Hunger States Switch a Flip-Flop Memory Circuit via a Synaptic AMPK-Dependent Positive Feedback Loop

Synaptic plasticity in response to changes in physiologic state is coordinated by hormonal signals across multiple neuronal cell types. Here, we combine cell-type-specific electrophysiological, pharmacological, and optogenetic techniques to dissect neural circuits and molecular pathways controlling synaptic plasticity onto AGRP neurons, a population that regulates feeding. We find that food deprivation elevates excitatory synaptic input, which is mediated by a presynaptic positive feedback loop involving AMP-activated protein kinase. Potentiation of glutamate release was triggered by the orexigenic hormone ghrelin and exhibited hysteresis, persisting for hours after ghrelin removal. Persistent activity was reversed by the anorexigenic hormone leptin, and optogenetic photostimulation demonstrated involvement of opioid release from POMC neurons. Based on these experiments, we propose a memory storage device for physiological state constructed from bistable synapses that are flipped between two sustained activity states by transient exposure to hormones signaling energy levels. [Display omitted] ► Ghrelin and food deprivation induce synaptic plasticity at AGRP neurons ► An AMPK-dependent positive feedback loop results in synapse bistability ► Leptin and POMC opioids switch off AMPK, positive feedback, and persistent activity ► Bistable synapses can store a reversible memory of hormonal state in hunger circuits Hunger stimulates synaptic activity that drives feeding behavior and continues until leptin signals satiety. This persistent synaptic activity is driven by a positive feedback loop of AMPK and Ca 2+ signaling.