopamine cells in the VTA, and we hypothesize that this will dampen dopamine release. Interestingly, MCH also had a delayed effect that could increase the activity of dopamine cells in the VTA, and we hypothesize that this would restore dopamine output. This Discovery Grant uses three short-term objectives to test the working model that MCH regulates dopamine output in a biphasic manner. Objective 1 focuses on the acute phase of MCH action that inhibits dopamine cells. We will determine if the loss of MCH receptors at dopamine cells will lead to an increase in dopamine output and locomotor activity. Objective 2 and Objective 3 focus on the delayed phase of MCH action, which is based on our finding that MCH suppresses inhibitory tone from local GABA cells onto excitatory glutamate projections, which would disinhibit dopamine cells. Therefore, in this model, both GABA and glutamate cells are required for delayed MCH actions at dopamine cells, and we will determine if removing local GABA release (Objective 2) or glutamate release (Objective 3) would prevent the restorative effects of MCH and culminate in diminished locomotor activity. Given that most studies on energy balance focus on food-related behaviors, these studies address a gap in our knowledge by defining how and what brain processes contribute to motivation and locomotor activity to regulate energy balance. This project will contribute evidence-based research output that strengthen the foundation of Canadian research aimed at identifying specialized brain cells and how they control energy balance.