Fig. 5: Activation of the LHb input pathway at different ambient ketamine levels bidirectionally regulates the sustained antidepressant effects of ketamine.
From: Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb
a, Schematic of viral construct, viral injection in the LH and optic fibre implantation in the LHb of CRS mice. b, An example image showing bilateral viral injection sites in the LH (top), viral expression in axon terminals in the LHb and canular sites for optic fibre implantation (bottom). EP, entopeduncular nucleus. Scale bar, 200 μm. c, RTPA induced by constant 40 Hz light stimulation of the LH–LHb axon terminals. Left, representative heatmaps. Right, percentage of time spent in the light-stimulated chamber. d, Equation of the dynamic equilibrium for the ketamine–NMDAR interaction. e, When the ambient ketamine concentration ([Ket]) is lower than the Kd, the interaction between ketamine and NMDAR leads to more unbinding. f, Experimental paradigm of stimulating the LH–LHb at low ketamine concentrations to untrap ketamine. After CRS, RTPA was conducted to confirm the effectiveness of LH–LHb stimulation. One hour after a ketamine injection (intraperitoneal, 10 mg kg−1), stimulation was delivered to LH–LHb terminals when the brain concentration of ketamine has dropped to 0.23 μM. Electrophysiological recording or behavioural testing was conducted 23 h later. g,h, NMDAR-eEPSCs of LHb neurons (g) and behavioural effects (h) at 24 h after ketamine or saline injection from the experiment in f. i, When the ambient ketamine concentration is higher than the Kd, the interaction between ketamine and NMDAR leads to more binding. j, Experimental paradigm of stimulating the LH–LHb at high ketamine concentrations to block more NMDARs. Immediately after a ketamine injection (intraperitoneal, 5 mg kg−1), stimulation was delivered to LH–LHb terminals, when the brain concentration of ketamine is above 6 μM. Electrophysiological recording or behavioural testing was conducted 24 h later. k,l, NMDAR-eEPSCs of LHb neurons (k) and behavioural effects (l) at 24 h after ketamine or saline injection from the experiment in j. Error bars indicate the s.e.m. (see Supplementary Table 1 for statistical analyses and n numbers).
