Obesity is the greatest threat to longer, healthier lives for millions of people. It is a potent risk factor for heart failure and premature death and is tightly associated with food overconsumption. Homeostatic centers in the brain control feeding behavior, yet how these feeding centers work is still not well understood. Our lab has shown that acetylcholine (ACh)-releasing neurons in the diagonal band of Broca (DBB) regulate appetite in mice. When we ablate ACh-releasing neurons in the DBB we see a more dramatic obesity phenotype than when we simply remove ACh, suggesting that these neurons release another signal. Indeed, populations of ACh neurons in the DBB release GABA, a known inhibitory signal in the brain. Stimulation of GABA-releasing neurons in the DBB results in feeding dysregulation, supporting the hypothesis that GABAergic release from ACh-releasing DBB neurons regulates feeding behavior. Co-transmitting neurons in other brain circuits use each transmitter to potently regulate circuit activity. Thus, it is the goal of this proposal to understand how co-transmitting DBB neurons regulate feeding behavior in mice. To this end, I will selectively remove co-transmitting DBB neurons while monitoring feeding behavior to determine how these neurons act within feeding circuits. Conversely, I will selectively activate these neurons to test if they are sufficient to drive feeding. I will use viral and genetic tools to map functional connections between these co-transmitting neurons and other known feeding-regulating neurons. Finally, using super resolution microscopy, I will describe the subcellular mechanisms that ACh/GABA co-transmitting DBB neurons employ to regulate feeding behavior. Insights gathered from this work will build a foundation for unraveling the circuits that govern eating. Therapies that target eating dysregulation will greatly benefit from a precise understanding of the underlying mechanisms of feeding. Thus, this work will guide future therapies, ultimately reducing the mortality associated with obesity and promoting longer and healthier lives.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|