Fig. 3: Bidirectional control of SST neurons bidirectionally modulates depression-related behavior.

a Injection of the NpHR3-GFP virus into the HBX of SST-CRE/Ai14 mice, in which Ail4 was expressed in SST neurons by crossing SST-CRE mice with CRE-dependent Ail4 reporters. b Representative images showing bilateral expression of NpHR3-GFP and fiber location in Ail4-labeled SST neurons (n = 8 mice). c–e Optogenetic inhibition (yellow: light on) of SST^NpHR3 neurons induces depression-like behaviors, based on the TST (c), the TBP (d), and the SIT (e). Data are presented as mean ± SEM (n = 8 mice per group, ON: ***p = 1.03 × 10⁻⁵ in (c), ON: **p = 1.57 × 10⁻⁴ in (d), ON: ***p = 3.87 × 10⁻⁷ in (e) two-way repeated measures ANOVA). f Illustration showing the injection of the ChR2-GFP virus into the HBX of SST-CRE mice and representative images showing the expression of ChR2-GFP in SST neurons (n = 8 mice). g, h Experimental design (g) and optogenetic activation of SST^ChR2GFP neurons validated by recording single-unit spikes in freely behaving mice (h), data are presented as mean ± SEM in (h). i–l Optogenetic activation (blue: light on) of SST^ChR2GFP neurons generates antidepressant action, based on the LDT (i), the EPM (j), the SIT (k), and the OFT (l) before (baseline), during (on), and after (off) light illumination. In this study, depression-like behaviors were induced by CMS. The non-CMS mice were used as controls. Data are presented as mean ± SEM (n = 8 mice per group, ON: CMS^GFP vs. CMS^ChR2 ***p = 1.48 × 10⁻⁸ in (i), ON: CMS^GFP vs. CMS^ChR2 ***p = 1.29 × 10⁻⁷ in (j), ON: CMS^GFP vs. CMS^ChR2 ***p = 6.53 × 10⁻⁹ in (k), ON: CMS^GFP vs. CMS^ChR2 ***p = 1.64 × 10⁻⁸ in (l), ns, no significant difference, two-way repeated measures ANOVA). TST: tail suspension test; SIT: social interaction test; CMS: chronic mild stress; EPM: elevated plus maze; OFT: open field test. Source data are provided as a Source Data file.