Hormonal Regulation of Oligodendrogenesis I: Effects across the Lifespan

Abstract

The brain’s capacity to respond to changing environments via hormonal signaling is critical to fine-tuned function. An emerging body of literature highlights a role for myelin plasticity as a prominent type of experience-dependent plasticity in the adult brain. Myelin plasticity is driven by oligodendrocytes (OLs) and their precursor cells (OPCs). OPC differentiation regulates the trajectory of myelin production throughout development, and importantly, OPCs maintain the ability to proliferate and generate new OLs throughout adulthood. The process of oligodendrogenesis, the creation of new OLs, can be dramatically influenced during early development and in adulthood by internal and environmental conditions such as hormones. Here, we review the current literature describing hormonal regulation of oligodendrogenesis within physiological conditions, focusing on several classes of hormones: steroid, peptide, and thyroid hormones. We discuss hormonal regulation at each stage of oligodendrogenesis and describe mechanisms of action, where known. Overall, the majority of hormones enhance oligodendrogenesis, increasing OPC differentiation and inducing maturation and myelin production in OLs. The mechanisms underlying these processes vary for each hormone but may ultimately converge upon common signaling pathways, mediated by specific receptors expressed across the OL lineage. However, not all of the mechanisms have been fully elucidated, and here, we note the remaining gaps in the literature, including the complex interactions between hormonal systems and with the immune system. In the companion manuscript in this issue, we discuss the implications of hormonal regulation of oligodendrogenesis for neurological and psychiatric disorders characterized by white matter loss. Ultimately, a better understanding of the fundamental mechanisms of hormonal regulation of oligodendrogenesis across the entire lifespan, especially in vivo, will progress both basic and translational research.

Hormonal Regulation of Oligodendrogenesis II: Implications for Myelin Repair

“…Steroids are hydrophobic molecules synthesized from cholesterol that have important actions within the CNS, including regulation of oligodendrogenesis [33]. For this review, we will focus on a subset of steroid hormones synthesized primarily in the adrenal cortex and gonads, namely, glucocorticoids (GCs) and sex hormones, which canonically act through nuclear receptor signaling [35,36].…”

“…For this review, we will focus on a subset of steroid hormones synthesized primarily in the adrenal cortex and gonads, namely, glucocorticoids (GCs) and sex hormones, which canonically act through nuclear receptor signaling [35,36]. As we describe in our companion review, steroid hormones act to increase OPC differentiation and enhance maturation/myelination of OLs under physiological conditions [33]. In line with their effects on oligodendrogenesis, stress hormones such as GCs, and sex hormones such as estrogens, progestogens, and androgens, are associated with MS and other myelin related diseases and may aid in some aspects of myelin repair [37][38][39].…”

“…This family includes endogenous cortisol (the primary GC for humans), corticosterone (the primary GC for rodents), and synthetic hormones such as dexamethasone (Dex). Like many steroid hormones, GCs enhance oligodendrogenesis in vitro and in vivo, specifically by enhancing differentiation of neural stem cells (NSCs) and OPCs, via activation of glucocorticoid receptors (GRs) [33,40], and ultimately increasing expression of myelin basic protein (MBP) [41,42]. However, prolonged exposure to corticosterone or Dex can reduce myelination, indicating the effects of GCs may depend on dosing and duration [43].…”

“…Oligodendrogenesis is regulated by numerous endogenous factors, including many different hormones (for a detailed review, see Reference [33]). In fact, MS, the most common demyelinating disorder, is almost three times more common in women than in men, suggesting that sex hormones may play a role in disease pathology [11].…”

“…In this review, we will explore how hormonal factors affect oligodendrogenesis within disease contexts. The accompanying review introduces the hormones discussed and explores the hormonal regulation of oligodendrogenesis under physiological conditions [33]. As in our companion review, we will restrict our discussion to the "classic" endocrine signaling molecules, which are typically released from a gland into circulation to act upon distant tissues.…”