Contribution of hippocampal BDNF/CREB signaling pathway and gut microbiota to emotional behavior impairment induced by chronic unpredictable mild stress during pregnancy in rats offspring

Numerous studies have shown that exposure to prenatal maternal stress (PMS) is associated with various psychopathological outcomes of offspring. The accumulating evidence linking bacteria in the gut and neurons in the brain (the microbiota-gut-brain axis) has been aconsensus; however, there is a lack of research on the involvement mechanism of gut microbiota in the regulation of the BDNF/CREB signaling pathway in the hippocampus of prenatally stressed offspring.

Prenatal maternal stress leads to high corticosterone status and abnormal emotion behavior of offspring, which may be associated with the abnormal BDNF/CREB signaling in hippocampus of offspring caused by the change of gut microbiota composition.

Pregnant rats were subjected to chronic unpredictable mild stress (CUMS) to establish the prenatal maternal stress model. The body weight was measured and the behavioral changes were recorded. Offspring were tested to determine emotional state using sucrose preference test (SPT), open-field test (OFT) and suspended tail test (STT). Gut microbiota was evaluated by sequencing the microbial 16S rRNA V3-V4 region, and the interactive analysis of bacterial community structure and diversity was carried out. The expression of hippocampal BDNF, TrkB and CREB mRNA and proteins were respectively measured using RT-PCR and Western blotting.

Prenatal maternal stress increased maternal plasma corticosterone levels, slowed maternal weight gain and caused depression-like behaviors (all P < 0.05). In offspring, prenatal maternal stress increased plasma corticosterone levels (P < 0.05) and emotional behavior changes (depression-like state) were observed (P < 0.05). The species abundance, diversity and composition of the offspring's gut microbiota changed after the maternal stress during pregnancy (P < 0.05). Compared with the control group's offspring, the species abundance of Lactobacillaceae was dropped, while the abundance of the Muribaculaceae species abundance was risen. Concurrent, changes in the hippocampal structure of the offspring and decreases in expression of BDNF/CREB signaling were noted (P < 0.05). Conclusions: Prenatal maternal stress leads to high corticosterone status and abnormal emotion behavior of offspring, which may be associated with the abnormal BDNF/CREB signaling in hippocampus of offspring caused by the change of gut microbiota composition.