IGFBP2 ATTENUATES RESTRAIN STRESS-INDUCED ANXIETY-LIKE BEHAVIOR VIA MODULATING THE MYELINATION AND SYNAPTIC PLASTICITY IN THE MEDIAL PREFRONTAL CORTEX

Abstract Background Exposure to stress markedly impairs the emotional functions of the highly evolved prefrontal association cortex (PFC). However, the underlying molecular mechanisms are poorly understood and limited options for treatment. Our previous study has found that the level of IGFBP2 in serum is related to stress resilience in individuals. Insulin-like growth factor binding protein 2 (IGFBP2), a neurotrophic factor, has been associated with neurite outgrowth and synaptic plasticity in central nervous system, enhancing stress resilience. Aim To examine the protective effects of IGFBP-2 on stress related disorder and explore its mechanism in SD rats and provide new targets for the intervention. Method Here, using a model of restrain stress (RS), we found that RS induces obvious anxiety-like behavior in the open field (OFT) and elevated plus maze test (EPM). RNA-sequencing was further applied to analyze the molecular mechanisms of mPFC following RS. Then we injected IGFBP2 by tail vein administrations to evaluate the anxiolytic effect of IGFBP2. Immunofluorescence and electron microscopy experiments were applied to verify the effect of IGFBP2 on RS-induced brain structural and functional abnormalities. Result RS enhances susceptibility to anxiety-like behavior in rats, with injured myelination in mPFC. Systemic delivery of IGFBP2 significantly attenuated anxiety-like behavior in OFT and EPM. Besides, IGFBP2 treatment rats showed enhanced myelination of axons compared to controls. To further confirm the pro-myelinating function of IGFBP2, lysolecithin-induced rat model of focal demyelination was used. Our results showed that IGFBP2 treatment was sufficient to attenuate anxiety-like behaviors and promote remyelination in lysolecithin-induced rat model of focal demyelination. In addition, the RS rats treated with IGFBP2 significant increase in the thickness and length of PSD. Discussion & Conclusion Collectively, our results demonstrate that the ultrastructural and functional changes of myelin and synaptic alterations in mPFC could be involved in stress-induced anxiety-like behavior. Notably, our study provides the first evidence that systemic delivery of IGFBP2 produced rapid-acting effects in rescuing the anxiety like behavior in RS rat models, which provides a critical rationale about IGFBP2 may has therapeutic potential for the treatment of anxiety disorders from a translational perspective clinically and deserves further study to provide more evidence for the treatment of anxiety disorder in the future.