Myelin plasticity in mouse resilience and susceptibility to psychosocial stress : implications for anxiety disorders
Year: 2021
Type: dissertation
Abstract: Psychiatric disorders are very common, with anxiety disorders being the most prevalent (16 % lifetime prevalence). While moderately heritable, their incidence is also strongly influenced by environmental risk factors, chiefly psychosocial stress. However, our knowledge of how, in neurobiological terms, these disorders arise is lacking, slowing down the development of efficient treatments. The aim of this thesis was firstly to identify which brain regions are recruited by chronic psychosocial stress, by using mice as model organisms. To model psychosocial stress we used chronic social defeat stress (CSDS), which involves short confrontations between intruder and resident-aggressor male mice, repeated daily for 10 consecutive days. A week after stress exposure C57BL/6NCrl (B6) mice had a higher number of cells expressing ΔFOSB, a marker of repeated neural activation, in several stress-related brain regions. These included the bed nucleus of the stria terminalis (BNST) and ventral hippocampus (vHPC). We also found significant correlations in the numbers of ΔFOSB+ cells between medial prefrontal cortex (mPFC) subregions (infralimbic and prelimbic cortices) and the vHPC of stress-exposed but not non-stressed control mice. Our second aim was to discover, by using unbiased RNA-sequencing (RNA-seq) of stress-related brain regions (the mPFC and vHPC), biological pathways perturbed by CSDS. Additionally, we used mice from two inbred strains, representing different levels of baseline anxiety-like behaviour: B6 (low-anxiety) and DBA/2NCrl (D2, high-anxiety). This enabled us to explore how genetic background modulates the response to stress. While some mice exposed to CSDS show social avoidance (called stress-susceptibility), others are behaviourally similar to non-stressed control mice. This phenomenon, known as resilience, is also observed in humans. We found that B6 and D2 mice showed vastly different behavioural responses to CSDS. B6 mice displayed a predominantly resilient phenotype (66.1 % of CSDS-exposed mice across several cohorts), while the majority (85.0 %) of D2 mice were susceptible. Pathway analysis of RNA-seq data suggested that differentially expressed genes (DEGs) were enriched in genes related to oligodendrocytes (OLGs), the myelin-producing cells of the CNS. For example, genes encoding myelin components were downregulated in the mPFC and vHPC of B6 susceptible mice compared to controls. Myelin is a lipid-rich ensheathment around axons, and it enables both fast nerve conduction and adjustment thereof via myelin plasticity. We followed up the gene expression findings with a structural analysis of myelinated axons using transmission electron microscopy (TEM). We found that in the vHPC, B6 susceptible mice had thinner myelin sheaths than controls. In the mPFC, B6 resilient mice had thicker myelin than controls, restricted to axons with small diameters. By contrast, D2 resilient mice had thinner myelin in this region than susceptible mice, indicating potential bidirectional dynamics of myelin plasticity in resilience. Lastly, we performed RNA-seq of enriched OLGs and myelin from the mPFC. The aim of this experiment was to identify pathways affected by CSDS specifically in these cells and in myelin. Additionally, we used this dataset to identify genes (24.8 % of all genes and 18.8 % of expressed micro-RNAs [miRNAs]) which were enriched in the myelin fraction compared to OLGs in nonstressed control mice. This suggests selective transport of certain mRNAs and microRNAs into the myelin sheath, potentially for local regulation. When comparing CSDS-exposed mice and controls, we found lower expression of myelin-related genes in B6 susceptible, D2 susceptible and D2 resilient mice compared to same-strain controls. In the B6 strain this was found in the myelin fraction, while in the D2 strain these genes were differentially expressed only in OLGs. Ingenuity Pathway Analysis (IPA) predicted TCF7L2, a transcription factor, to be an upstream regulator of these DEGs. In summary, we showed involvement of a broad but selective network of brain regions in CSDS. Genetic background had a large influence on the response to stress, highlighting a source of individual variation with implications for understanding human stress-resilience and -susceptibility. This moderation by genetic background was also seen at the level of gene expression in the brain. Finally, our findings suggest that myelin plasticity is an important part of the chronic response to stress. Future work will identify by which mechanisms stress influences myelin, and how this could be best harnessed for improving therapeutic strategies.
Source: Työväentutkimus Vuosikirja
Author: Mikaela A. Laine
Language: English
Subfield: Behavioral Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3123832777