The Effects of Chronic Stress on Brain Myelination in Humans and in Various Rodent Models

Antontseva, E. V.; Bondar, Natalia P.; Reshetnikov, Vasiliy V.; Merkulova, T. I.

doi:10.1016/j.neuroscience.2020.06.013

Cited by 45 publications

(17 citation statements)

References 117 publications

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“…Conversely, there is a high prevalence of depression in patients with multiple sclerosis, an autoimmune demyelinating disorder (21). Animal studies provide further support for this link between demyelination, oligodendrocyte dysfunction and depression-related behaviours (22,23). In particular, focal demyelination in the medial prefrontal cortex (mPFC) is sufficient to induce behaviors relevant to depression in mice (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

The Eph receptor A4 plays a role in demyelination and depression-related behavior

Chen

et al. 2022

Journal of Clinical Investigation

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Proper myelination of axons is crucial for normal sensory, motor and cognitive function. Abnormal myelination is seen in brain disorders such as major depressive disorder (MDD), but the molecular mechanisms connecting demyelination with the pathobiology remain largely unknown. We observed demyelination and synaptic deficits in mice exposed to either chronic unpredictable mild stress (CUMS) or lipopolysaccharide (LPS), two paradigms for inducing depression-like states.Pharmacologically restoring myelination normalized both synaptic deficits and depression-related behaviours. Furthermore, we found increased EphA4 expression in the excitatory neurons of CUMS mice and shRNA knockdown of EphA4 prevented demyelination and depression-like behaviours. These animal data are consistent with the decreased myelin basic protein and increased EphA4 levels we observed in postmortem brain from patients with MDD. Our results provide novel insights into the etiology of depressive symptoms in some patients and suggest that inhibiting EphA4 or promoting myelination could be a promising and novel strategy for treating depression.

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Section: Introductionmentioning

confidence: 99%

The Eph receptor A4 plays a role in demyelination and depression-related behavior

Chen

et al. 2022

Journal of Clinical Investigation

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“…Since MDD decreases myelin sheath thickness in PFC 24, 25 , we hypothesized that this effect might be mediated by FEDORA function within oligodendrocytes. To test our hypothesis, we expressed Oligo-FEDORA or Oligo-GFP in mPFC of mice of both sexes and performed electron microscopy analysis of myelin thickness.…”

Section: Resultsmentioning

confidence: 99%

The Long Noncoding RNA FEDORA is a Cell-Type- and Sex-Specific Regulator of Depression

Issler

Zee

Ramakrishnan

et al. 2021

Preprint

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Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify dramatic baseline sex differences in expression of long noncoding RNAs (lncRNAs) in human postmortem brain tissue that are profoundly lost in depression. One such lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and upregulated in several cortical regions of depressed females but not males. We found that virally-expressing FEDORA selectively either in neurons or in oligodendrocytes of prefrontal cortex promoted depression-like behavioral abnormalities in female mice only, changes associated with cell-type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic significance for depressed women. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

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“…In clinical studies, myelin has been reported to be involved in MDD [ 47 , 48 ]. Demyelination has also been reported to occur in various depression-like animal models in preclinical studies [ 49 , 50 ]. Liu et al [ 13 ] suggested that clemastine, a myelination-promoting drug, alleviates depression-like behaviors in socially isolated mice.…”

Section: Discussionmentioning

confidence: 99%

Exercise rather than fluoxetine promotes oligodendrocyte differentiation and myelination in the hippocampus in a male mouse model of depression

et al. 2021

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Although selective serotonin reuptake inhibitor (SSRI) systems have been meaningfully linked to the clinical phenomena of mood disorders, 15–35% of patients do not respond to multiple SSRI interventions or even experience an exacerbation of their condition. As we previously showed, both running exercise and fluoxetine reversed depression-like behavior. However, whether exercise reverses depression-like behavior more quickly than fluoxetine treatment and whether this rapid effect is achieved via the promotion of oligodendrocyte differentiation and/or myelination in the hippocampus was previously unknown. Sixty male C57BL/6 J mice were used in the present study. We subjected mice with unpredictable chronic stress (UCS) to a 4-week running exercise trial (UCS + RN) or intraperitoneally injected them with fluoxetine (UCS + FLX) to address these uncertainties. At the behavioral level, mice in the UCS + RN group consumed significantly more sugar water in the sucrose preference test (SPT) at the end of the 7th week than those in the UCS group, while those in the UCS + FLX group consumed significantly more sugar water than mice in the UCS group at the end of the 8th week. The unbiased stereological results and immunofluorescence analyses revealed that running exercise, and not fluoxetine treatment, increased the numbers of CC1+ and CC1+/Olig2+/BrdU+ oligodendrocytes in the CA1 subfield in depressed mice exposed to UCS. Moreover, running exercise rather than fluoxetine increased the level of myelin basic protein (MBP) and the G-ratio of myelinated nerve fibers in the CA1 subfield in the UCS mouse model. Unlike fluoxetine, exercise promoted hippocampal myelination and oligodendrocyte differentiation and thus has potential as a therapeutic strategy to reduce depression-like behaviors induced by UCS.

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The Effects of Chronic Stress on Brain Myelination in Humans and in Various Rodent Models

Cited by 45 publications

References 117 publications

The Eph receptor A4 plays a role in demyelination and depression-related behavior

The Eph receptor A4 plays a role in demyelination and depression-related behavior

The Long Noncoding RNA FEDORA is a Cell-Type- and Sex-Specific Regulator of Depression

Exercise rather than fluoxetine promotes oligodendrocyte differentiation and myelination in the hippocampus in a male mouse model of depression

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