The Journal of Neuroscience, November 9, 2016 • 36(45):11449–11458 • 11449 Mini-Symposium Actions of Steroids: New Neurotransmitters X Lauren M. Rudolph,1 XCharlotte A. Cornil,2 Melinda A. Mittelman-Smith,1 XJennifer R. Rainville,3 Luke Remage-Healey,4 XKevin Sinchak,5 and XPaul E. Micevych1 1Department of Neurobiology and Laboratory of Neuroendocrinology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California 90095, 2Behavioral Neuroendocrinology Group, GIGA Neurosciences, University of Lie`ge, 4000 Liege, Belgium, 3Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118, 4Department of Psychological and Brain Sciences, Center for Neuroendocrine Studies, University of Massachusetts, Amherst, Massachusetts 01003, and 5Department of Biological Sciences, California State University, Long Beach, Long Beach, California 90840 Over the past two decades, the classical understanding of steroid action has been updated to include rapid, membrane-initiated, neurotransmitter-like functions. While steroids were known to function on very short time spans to induce physiological and behavioral changes, the mechanisms by which these changes occur are now becoming more clear. In avian systems, rapid estradiol effects can be mediated via local alterations in aromatase activity, which precisely regulates the temporal and spatial availability of estrogens. Acute regulation of brain-derived estrogens has been shown to rapidly affect sensorimotor function and sexual motivation in birds. In rodents, estrogens and progesterone are critical for reproduction, including preovulatory events and female sexual receptivity. Membrane pro- gesterone receptor as well as classical progesterone receptor trafficked to the membrane mediate reproductive-related hypothalamic physiology, via second messenger systems with dopamine-induced cell signals. In addition to these relatively rapid actions, estrogen membrane-initiated signaling elicits changes in morphology. In the arcuate nucleus of the hypothalamus, these changes are needed for lordosis behavior. Recent evidence also demonstrates that membrane glucocorticoid receptor is present in numerous cell types and species, including mammals. Further, membrane glucocorticoid receptor influences glucocorticoid receptor translocation to the nucleus effecting transcriptional activity. The studies presented here underscore the evidence that steroids behave like neurotransmitters to regulate CNS functions. In the future, we hope to fully characterize steroid receptor-specific functions in the brain. Introduction 2006; Dewing et al., 2007; Saldanha et al., 2011; Remage-Healey, At one time, the actions of steroid hormones were thought to 2014). Here we discuss the ever-growing body of evidence detail- mediate physiological changes through changes in gene tran- ing nonclassical, neurotransmitter-like steroid hormone action scription over an extended time course. This incomplete picture across neural systems, species, and classes of steroids, and suggest of steroid action has been filled in by the additional under- that these compounds should also be considered neurotransmit- standing that these compounds can have rapid, extragenomic, ters, as they regularly function independently of classical hor- membrane-initiated actions. It has been known for decades that mone signaling in an increasing number of systems and species. steroid hormones can have acute actions (within minutes) on physiology (Szego and Davis, 1967), the activity of neurons (Kelly Neurotransmitter-like effects of steroids et al., 1976), and the expression of behavior (Hayden-Hixson and Estrogens in birds Ferris, 1991). More recently, data demonstrate that steroids can An important update to the classical view of steroid function and do function in ways that are “neurotransmitter-like,” as they involved our understanding of how and where steroids could be are synthesized at precise spatial locations within neural circuits produced. Historically, it was accepted that steroids were synthe- and can act within minutes as local neuromodulators to rapidly sized in peripheral endocrine organs and traveled great distances regulate cognitive functions and behaviors (Balthazart and Ball, to exert physiological effects at target tissues. We have known that neurosteroid production occurs in rodents for some time (e.g., Received Aug. 3, 2016; revised Aug. 30, 2016; accepted Sept. 9, 2016. for review, see Baulieu, 1991) and now understand that estrogens ThisworkwassupportedbyNationalInstitutesofHealthR01HD058638,ArnoldandMabelBeckmanFoundation, can be synthesized centrally, by neurons, both in their cell somata Howell-CSUPERB Research Scholars Awards, and National Science Foundation Grant HRD-1302873 LSAMP to K.S., and at discrete synaptic junctions in birds as well (Naftolin et al., National Institutes of Health R01/MH50388, BELSPO-SSTC PAI P7/17 (Belgian Interuniversity Attraction Poles), 1996; Saldanha et al., 2000; Peterson et al., 2005). FRS-FNRS PDR T.00.15, FRS-FNRS CDR J.0101.13, and FSRC-14/40 (Special Fund for Research University of Liege) to C.A.C., National Institutes of Health R01 NS082179 and National Science Foundation IOS 1354906 to L.R.