Abstract
Body energy and fluid homeostasis are fundamental for our survival. However, our inability to quantify theinternal states that drive this homeostasis - hunger, thirst, and satiety - has limited our understanding of homeostatic mechanisms. To overcome this, we apply a free feeding and drinking behavioral paradigm combined with a novel hunger-thirst transition model to reveal relative degrees of hunger and thirst. By using this method coupled with in vivo calcium imaging of cells in the insula, a region linked to interoception, we identified specific neural dynamics representing hunger or thirst state through the mapping of population neural activity and hunger/thirst degrees calculated by feeding/drinking behavioral patterns in the Hidden Markov Model. Additionally, we discovered a small, but morphologically diverse, population of glutamatergic leptin receptor (LepR) positive cells in the insula and claustrum (INSLepR cells) that form local connections within the insula and external connections to the basolateral amygdala (BLA). These cells are well suited to directly detect circulating leptin levels as the signal of body fat composition or satiety and to regulate homeostatic ingestive behavior. Leptin administration in the insula selectivelyincreased the intrinsic excitability of INSLepR cells, suppressed feeding, and reduced body weight. Finally,optogenetic stimulation of INSLepR cells or their axonal terminals in the BLA suppressed feeding.Taken together, our data supports a model that insula neural population dynamics represent hunger and thirst internal states, and INSLepR cells integrate satiety signals through direct interoceptive input via leptin to regulate body energy homeostasis.