PT  - JOURNAL ARTICLE
AU  - Mikaela A. Laine
AU  - Kalevi Trontti
AU  - Zuzanna Misiewicz
AU  - Ewa Sokolowska
AU  - Natalia Kulesskaya
AU  - Aino Heikkinen
AU  - Suvi Saarnio
AU  - Ingrid Balcells
AU  - Pierre Ameslon
AU  - Dario Greco
AU  - Pirkko Mattila
AU  - Pekka Ellonen
AU  - Lars Paulin
AU  - Petri Auvinen
AU  - Eija Jokitalo
AU  - Iiris Hovatta
TI  - Genetic Control of Myelin Plasticity after Chronic Psychosocial Stress
AID  - 10.1523/ENEURO.0166-18.2018
DP  - 2018 Jul 02
TA  - eneuro
PG  - ENEURO.0166-18.2018
4099  - http://www.eneuro.org/content/early/2018/07/02/ENEURO.0166-18.2018.short
4100  - http://www.eneuro.org/content/early/2018/07/02/ENEURO.0166-18.2018.full
AB  - Anxiety disorders often manifest in genetically susceptible individuals after psychosocial stress, but the mechanisms underlying these gene-environment interactions are largely unknown. We used the chronic social defeat stress (CSDS) mouse model to study resilience and susceptibility to chronic psychosocial stress. We identified a strong genetic background effect in CSDS-induced social avoidance using four inbred mouse strains: 69% of C57BL/6NCrl (B6), 23% of BALB/cAnNCrl, 19% of 129S2/SvPasCrl, and 5% of DBA/2NCrl (D2) mice were stress-resilient. Furthermore, different inbred mouse strains responded differently to stress, suggesting they use distinct coping strategies. To identify biological pathways affected by CSDS, we used RNA-seq of three brain regions of two strains, B6 and D2: medial prefrontal cortex (mPFC), ventral hippocampus (vHPC), and bed nucleus of the stria terminalis. We discovered over-representation of oligodendrocyte-related genes in the differentially expressed gene population. Because oligodendrocytes myelinate axons, we measured myelin thickness and found significant region and strain-specific differences. For example, in resilient D2 mice mPFC axons had thinner myelin than controls, whereas susceptible B6 mice had thinner myelin than controls in the vHPC. Neither myelin-related gene expression in several other regions, nor corpus callosum thickness, differed between stressed and control animals. Our unbiased gene expression experiment suggests that myelin plasticity is a substantial response to chronic psychosocial stress, varies across brain regions, and is genetically controlled. Identification of genetic regulators of the myelin response will provide mechanistic insight into the molecular basis of stress-related diseases, such as anxiety disorders, a critical step in developing targeted therapy.Significance Statement Chronic psychosocial stress is a well-established risk factor for anxiety disorders, but the development of targets for therapeutic intervention is limited by ignorance of the underlying molecular and cellular mechanisms. We used inbred genetically defined mice to identify neurobiological pathways that underlie stress-induced social avoidance, a type of anxiety. We found genetically controlled differences in myelin-related gene expression in stress-exposed mice, with concurrent differences in myelin thickness, suggesting that myelin plasticity is a major stress response of the brain. The adaptive response to stress may increase or decrease myelin thickness, depending on the demands of the specific circuit. Our findings provide a foundation for the identification of specific genetic regulators of chronic stress-induced myelin plasticity.