-H., In vitro work in quail hypothalamus/preoptic area followed by HD042635 and DA013185 to P.E.M., and HD07228 to L.M.R. in vivo studies in behaving zebra finches demonstrated that brain The authors declare no competing financial interests. estrogen synthesis is acutely controlled within neurons and Correspondence should be addressed to Dr. Lauren M. Rudolph, University of California Los Angeles Department driven by changes in neuronal activity (Balthazart et al., 2001, of Neurobiology, CHS 63-170, 650 Charles E. Young Drive South, Los Angeles, CA 90095. E-mail: [email protected]. 2006; Remage-Healey et al., 2008) via acute regulation of brain DOI:10.1523/JNEUROSCI.2473-16.2016 aromatase activity by calcium-dependent phosphorylation Copyright © 2016 the authors 0270-6474/16/3611449-10$15.00/0 (Balthazart et al., 2001, 2003; Charlier et al., 2011; Cornil et al., 11450 • J. Neurosci., November 9, 2016 • 36(45):11449–11458 Rudolph et al. • Steroids: New Neurotransmitters Figure1. Schematicrepresentationofthedualactionofestrogenhypothesisfortheregulationofmalesexualbehavior.Thenuclear-initiatedeffectsofbrainestrogensassociatedwithlong-term changesingonadaltestosteronesecretionwouldactivatethecircuitsunderlyingtheexpressionofsexualbehavior,whilemembrane-initiatedeffectswould,inamannersimilartoneuromodulators, acutely (within 15 min) modulate these primed circuits and determine whether animals engage in this behavior at a specific moment. These two complementary modes of action of the same chemical messenger would thus cooperate to regulate the long- and short-term aspect of the same behavior. 2012b; Comito et al., 2015). Interestingly, this acute regulation of 2009). The effects of estrogens on behavior are typically associ- brain estrogen production can occur specifically at presynaptic ated with long-term changes in circulating levels of testosterone terminals, providing very fine spatial and temporal control over and are therefore mainly considered to result from the transcrip- estrogen availability (Remage-Healey et al., 2011; Cornil et al., tional activity of their nuclear receptors (McEwen and Alves, 2012b). This fine regulation of estradiol synthesis appears to be 1999). According to this view, the long-term effects of brain- driven by the activity of aromatase. The aromatase enzyme uses derived estrogens (neuroestrogens) would prime the neural cir- androgens (typically testosterone) as precursors. Increasing evi- cuits involved in the regulation of behavior, which would then be dence indicates that, particularly in the songbird, the concentra- acutely modulated by neurotransmitter systems conveying infor- tion of brain androgens is acutely modulated through the mation from the environment (e.g., presence of a sexual partner regulation of their local synthesis (Pradhan et al., 2010; Heimov- or predator; Fig. 1). The discovery that neuroestrogens are also ics et al., 2016). However, a rapid and reversible reduction in able to produce much faster effects at the cellular level than pre- aromatase activity, paralleled by a change in estradiol brain con- viously anticipated (Maggi et al., 2004; Vasudevan and Pfaff, centration, was measured ex vivo in whole or specific hypothala- 2007) and that their synthesis can be acutely regulated in the mus/preoptic area subregions collected immediately after visual brains of avian species (Remage-Healey et al., 2008; Charlier et or sexual interactions with a female (Cornil et al., 2005; de Bourn- al., 2015) prompted further research on the short-term regula- onville et al., 2013; Dickens et al., 2014), suggesting that aroma- tion of behavior by brain-derived estrogens. Although it is now tase activity is the critical component that determines estradiol clear that neuroestrogens acutely influence numerous physiolog- availability. aromatase activity is upregulated in distinct brain ical or behavioral processes in birds, many advances on the rapid regions following brief exposure to acute stress (Dickens et al., effects of estrogens on behavior have been obtained in the study 2011), an effect that is counteracted by sexual interaction (Dick- of male sexual behavior and auditory processing (Cornil et al., ens et al., 2012). Therefore, brain aromatase activity is also 2012a; Krentzel and Remage-Healey,