CHRONIC PSYCHOSOCIAL STRESS IN MICE ALTERS BRAIN MYELINATION IN A GENETIC BACKGROUNDDEPENDENT MANNER

Chronic psychosocial stress is a well-established risk factor for anxiety disorders and major depression. Mechanisms by which chronic stress impacts susceptibility and resilience to psychiatric disorders are largely unknown. The Chronic Social Defeat Stress (CSDS) mouse model allows us to investigate resilience and susceptibility to chronic psychosocial stress, in a controlled manner not possible in human settings. It involves daily 5–10 minute confrontations of two conspecific male mice using the resident-intruder paradigm for 10 days. This naturalistic stress model leads to long-term plastic changes in the brain, and consequently the defeated mice show increased depression and anxiety-like behavior. Importantly, not all mice show the typical social avoidance phenotype after CSDS. The defeated animals can be divided into stress susceptible and resilient, allowing us to investigate mechanisms that make individuals resistant to behavioral effects of stress. To identify brain gene expression changes taking place after chronic psychosocial stress, we used CSDS, and carried out RNA-seq from Medial Prefrontal Cortex (mPFC) and Ventral Hippocampus (vHPC) of C57BL/6 (B6; a non-anxious inbred strain) and DBA/2 (D2; an anxious inbred strain) mice. To establish whether and how myelin thickness and structure are altered after stress, we carried out Transmission Electron Microscopy (TEM). The two mouse strains showed a distinct behavioral response to stress, as measured by the social avoidance test carried out after social defeat. 69% of the B6 mice but only 11% of D2 mice were resilient to stress, the remainder being susceptible. We discovered that the expression levels of several myelination-related genes differed substantially due to chronic stress in both brain regions, and ‘myelination’ pathway was over-represented in gene-set enrichment analysis. Using TEM we established that the B6 stress resilient mice had significantly thicker myelin of small diameter mPFC axons compared to the B6 control mice. In the vHPC susceptible B6 mice had thinner myelin compared to B6 control mice. D2 resilient mice had thinner myelin in both brain regions compared to controls or susceptible mice. Our findings suggest significant white matter plasticity in response to chronic psychosocial stress in mice. Such differences have previously been observed in response to early-life stress or social isolation in adult mice. Our results extend these previous findings to psychosocial stress, and demonstrate that the pattern of myelination differences is dependent on the genetic background and varies across brain regions.