Steroids and the brain: 50 years of research, conceptual shifts and the ascent of non-classical and membrane-initiated actions

Abstract

This brief commentary reviews key steps in the history of steroid endocrinology that have resulted in important conceptual shifts. Our understanding of the "Fast Effects of Steroids" now reflect substantial progress, including the major concept that steroids act rapidly on a variety of physiological and behavioral responses, via mechanisms that are too fast to be fully accounted for by classical receptor-dependent regulation of gene transcription. Several so-called 'non-classical' mechanisms have been identified and include binding to membrane receptors and regulating non genomic signaling cascades. We survey the discovery of steroids, the initial characterization of their intracellular receptors, key progress in the understanding of the genomic effects of steroids and then the progressive discovery of the rapid non-classical and membrane-initiated actions of steroids. Foundational discoveries about brain steroid synthesis in neural processes and terminals has converged with emerging evidence for the rapid actions of steroids on brain and behavior. Had the rapid effects of steroids in the central nervous system been discovered first, these molecules would likely now be considered as a class of neurotransmitter.

Selective activation of estrogen receptors, ERα and GPER-1, rapidly decreases food intake in female rats

“…Ligand-bound, extra-nuclear ERs promote rapid alterations in cell signaling by interacting with effector proteins that activate kinase cascades and other second messenger systems. As a result, extra-nuclear ERs transduce estradiol signals into more rapid changes in cellular activity, and thus behavior, than the canonical nuclear ERs, which require hours to days to manifest a change in behavior (Balthazart et al, 2018). It should be noted, however, that extra-nuclear ER-initiated signaling can also affect gene expression via targeted interactions with downstream transcription factors (Vasudevan et al, 2005).…”

Neuroestrogens rapidly shape auditory circuits to support communication learning and perception: Evidence from songbirds

“…Estrogens can be rapidly synthesized within sensory circuits to act as neuromodulators Estrogens were classically thought to be secreted exclusively from the gonads. However, it is now clear that estrogens and other steroid hormones are also synthesized within the brain (Balthazart et al, 2018;London, 2016). Initial evidence for brain-derived estrogens (neuroestrogens) arose from the discovery of brain aromatase expression in multiple vertebrate species.…”

“…More recently, rapid actions of estrogens have also been found to act through a G-protein coupled estrogen receptor, GPER1 (formerly the orphaned 'GPR30') (Barton et al, 2017;Rudolph et al, 2016;Srivastava et al, 2013). The emergent understanding of these many mechanisms for steroid actions were presented in a recent review previewing the current Special Issue (Balthazart et al, 2018). Below, we describe the contribution of recent work in songbirds testing the role of rapid neuroestrogen signaling in shaping sensory processing, and place this work in a broader context.…”

De Novo Synthesized Estradiol: A Role in Modulating the Cerebellar Function

“…However, to produce detectable functional effects on the cellular level or the entire organism, the "classical" mode of action requires post-transcriptional events that take hours to days to occur [7,18,19]. In the brain, faster non-classical and often membrane-initiated mechanisms are observable within a few seconds (for some electrophysiological effects) to minutes after estradiol activated signaling involving intracellular cascades that may include several protein kinases and result in cytoplasmatic fluctuations of calcium concentration ( Figure 2) [19][20][21][22][23][24]. Some of these intracellular signalings could also affect the gene transcription through the so-called "indirect genetic 17β-HSD, 17beta-hydroxysteroid dehydrogenase; 3β-HSD 3beta-hydroxysteroid dehydrogenase D5-D4 isomerase; 5α-R, 5alfa-reductase; p450ARO, cytochrome P450 aromatase; 3α-HSD 3alfa-hydroxysteroid dehydrogenase D5-D4 isomerase.…”