Fig. 5: Optogenetic modulation of the projection terminals in the dorsomedial hypothalamus (DMH) and lateral habenula (LHb) of A_2AR-containing neurons in the lateral septum (LS) influences depressive-like behaviors.

a–d Schematic representation of the optogenetic activation of the LS-A_2AR⁺ → DMH terminals (a). Optogenetic activation of LS-DMH projection terminals of A_2AR-containing neurons increased immobility in the tail suspension test (TST) (n = 9 and 7 mice per group for EYFP and ChR2, respectively, Unpaired t test, p = 0.0002, t(14)=5.041) (b), without altering the total distance traveled (n = 9 and 7 mice per group for EYFP and ChR2, respectively, Unpaired t test, p = 0.7847, t(14)=0.2785) and the time spent in the center (n = 9 and 7 mice per group for EYFP and ChR2, respectively, Unpaired t test, p = 0.6503, t(14)=0.4633) in the open field test (OFT) (c, d). e–h Schematic representation of the optogenetic activation of the LS-A_2AR⁺ →LHb terminals (e). Optogenetic activation of LS-LHb projection terminals increased immobility in TST (n = 13 mice/group, Mann-Whitney test, p = 0.0441, U = 45) (f), without altering the total distance traveled (n = 13 mice/group, Mann–Whitney test, p = 0.5788, U = 73) and the time spent in the center (n = 13 mice/group, Mann–Whitney test, p = 0.4714, U = 70) in the OFT (g, h). i–l Schematic representation of the optogenetic inhibition of the LS-A_2AR-DMH terminals (i). Optogenetic inhibition of the LS-A_2AR⁺ →DMH projections reduced the immobility time in the TST (n = 10 and 13 per group for EYFP and eNpHR3.0, respectively, Unpaired t test, p = 0.0238, t(21) = 2.437) (j), without altering the total distance traveled (n = 10 and 13 per group for EYFP and eNpHR3.0, respectively, Unpaired t test, p = 0.0947, t(21) = 1.750) and the time spent in the center (n = 10 and 13 per group for EYFP and eNpHR3.0, respectively, Unpaired t test, p = 0.5013, t(21) = 0.6843) in the OFT (k, l). m–p Schematic representation of the optogenetic inhibition of the LS-A_2AR-LHb terminals (m). Optogenetic inhibition of the  LS-A_2AR⁺ →LHb projections reduced the immobility time in the TST (10 and 11 per group for EYFP and eNpHR3.0, respectively, Unpaired t test, p = 0.0418, t(19) = 2.183) (n), without affecting the total distance traveled (n = 10 and 11 per group for EYFP and eNpHR3.0, respectively, Unpaired t test, p = 0.4878, t(17) = 0.7093) or the time spent in the central area of the OFT (n = 10 and 11 per group for EYFP and eNpHR3.0, respectively, Unpaired t test, p = 0.3394, t(17) = 0.9830) (o, p). Data were shown as mean ± SEM. *p < 0.05, ***p < 0.001; n.s., no significant difference. Source data are provided as a Source Data file.