Abstract
The medial prefrontal cortex (mPFC) plays a key role in top-down control of the brain’s stress axis, and its structure and function are particularly vulnerable to stress effects, which can lead to depression in humans and depressive-like states in animals. We tested whether chronic social defeat produces structural alterations in the mPFC in mice. We first performed a microarray analysis of mPFC gene expression changes induced by defeat, and biological pathway analysis revealed a dominant pattern of down-regulation of myelin-associated genes. Indeed, 69% of the most significantly down-regulated genes were myelin-related. The down regulation was confirmed by in situ hybridization histochemistry for two strongly down-regulated genes, myelin oligodendrocyte glycoprotein (Mog) and ermin (Ermn), and by immunohistochemistry for myelin basic protein. To test for stress-induced changes in myelin integrity, aurophosphate (Black Gold) myelin staining was performed on mPFC sections. Quantitative stereologic analysis showed reduced myelinated fiber length and density. Behavioral analysis confirmed that the 14-day social defeat sessions resulted in induction of depressive-like states measured in social interaction and light/dark tests. The combined data suggest that chronic social defeat induces molecular changes that reduce myelination of the prefrontal cortex, which may be an underlying basis for stress-induced depressive states.
Highlights
The medial prefrontal cortex plays a key role in top-down control of the brain’s stress axis, and its structure and function are vulnerable to stress effects, which can lead to depression in humans and depressive-like states in animals
We first used two behavioral tests to ensure that within-treatment groups were behaviorally homogeneous. 72 h prior to sample collection, we measured anxiety and sociability with the light/ dark (L/D) and social interaction (SI) tests, respectively; declines in these behaviors are maladaptive responses, and they occur coincidently with anxiety-like and depressive-like behaviors measured in open field, elevated zero maze, forced swim test, and tail suspension test[16,17,19,20,21]
The medial prefrontal cortex (mPFC) is a key structure involved with emotional regulation, and it has been associated with an inhibitory function on limbic areas activated by emotionally arousing stimuli and with a particular sensitivity to dysregulation by those stimuli[15]
Summary
The medial prefrontal cortex (mPFC) plays a key role in top-down control of the brain’s stress axis, and its structure and function are vulnerable to stress effects, which can lead to depression in humans and depressive-like states in animals. Brain-imaging studies in patients with mood and anxiety disorders provide evidence of volume and connectivity reductions in cortical brain regions[5,6,7,8] Such changes are hypothesized to lead to disruption of homeostatic mechanisms, resulting in destabilization and loss of synaptic connections in emotional/cognitive circuitry. We performed a microarray-based assay of gene expression in dissected mPFC brain tissue from homecage (HC) and chronic social defeat (CSD) mice to provide a snapshot of how this structure changes after chronic psychosocial stress. Stress-induced changes in the transcriptome were confirmed visually with fluorescent in-situ hybridization (FISH) histochemistry for two myelin-related genes, with a myelin stain, and with immunohistochemistry for myelin basic protein (MBP)
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