Endogenous Neurosteroid Hormone Production and Early Oligodendricyte Development

The field of neuroendocrinology grew immensely with the realization that steroid hormone production is not confined to the adrenal and reproductive glands but also occurs in the central nervous system (CNS). Steroids synthesized de novo in the brain and spinal cord are referred to as neurosteroid or neuroactive hormones and encompass estrogens, androgens, glucocorticoids, and mineralocorticoids. Though all substrates and enzymes required for neurosteroid biosynthesis exhibit CNS expression, a thorough comprehension of their functionality is lacking. In addition to mediating stress responses, neurosteroids influence CNS-specific processes known to regulate neural development and pathology. Multiple sclerosis (MS), a debilitating neurodegenerative disorder classified by rampant demyelination, exemplifies the neuroendocrine crosstalk facilitated by CNS-resident steroids. Local steroid production from cholesterol, which also happens to be the primary lipid component of myelin sheaths, is critical to myelin repair. Progesterone in particular is implicated in expediting remyelination following demyelinating insults in animal models via an unknown mechanism. Despite the established effect of progesterone on myelin regeneration, its impact on early myelinogenesis remains unclear. This observation inspired the work presented here, in which I investigated a potential role for progesterone in embryonic oligodendrocyte development. Applying the synthetic progestin Nestorone to mouse cerebellar slice cultures, I found that progesterone stimulates the expression of the mature myelin protein, myelin basic protein. Curious as to whether this phenomenon mirrors progesterone-induced remyelination at the molecular level, I implemented the same experimental system in mice genetically altered to delete expression of the nuclear progesterone receptor. Unexpectedly, removal of this receptor from cerebellar slices led not only to an increase in myelin basic protein expression but more robust oligodendrocyte maturation into myelinating cells actively extending processes to axons and participating in fiber formation. The fact that this surprising effect could not be mediated by the nuclear progesterone receptor prompted me to examine potential caveats to studying individual hormones like progesterone in isolation