*3.1. Antidepressant E*ff*ects of PAPZ*

To investigate the effect of PAPZ on depressive-like behavior, we chose the chronic CORT model of depression, which has been widely used in depression-related research (Figure 1). Mice were administrated subcutaneously with CORT once daily for 21 consecutive days, and PAPZ were administered by oral gavage 30 minutes prior to the CORT injection. Behavioral tests were performed after the treatments had finished (Figure 1a). The chronic CORT injection resulted in a significant prolonged immobility time in the TST when compared with the control group (Figure 1b). The PAPZ+CORT treated group exhibited a significantly decreased immobility time compared with the model group, which suggested that PAPZ could protect against the CORT-induced depressive-like behavior in the TST test. An OFT was conducted to assess the influence of PAPZ on the locomotor activities of mice. PAPZ administration had no significant impact on the total distance and movement speed of mice spent in the zone in the OFT (Figure 1c,d).

**Figure 1.** PAPZ ameliorated depressive-like behavior induced by corticosterone (CORT) in mice. (**a**) Schematic representation of the treatment protocol. (**b**) The immobility time in the tail suspension test (TST). (**c**) Total distance travelled in the open field test (OFT). (**d**) Movement speed during bouts of walking in the OFT. Data from the CORT group and PAPZ+CORT group were normalized to the control group and data are expressed as mean ± SEM. \* *p* < 0.05, \*\* *p* < 0.01 represent significant differences. s.c.: sub-cutaneous.

#### *3.2. E*ff*ects of PAPZ on Learning and Memory Capacity*

We evaluated the effect of PAPZ on cognitive capacity in CORT-induced mice using the NOR test and learning, and memory ability using the MWM test, respectively (Figure 2). The discrimination index (DI), representing cognitive ability, was determined from the NOR task. CORT induced a significant decrease in the DI score for the novel object when compared with the control group. As expected, we found a significant increase in the DI score for the novel object in the PAPZ+CORT treated group when compared to the group treated with CORT alone. The DI score for the novel location in the CORT-treated group demonstrated a decreasing tendency, although there was no significant difference when compared with the control group (Figure 2a). Treatment with PAPZ significantly increased the DI score for the novel location when compared with the CORT group (Figure 2b). In the MWM test, latency refers to the time spent by the mouse to find the platform. There was a relative increasing tendency of latency in the chronic CORT-treated group when compared with the control group. PAZA treatment significantly decreased the latency when compared with the CORT-treated group, especially on the fifth and sixth day (Figure 2c). All these results indicated that PAPZ could ameliorate depressive-like behavior and improve cognitive capacity and learning ability in depressive-like mice induced by the chronic administration of CORT.

**Figure 2.** PAPZ ameliorated learning and memory impairment induced by CORT in mice. (**a**,**b**) The relative discrimination index (DI) for the novel object, (**a**) for novel location and (**b**) in the novel object recognition (NOR) test. (**c**) The total latency in the Morris water maze (MWM) test. Data from the CORT group and PAPZ+CORT group were normalized to the control group and data are expressed as mean ± SEM. \* *p* < 0.05 represents a significant difference.
