Hypoxic Preconditioning Modulates BDNF Signaling to Alleviate Depression-like Behaviors in Mice and Its Whole Transcriptome Sequencing Analysis

Depression, a neurological disorder triggered by stressful stimuli such as hypoxia, is associated with high morbidity and mortality. Hypoxic preconditioning (HPC) is an endogenous mechanism that has been used in recent research to upregulate BDNF, a marker of depression, to elicit neuroprotective effects. However, the mechanisms by which HPC protects against depression remain poorly understood. Therefore, this study aimed to investigate the effects of HPC on depressive behaviors via BDNF signaling. Initially, ICR mice were subjected to HPC, followed by the establishment of a 24-hour restraint stress model to mimic depressive behaviors. Subsequent analysis focused on changes in depressive behaviors, biochemical markers, and the levels of BDNF and its ability to modulate synaptic structure and neurogenesis. Furthermore, whole transcriptome sequencing was conducted. The results indicated that HPC relieved characteristic depressive behaviors in restraint stress model mice, regulated neurotransmitter levels, elevated antioxidant capacity, and promoted BDNF signaling in the hippocampus. PSD-95 expression, the number and complexity of neuronal dendritic spines, and hippocampal neurogenesis in model mice were increased via HPC. Restraint stress regulated 373 DElncRNAs, 166 DEcircRNAs, 29 DEmiRNAs and 1235 DEmRNAs, which were also modulated by HPC. The ceRNA networks were constructed on the basis of these DERNAs. Functional enrichment analysis revealed that these genes are related to synapses, neurogenesis and neurotrophin signaling. These results suggested that HPC upregulated BDNF and activated BDNF/PLCγ/CREB signaling to alleviate synaptic deficits and promote hippocampal neurogenesis, ultimately ameliorating depressive behaviors in mice. The identification of various mRNAs and ncRNAs and their constituent ceRNAs provides theoretical guidance for the clinical treatment of depression with HPC.