Date of Award
Doctor of Philosophy (PhD)
John N. Betley
Survival requires neural circuits regulating behavior to rapidly adapt to an animal’s needs. Energy homeostasis is a basic need that drives feeding behavior. The ability to manipulate access to food in the laboratory allows us to assess how the brain responds to dynamic environmental challenges. The brain must properly gauge energy needs and coordinate behavior to find and consume food. There are three main components to this process that are addressed in this dissertation. First, circuits in the brain that coordinate feeding behavior must be well tuned to both external and internal cues signaling energy need and food availability. Second, when hunger circuits are active and food is not available, competing needs that impair food seeking are devalued. Third, hunger circuits promote food consumption by modulating motivation and reward. Hypothalamic agouti-related protein (AgRP)-expressing neurons are active during food deprivation and their activity drives food seeking and consumption. Precisely how AgRP neuron activity is regulated, however, is not completely understood. We used in vivo calcium imaging and gut-brain manipulations to identify multiple pathways that are utilized by nutrients along the gastrointestinal tract to inhibit AgRP neuron activity. When AgRP neurons are active in the absence of food, they suppress persistent inflammatory pain to promote feeding. We show here, using neural activity recordings, that peptidergic signaling blunts the activation of a population of glutamatergic neurons in a hindbrain hub that is a critical relay point for pain information. This work significantly advances our understanding of a relatively unexplored endogenous analgesic circuit. Finally, we demonstrate that AgRP neuron activity is sufficient to increase dopamine release in the striatum following food intake and that tonic elevations of striatal dopamine by drugs or input from a novel satiation center in the cerebellum suppress food intake by attenuating further release in response to food. Together, our findings reveal that hypothalamic neurons are regulated by rapid neural signals from the gut in order to properly enhance reward circuit activation and suppress activity in pain-responsive neurons to ensure survival.
Goldstein, Nitsan, "Dynamic Control Of Behavior By Hypothalamic Hunger Neurons" (2022). Publicly Accessible Penn Dissertations. 5294.