Fig. 7: PMd^CCK-projecting mPFC neurons are necessary for learning-induced escape adaptation.

a Left: scheme showing the strategy used to express DREADD or mCherry in PMd^CCK-projecting mPFC neurons. Representative images showing the expression of mCherry in PMd^CCK-projecting mPFC neurons (Middle) and the neuron axon terminals in the PMd (Right). Middle, scale bar, 1 mm; Right, 150 μm. b Chemogenetic excitation of PMd^CCK-projecting mPFC neuron did not affect the escape velocity and the number of escapes in naïve mice from live rat (Saline, n = 8 mice; CNO, n = 8 mice; Student t-test, p > 0.05). c Excitation of PMd^CCK-projecting mPFC neurons also did not affect the escape behavior in the presence of 15% CO₂ (Saline, n = 8; CNO, n = 8; Student t-test, p > 0.05). d Schematic diagram of experimental design. e Exp I: chemogenetic inhibition of PMd^CCK-projecting mPFC neurons during the escape-inducing assay period significantly decreased exaggerated flight behavior in the rat assay (left, both escape velocity and the number of climbs). Exp II: chemogenetic inhibition of PMd^CCK-projecting mPFC neurons during the conditioning period, the mice in the repeated group did not show exaggerated escape behavior in rat assays (right). (Saline, n = 8 mice; CNO, n = 8 mice; Student t-test, ***p < 0.001 and ns p > 0.05). f Escape velocity and the number of flights for the same groups as in (e) during exposure to 15% CO₂. Exp I: Inhibition of PMd^CCK-projecting mPFC neurons during the escape-inducing assay period significantly decreased both escape velocity and the number of jumps. Exp II: Inhibition of PMd^CCK-projecting mPFC neurons during the conditioning period, the mice did not show exaggerated flight behavior in CO₂ assays (right). (Saline, n = 8 mice; CNO, n = 8 mice; Student t-test, ***p < 0.001 ns p > 0.05). g Model of a tripartite mPFC/VTg^PV → PMd^CCK synapses that utilizes eCB signal for heterosynaptic plasticity to control threat history-driven escape adaptation. Data are presented as means ± SEM. See also Supplementary Fig. 6. Source data are provided as a Source Data file. CNO, Clozapine-N-oxide; Exp I, experiment I; Exp II, experiment II; GABAR, gamma-aminobutyric acid receptor, GABA, gamma-aminobutyric acid.