(A) A core circuit in which AGRP neurons synaptically inhibit POMC neurons and are regulated by circulating hormones is controlled by ghrelin-responsive excitatory synapses. These synapses give this circuit a memory property based on an AMPK-dependent positive feedback loop (inset), which can be reversed by POMC neuron output, likely β-endorphin.
(B) A heuristic for the logic of this circuit is the SR flip-flop memory storage circuit. In the analogy with the neural circuit reported here, the set signal is ghrelin, which activates the green NOR gate, representing the conglomeration of AGRP neurons and their ghrelin-sensitive excitatory presynaptic terminals. The reset signal is leptin which interacts with POMC neurons represented as the blue NOR gate. Notably, when R and S are both high, the circuit does not support memory, and this condition is consistent with the case of ghrelin treatment of fed mice where opioid signaling is sufficiently high to prevent persistent synaptic upregulation (Figure 5G).