Genetic Variation in CNS Myelination and Functional Brain Connectivity in Recombinant Inbred Mice

Abstract

Myelination greatly increases the speed of action potential propagation of neurons, thereby enhancing the efficacy of inter-neuronal communication and hence, potentially, optimizing the brain’s signal processing capability. The impact of genetic variation on the extent of axonal myelination and its consequences for brain functioning remain to be determined. Here we investigated this question using a genetic reference panel (GRP) of mouse BXD recombinant inbred (RI) strains, which partly model genetic diversity as observed in human populations, and which show substantial genetic differences in a variety of behaviors, including learning, memory and anxiety. We found coherent differences in the expression of myelin genes in brain tissue of RI strains of the BXD panel, with the largest differences in the hippocampus. The parental C57BL/6J (C57) and DBA/2J (DBA) strains were on opposite ends of the expression spectrum, with C57 showing higher myelin transcript expression compared with DBA. Our experiments showed accompanying differences between C57 and DBA in myelin protein composition, total myelin content, and white matter conduction velocity. Finally, the hippocampal myelin gene expression of the BXD strains correlated significantly with behavioral traits involving anxiety and/or activity. Taken together, our data indicate that genetic variation in myelin gene expression translates to differences observed in myelination, axonal conduction speed, and possibly in anxiety/activity related behaviors.

Adolescent binge ethanol impacts H3K36me3 regulation of synaptic genes

“…DBA/2J mice were used as they show a more robust acute response to binge ethanol than the more commonly used C57BL/6J strain -DBA/2J mice show increased sensitivity to ethanol in a loss of righting reflex test (Linsenbardt et al, 2009), as well as increased locomotor activity compared to C57/B6 mice (Phillips et al, 1994;Kerns et al, 2005). Importantly, this strain also shows a more prominent decrease in myelin gene expression (Kerns et al, 2005;Goudriaan et al, 2020) important to our model as myelin decreases have been widely shown in human studies of adolescent binge drinking (De Bellis et al, 2005;Medina et al, 2008;Pfefferbaum et al, 2018;El Marroun et al, 2021). Mice were housed 4/cage in same sex cages in an AALAC-accredited facility under 12-h light/dark cycles with food and water available ad libitum for the entire experiment.…”

Adolescent binge ethanol impacts H3K9me3-occupancy at synaptic genes and the regulation of oligodendrocyte development

“…DBA/2 J mice were used as they show a more robust acute response to binge ethanol than the commonly used C57BL/6 J strain—DBA/2 J mice show increased sensitivity to ethanol in a loss of righting reflex test, as well as increased locomotor activity compared to C57/B6 mice ( Phillips et al, 1994 ; Kerns et al, 2005 ). Importantly, this strain also shows a more prominent decrease in myelin gene expression ( Kerns et al, 2005 ; Goudriaan et al, 2020 )—important to our model as myelin decreases have been widely shown in human studies of adolescent binge drinking ( De Bellis et al, 2005 ; Medina et al, 2008 ; Pfefferbaum et al, 2018 ; El Marroun et al, 2021 ). Male and female DBA/2 J mice arrived from Jackson Laboratories to the Virginia Commonwealth University vivarium at postnatal day 19–21 (Bar Harbor, ME, United States) for Experiments 1 and 2.…”

Genetic background modulates the effect of glucocorticoids on proliferation, differentiation and myelin formation of oligodendrocyte lineage cells

“…Strain differences in myelination patterns have also been found in adult mouse brain. Hippocampal myelinated fibres of C57BL/6J mice have higher expression levels of myelin genes and proteins, greater size of myelinated fibres and higher conduction velocity compared with DBA/2J mice (Goudriaan et al, 2020), and similarly, B6 non‐stressed control mice from a CSDS experiment have higher expression levels of myelin‐related genes compared with D2 control mice (Laine et al, 2018). These data suggest that genetic background influences the intrinsic ability of OLs to mature and produce myelin, affecting myelination patterns and network function.…”