OBJECTIVE The receptor-tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile.In the present study,we investigate the potential role of endothelial ErbB4 receptor signaling in the brain. METHODS ErbB4 conditional KO mice were generated by a lox P/Cre strategy. The experimenter conducting the experimentsand scoring the behavior was blinded to the genotype of the mice. Open field test,Y-maze and novel-object exploration test,novel object recognition task,step-through passive avoidance task,Morris water maze and memory reconsolidation task were carried out in WT and Cdh5-Cre; ErbB4~(loxP/loxP)mice. A high-resolution micro PET/CT scanner was used for brain metabolism imaging. RESULTS Here,we show that Cdh5Cre; ErbB4~(f/f) mice have lower levels ofexploration activity as measured by these particular behavior tests. However,our data indicate that conditional knockout of ErbB4 in endothelial cells did not impair working memory,memory acquisition,retrieval,and reconsolidation in mice. Furthermore,~(18)F-FDG-uptake was reduced in the Cdh5Cre; ErbB4~(f/f) mice as revealed by the significantly decreased SUVs in compared with the WT mice. Consistently,the immunoblot data demonstrate the downregulation of brain Glut1,phosphoULK1(Ser555) and TIGAR in the endothelial ErbB4 conditional knockout mice. Collectively,the endothelial ErbB4 deletion induced impairment in exploratory activity in adult mice,which may be due to the decreased brain energy metabolism. CONCLUSION Our study provides insight into the potential pathophysiological mechanisms of endothelial ErbB 4 and therapeutic strategies for neurological disorders. OBJECTIVE The receptor-tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile. In the present study, we investigate the potential role of endothelial ErbB4 receptor signaling in the brain. METHODS ErbB4 conditional KO mice were generated by a lox P / Cre strategy. The experimenter conducting the experiments and scoring the behavior was blinded to the genotype of the mice. Open field test, Y-maze and novel-object exploration test, novel object recognition task, step-through passive avoidance task, Morris water maze A high-resolution micro PET / CT scanner was used for brain metabolism imaging. RESULTS Here, we show that Cdh5Cre; ErbB4 ~ ( f / f) mice have lower levels ofexploration activity as measured by these particular behavior tests. However, our data indicates that conditional knockout of ErbB4 in endothelial cells did not impair working memory, memory acquisition, re ErbB4 ~ (f / f) mice as revealed by the significantly decreased SUVs in compared with the WT mice. Consistently, the immunoblot data demonstrated the downregulation of brain Glut1, phosphoULK1 (Ser555) and TIGAR in the endothelial ErbB4 conditional knockout mice. Collectively, the endothelial ErbB4 deletion induced impairment in exploratory activity in adult mice, which may be due to the decreased brain energy metabolism. CONCLUSION Our study provides insight into the potential pathophysiological mechanisms of endothelial ErbB 4 and therapeutic strategies for neurological disorders.