Figure 4. Models of anesthesia depend on feedback underlying bistability.

(a) Simple kinetic model describing drug-dependent behavioral state changes in the absence of bistability. (b) In the absence of feedback and bistability, dose-response curves for anesthesia induction and emergence are independent of history of prior behavioral state and thus coincide. (c) Addition of feedback upon binding or unbinding of drug leads to additional, more stable anesthesia and waking states. (d) Feedback and bistability lead to hysteresis in dose-response curves for anesthesia induction and emergence. (e) Three cell circuit model underlying bistability of waking and anesthesia in Drosophila. Arrows and perpendicular bars indicate feedforward excitation and inhibition, respectively. Red cells promote and blue cells inhibit waking (W). Cells 1 and 2 express sss and are excited by loss-of-function mutations in this gene, whereas cells 1 and 3 express na and are inhibited by loss-of-function mutations in this gene. For the sake of simplicity, Sh and unc79 have been omitted but may be coexpressed with sss and na, respectively.