White-Matter Repair as a Novel Therapeutic Target for Early Adversity

Abstract

Early adversity (EA) impairs myelin development in a manner that persists later in life across diverse mammalian species including humans, non-human primates, and rodents. These observations, coupled with the highly conserved nature of myelin development suggest that animal models can provide important insights into the molecular mechanisms by which EA impairs myelin development later in life and the impact of these changes on network connectivity, cognition, and behavior. However, this area of translational research has received relatively little attention and no comprehensive review is currently available to address these issues. This is particularly important given some recent mechanistic studies in rodents and the availability of new agents to increase myelination. The goals of this review are to highlight the need for additional pre-clinical work in this area and to provide specific examples that demonstrate the potential of this work to generate novel therapeutic interventions that are highly needed.

Early adversity causes sex-specific deficits in perforant pathway connectivity and contextual memory in adolescent mice

“…Abnormal myelination is one of the most consistent findings in individuals exposed to early deprivation, with similar findings reported in nonhuman primates and rodents [ 82 ]. Only a few studies have examined the effects of LB on myelin development [ 47 , 83 ], and the mechanisms responsible for these changes are yet to be clarified.…”

“…4 ) suggests that other factors also contributed to reduced myelination. Since myelination is driven by neuronal activation [ 82 ], it is possible that the impoverished conditions associated with LB cause abnormally low levels of neuronal activation in perforant pathway terminals that further impair OPC differentiation. In addition, recent work has shown that LB reduces the expression of sodium channels in OPC located in the developing hippocampus [ 83 ].…”

White Matter Changes Following Chronic Restraint Stress and Neuromodulation: A Diffusion Magnetic Resonance Imaging Study in Young Male Rats

“…The combination of an increase in FC and myelination in the corpus callosum ( 78 ) reflects normal cerebral development in rats, and these changes typically continue well into adulthood (3–6 mo) but were impaired in sham and depression control animals. It is well established that exposure to early life stress alters WM development in humans, nonhuman primates, and rodents ( 79 ). In addition, abnormal myelination has been reported in human patients with depression and animal models of depression and anxiety-like behaviors ( 15 , 80 ).…”

Association of Outdoor Ambient Fine Particulate Matter With Intracellular White Matter Microstructural Properties Among Children

“… 14 Myelination and improved microstructural organization of white matter pathways continue throughout childhood and into young adulthood, ultimately allowing for improved signal transduction and communication between distal brain regions among cognitive and emotional systems. 15 , 16 , 17 Studies have found that air pollution is associated with smaller white matter surface area in children, 11 increases in myo-inositol, a brain metabolite involved in cell membrane and myelination, 18 and reduced fractional anisotropy (FA). 12 , 19 These studies 11 , 12 , 18 , 19 are primarily based on smaller, localized populations, and results may have limited generalizability.…”

“…The potential impingement on key neurodevelopmental processes by PM 2.5 exposure may cause lifelong health effects . Myelination and improved microstructural organization of white matter pathways continue throughout childhood and into young adulthood, ultimately allowing for improved signal transduction and communication between distal brain regions among cognitive and emotional systems . Studies have found that air pollution is associated with smaller white matter surface area in children, increases in myo-inositol, a brain metabolite involved in cell membrane and myelination, and reduced fractional anisotropy (FA) .…”