Sodium aescinate improve behavioral performance by inhibiting dorsal raphe nucleus NLRP3 inflammasome in Post-traumatic stress disorder Rat Model.

Growing evidence suggest that NLRP3 inflammasome activation in hippocampus and amygdala is involved in the pathophysiology of PTSD. Our previous studies have demonstrated that apoptosis of dorsal raphe nucleus (DRN) contributes to the pathological progression of PTSD. Recent studies by others have shown that in brain injury sodium aescinate (SA) has a protective effect on neurons by inhibiting inflammatory response pathways, thereby relieving symptoms. Here, we extend the therapeutic effects of SA to PTSD rats. We found that PTSD was associated with significant activation of the NLRP3 inflammasome in DRN, whereas administration of SA significantly inhibited DRN NLRP3 inflammasome activation and reduced DRN apoptosis level. SA also improved learning and memory ability and reduced anxiety and depression level in PTSD rats. In addition, NLRP3 inflammasome activation in DRN of PTSD rats impaired mitochondria function by inhibiting ATP synthesis and increasing ROS production, whereas SA can effectively reverse the pathological progression of mitochondria. We recommend SA as a new candidate for the pharmacological treatment of PTSD.

Activated cell-cycle CDK4/CyclinD1-pRB-E2F1 signaling pathway is involved in the apoptosis of dorsal raphe nucleus in the rat model of PTSD.

Dysregulation of the dorsal raphe nucleus (DRN) has been revealed to contribute to cognitive and arousal impairments associated with post-traumatic stress disorder (PTSD) in an animal model. In our research an acute exposure to single prolonged stress (SPS) was used to establish PTSD rat model and the effects related to cell-cycle signaling pathway in DRN were examined. Apoptosis in DRN was detected by TUNEL staining, showing that DRN apoptosis number was sharply increased after SPS. SPS triggered cell-cycle CDK4/CyclinD1-pRB-E2F1 signal pathway. Treatment with CDK4 inhibitor Abemaciclib successfully attenuated the DRN apoptosis and rescued decreased spatial learning and memory abilities in SPS rats, indicating that activation of CDK4/CyclinD1-pRB-E2F1 pathway was involved in DRN apoptosis, which may be one of the pathogenesis for PTSD.

Enhanced apoptosis and decreased ampa receptors are involved in deficit in fear memory in rin1 knockout rats.

BACKGROUND: Ras and Rab interactor 1 (Rin1) is predominantly expressed in memory-related brain regions, and has been reported to play an important role in fear memory. Increased expression of Rin1 in an animal model of posttraumatic stress disorder (PTSD) has been associated with enhanced acquisition of fear memories, but the exact mechanism of Rin1 in memory regulation are not clear. METHODS: Here, we used Rin1-knockout rats to examine the effect of Rin1 on fear memories by fear conditional test and the molecular mechanisms that regulate these effects by immunofluorescence, western blotting and TUNEL. RESULTS: Our results show that Rin1-knockout rats have a deficit in formation and extinction of Auditory fear memories. Lack of Rin1 results in enhanced apoptosis in the hippocampus through a pathway related to the mitochondria rather than the endoplasmic reticulum-related pathway. Importantly, the lack of Rin1 induces a decrease in α-amino-3­hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) found in the cytoplasm, but not in those found in the membrane. Expression of CaMKII (which is important for insertion of cytoplasmic AMPAR into the membrane) and stargazin (which is important for immobilization of AMPAR in the membrane) was not changed. The lack of Rin1 also induced changes in AMPAR distribution, from diffuse spread in the cells to clusters around the edge of the cell. Additionally, clustered AMPAR distribution showed a high degree of overlap with actin distribution. CONCLUSION: These findings indicate that Rin1 affects not only apoptosis, but also the concentration and distribution pattern of AMPAR, which are important in the formation and extinction of fear memory.