Grant: Discovery Grants Program - Individual

The brain is responsible for maintaining an organism's body weight stable. Several mechanisms work in parallel in the central nervous system, in particular within the hypothalamus, to ensure body weight homeostasis by adjusting energy balance. This is achieved via the fine tuning of food intake and energy expenditure. One important component of this hypothalamic homeostatic network is the melanocortin system, which includes two neuronal populations acting in a yin-yang fashion: the "Agrp" neurons on one side promote appetite and energy sparing, while "Pomc" neurons on the other side promote satiety and energy expenditure. Pomc neurons, in particular, become dysfunctional upon prolonged exposure to high concentrations of nutrients, hormones and cytokines, which impairs their ability to trigger satiety and increase energy expenditure, ultimately harming the organism's homeostatic regulation. While the neurotransmitter profile of a neuron has traditionally been considered fixed in time, evidence has been accumulating that challenges this dogma, in both laboratory rodents and humans. Recent research, including my postdoctoral work, has shown that several transcription factors are required to maintain a neuron's profile of neurotransmitters, or what could be termed as a neuron's "identity". Genetic loss of these transcription factors can impair the ability of a neuron to secrete specific neurotransmitters, as in the case with the transcription factor Tbx3 and the secretion of Pomc. This phenomenon, the gain, loss or permutation of neurotransmitter secretion capacity by a neuron, is a conserved biological process defined as neurotransmitter respecification, which has been described as an additional layer of neuronal plasticity (in addition to changes in synaptic strength and scaling). While this novel and understudied process has been observed in neurons responsible for motor skill learning, lactation, neurological and psychiatric disorders, it is not known whether neurotransmitter respecification contributes to the plasticity of hypothalamic networks in charge of body weight homeostasis. Thus, the goal of the research program I propose is to investigate the fate and role of Pomc neurons in mice after prolonged exposure to metabolic stresses such as nutrients, hormones and cytokines, and understand the molecular underpinnings of the changes occurring. In conclusion, the proposed project aims to uncover and characterize a significant new layer of neuronal plasticity within the homeostatic networks of the hypothalamus. The completion of the proposed research project would allow a better understanding of the biology behind neuronal (mal)adaptation to metabolic stresses.