Heterogeneity and synaptic plasticity analysis of hippocampus based on db-/- mice induced diabetic encephalopathy

Abstract

Chronic hyperglycemia can cause changes in synaptic plasticity of hippocampal cells, which has accelerated the pathological process of cognitive dysfunction. However, the heterogeneity of the hippocampal cell populations under long term high glucose statement remains largely unknown. To mimic chronic hyperglycemia induced cognitive function deficit in vivo, db^-/- diabetic mice was selected and Novel Object Recognition(NOR) behavior tests were performed. Based on diabetic induced cognitive impairment(CI) animal model, single-cell RNA sequencing was performed in the hippocampus of CI group (21,379 cells) or control group (20,045 cells), and single cell RNA sequencing was applied, and then the single cell atlas of gene expression was profiled. The comprehensive analysis explicated 18 nerve cell clusters, including 9 distinct sub-clusters, More in-depth analysis of oligodendrocyte precursor cells(OPCs) showed five distinct OPCs sub-clusters including expressing marker gene Lingo2-OPCs, Kcnc1-OPCs, Sst-OPCs, Slc6a1-OPCs and Lhfpl3-OPCs, which seems to be able to proliferate, migrate, and finally differentiate into mature oligodendrocytes and produce myelin. To be noted, differentially expressed genes(DEGs) of the Sst-OPCs sub-cluster indicated that the genes participating in neuroactive ligand-receptor interaction, nervous system development and inflammatory process were up-regulated in diabetic induced cognitive impairment(DCI) groups compared to normal control groups. Integrating the data of neuroplasticity regulation, the 20th top-enriched biological process was associated with neuroplasticity regulation in CI groups compared to control groups. Among these neuroplasticity-related genes, the intersectional gene Sstr2 may play an important role in neuroplasticity regulation. Focused on neuroplasticity regulation and its related specific genes may provide potential new clues for the treatment of diabetes mellitus complicated with cognitive impairment. In summary, we showed the comprehensively transcriptional landscape of hippocampal cells in the db^-/- diabetic mice with cognitive dysfunction, distinctive cell sub-clusters and the gene expression characteristics were identified, and also their special functions were proposed, which may give new clues and potential targets for diagnosis and treatment of diabetic encephalopathy.

Keywords: Chronic hyperglycemia; Hippocampus; Neuroplasticity regulation; Oligodendrocyte precursor cells; ScRNA-seq.