Identification of TNR as a Potential Hippocampal Biomarker of Novelty Seeking Behavior with Integrated Quantitative...

Novelty-seeking (NS) refers to the tendency of humans and animals to explore novel and unfamiliar stimuli and environments. It is a core feature of Attention Deficit Hyperactivity Disorder (ADHD) and associated with multiple psychiatric disorders. Recent researches indicated that NS behavior has an effect on reward-related learning. The hippocampus is a core brain region linked to reward-related learning and memory. However, how the hippocampal proteome modulates NS behavior remain largely elusive. In current study, we identified 165 differentially expressed proteins in the hippocampus between high and low novelty response mice with mass-spectrometry-based proteomics. Among these proteins, the over-expression of Tenascin-R (TNR) in high novelty response mice was verified with Western Blot and Immunofluorescence imaging. Moreover, systematic genetic analysis based on the BXD strains showed the expression of TNR is genetically cis-regulation. Further, gene co-expression analysis revealed that TNR has a negative connection with the expression of dopamine receptor D2 (DRD2) (P = 0.003, r = -0.298). And the knockdown of TNR enhanced the expression of DRD2 in vitro. Finally, we constructed a correlation network to exhibit the links among TNR gene variant, expression of TNR and DRD2, and NS related behaviors. Our study provides a novel hippocampal biomarker with preliminary insights into its association with the dopaminergic synaptic pathway. ROC analysis further confirms TNR's robust discriminatory power for distinguishing novel open field behavior, a key NS - related phenotype, which may be a new strategy for diagnosis of NS-related traits.