Post-traumatic stress disorder (PTSD) is a mental disorder caused by suddenly experiencing or witnessing psychologically traumatic or catastrophic events. The core symptoms of PTSD are flashback of fear/trauma memory, avoidance of traumatic stimulation, increased alertness, anxiety and irritability, which seriously affect the life quality of patients. Fear generalization, as the most critical phenotype of PTSD (Kida, 2019; Richter-Levin et al., 2019; Wang et al., 2022) was likely caused by structural and functional changes of specific brain regions, especially the hippocampus (Li et al., 2021; Yanpallewar et al., 2022). Importantly, PTSD patients show atrophy of hippocampal formation (Apfel et al., 2011). Further microscopic studies showed that there were apparent pathological changes, as well as expression changes of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) GluA1 and N-methyl-D-aspartate receptor (NMDAR) GluN2A and GluN2B in the hippocampus of mice with PTSD (Yang et al., 2022, Yang et al., 2023; Zhang et al., 2021).

Mitochondria participate in cognition processing by maintaining synaptic plasticity (Rossi and Pekkurnaz, 2019). The structural abnormalities of mitochondria were observable in postmortem human brain samples of PTSD subjects (Mellon et al., 2019; Su et al., 2008; Zhang et al., 2015). Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1α) is one of the main molecules for coordinating mitochondrial biogenesis, cell respiration and energy metabolism (Jesse et al., 2017), maintaining neuronal survival and synaptic transmission (Panes et al., 2022; Zolezzi et al., 2017). The activation of PGC-1α requires both adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and sirtuin1 (SIRT1) acetylation (Kaarniranta et al., 2018). However, it is still unknown whether regulation of PGC-1α signal is useful for PTSD treatment.

The theory of traditional Chinese medicine (TCM) ascribes PTSD to emotional disease. Kaixinsan (KXS) is documented as a classic TCM prescription for the treatment of emotional disorders (Feng et al., 2016; Zhou et al., 2020), and contains Ginseng Radix Et Rhizoma (Panax ginseng C. A. Mey.), Polygalae Radix (Polygala tenuifolia Willd.), Poria [Poria cocos (Schw.) Wolf], and Acori Tatarinowii Rhizoma (Acorus tatarinowii Schott) (The names of all plants have been confirmed in www.worldfloraonline.org). Anshen Dingzhi prescription (ADP), which was first published in the masterpiece of TCM in the Qing Dynasty, “Yi Xue Xin Wu" (1732 CE), is one of the representative derived prescriptions of KXS. Compared with the original prescription, ADP adds two other TCM medicines, i.e. Poria cum radix pini (Poria cocos (Schw.) and dragon tooth (Dens Draconis). Based on TCM theory (Shaojie et al., 2021), clinical practice (Dufeng, 2017; Weijun, 2016; Xue et al., 2019) and experiment evidences (Yang, S. et al., 2022; Zhang et al., 2023), ADP is more suitable for PTSD treatment. However, the underlying mechanism of ADP against fear memory generalization in PTSD is still unclear.

In this study, the fingerprint of ADP was established by ultra-performance liquid chromatography (UPLC), and single prolonged stress (SPS) mouse model was used to evaluate the effect of ADP on PTSD-like behavior, and to explore the possible mechanism of ADP from the perspective of hippocampal mitochondrial dysfunction, so as to provide experimental basis for the application of ADP in the treatment of panic-related disorders.