A critical period for social experience-dependent oligodendrocyte maturation and myelination

Abstract

Early social isolation results in adult behavioral and cognitive dysfunction that correlates with white matter alterations. However, how social deprivation influences myelination and the significance of these myelin defects in the adult remained undefined. We show that mice isolated for 2 weeks immediately after weaning have alterations in prefrontal cortex function and myelination that do not recover with reintroduction into a social environment. These alterations, which occur only during this critical period, are phenocopied by loss of oligodendrocyte ErbB3 receptors, and social isolation leads to reduced expression of the ErbB3 ligand neuregulin-1. These findings indicate that social experience regulates prefrontal cortex myelination through neuregulin-1/ErbB3 signaling and that this is essential for normal cognitive function, thus providing a cellular and molecular context to understand the consequences of social isolation.

Fig. 1

PFC-dependent behaviors and mPFC oligodendrocytes are altered by juvenile isolation. (A and B) Mice reared in isolation starting at P21 (IS), by P50 show alterations in social interactions (A) and working memory (B) compared with mice in regular (RE) or enriched environment (EE) (n = 16 mice per group). (C to G) Rearing environment does not influence mPFC oligodendrocyte density by P65 (n = 3 mice per group), but social isolation results in mPFC oligodendrocytes with simpler morphology (cells per condition: IS = 12, RE = 16, EE = 16). (H) P21 to P65 isolation reduces mPFC MBP and MAG expression. AU = arbitrary units; (mice per group: IS = 8, RE = 8, EE = 4). (I to J) P21 to P65 isolation leads to reduced mPFC myelin thickness (n = 3 per group) without changes in axon diameters (450 axons per group). *P < 0.05, **P < 0.01, ***P < 0.001. Error bars, SEM.

Fig. 2

The effects of social isolation on mPFC oligodendrocytes and PFC-dependent behaviors occur only during a critical period and are not reversed by reintroduction to a social environment. (A to E) mPFC oligodendrocytes show morphological alterations in mice isolated P21 to P35 and then returned to regular environment until P65 (IS-RE), but not in mice housed in regular environment until P35 and isolated thereafter (RE-IS). Early social isolation does not affect oligodendrocyte density (n = 3 mice per group), but does alter morphology (cells per group: RE = 16, RE-IS = 11, IS-RE = 14). (F) IS-RE mice showed reductions in mPFC MBP and MAG expression (n = 8 mice per group) and alterations in (G) sociability and (H) working memory (n = 16 mice per group). *P < 0.05, **P < 0.01, ***P < 0.001. Error bars, SEM.

Fig. 3

Loss of ErbB3 signaling in oligodendrocytes during the critical period for myelination mimics the effects of social isolation. (A to D) When Cre-mediated ErbB3 knockdown in oligodendrocytes begins at P19 (Cre+), by P65 mice have (A) reduced mPFC MBP and MAG expression (n = 7 per group); (B) reduced myelin thickness (Cre−; n = 3, Cre+; n = 4), (C) altered sociability, and (D) altered working memory (Cre−; n = 15, Cre+; n = 14). (E to H) No effects were observed when tamoxifen was injected starting at P36 (mRNA measurement: Cre−; n = 4, Cre+; n = 5; myelin thickness: n = 3 for, behavioral tests: Cre−; n = 13, Cre+; n = 12). *P < 0.05, **P < 0.01, ***P < 0.001. Error bars, SEM.

Fig. 4

Social isolation alters mPFC type III NRG1 expression. (A and B) Isolation from P21 to P35 (IS) did not change mPFC expression levels of ErbB2, ErbB3, and ErbB4 but reduced NRG1 mRNA levels. (C) Isoform specific QRT-PCR showed that the effect of isolation was limited to type III NRG1 (n = 8 per group). *P < 0.05. Error bars, SEM.