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Review
. 2021 Apr 9:15:657693.
doi: 10.3389/fnins.2021.657693. eCollection 2021.

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

Rafiad Islam  1 , Arie Kaffman  1
Affiliations
Review

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

Rafiad Islam et al. Front Neurosci. .

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.

Keywords: animal models; early adversity; early life stress; myelin; non-human primates; rodents; translational research; white matter.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The basic myelin components. A single oligodendrocyte can myelinate several neighboring axons by forming internodal myelin sheaths that are interspaced with myelin free zones known as nodes of Ranvier. Compacted myelin (dark blue) increases nerve conduction and prevents axonal sprouting by expressing ligands such as Nogo A (no entry red signs), whereas uncompacted myelin (light blue) provides metabolic support to underlying axonal segment by expressing channels such as MCT1. Abbreviations: OL- mature oligodendrocyte, OPC- oligodendrocyte progenitor cell.
FIGURE 2
FIGURE 2
Adaptive myelination in adulthood. Environmental cues increase neuronal activity in specific circuits, leading to the release of ligands such as glutamate, adenosine and BDNF (small colored circles) that promote the expansion of existing internodes. In adult rodents, these ligands drive OPC proliferation and differentiation but this aspect of de novo myelination seems negligible in healthy adult humans. Adaptive myelination in adulthood increases network synchronization and improves performance in a variety of tasks. Myelinating agents such as Clemastine fumarate increase adaptive myelination while some forms of EA or prolonged social deprivation in adulthood impair it. EA, early adversity; OL, mature oligodendrocyte; OPC, oligodendrocyte progenitor cell.
FIGURE 3
FIGURE 3
Corpus callosum and myelin development. (A) Myelination in the corpus callosum proceeds from caudal to rostral to ensure sequential maturation of circuits that enhance attachment and escape behavior early in life. (B) OPCs are a large, heterogenous and somewhat redundant cell population that undergoes significant changes in composition during the first 10 days after birth. Emx2-OPC (red) populate the dorsal telencephalon, appear to be mammalian specific, and are highly responsive to demyelinating conditions. Gsh2-OPC (gray) are present in both the dorsal and ventral telencephalon. Both Emx-2 and Gsh2 OPC continue to be generated throughout life from the SVZ (red). OPCs, oligodendrocyte progenitor cells.
FIGURE 4
FIGURE 4
OPC differentiation and apoptosis are highly regulated by external signals. Nestin positive polypotent NSC differentiate into lineage specific OPC that give rise to pre-myelinating (P-OL) or undergo apoptosis. P-OL then differentiate into mature OL. These processes are tightly controlled by diffusible and non-diffusible molecules expressed by active or non-active axons. These instructive molecules can promote (black ↑) or inhibit (red ⊥) these processes by altering gene expression in these cells (shown as a box with matching color). Genes and proteins shown represent only a partial list of key molecules discussed in the text. For more comprehensive reviews see Mitew et al. (2014), Foster et al. (2019). NSC, polypotent neural stem cell; OPC, oligodendrocyte progenitor cells; P-OL, pre-myelinating oligodendrocytes; OL, mature oligodendrocytes.
FIGURE 5
FIGURE 5
Myelin promotes the selection of functional circuits during development. Environmental stimulation or deprivation early in life leads to changes in neuronal activity in the developing brain. Increased activation in appropriately connected functional units (neurons 1 & 3) but not in neurons 2 & 4 leads to preferential myelination, enhanced metabolic support, and axonal growth in neurons 1 & 3 at the expense of neuron 2. Neuron 4 undergoes axonal pruning commonly seen during a critical period of transcallosal-projection development and is irreversible later in life. Adaptive myelination coupled with axonal pruning promotes synchronization of functional circuits and maturation of network properties (e.g., increased global efficiency and reduced small-worldness) that improve cognition and perceptual accuracy. Exposure to EA interferes with different aspects of this process and can potentially be reversed by myelinating agents. EA, early adversity; OL, mature oligodendrocyte; OPC, oligodendrocyte progenitor cell; P-OL, pre-myelinating oligodendrocytes.
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