Aromatase inhibition rapidly affects in a reversible manner distinct features of birdsong

Abstract

Recent evidence has implicated steroid hormones, specifically estrogens, in the rapid modulation of cognitive processes. Songbirds have been a useful model system in the study of complex cognitive processes including birdsong, a naturally learned vocal behavior regulated by a discrete steroid-sensitive telencephalic circuitry. Singing behavior is known to be regulated by long-term actions of estrogens but rapid steroid modulation of this behavior has never been examined. We investigated if acute actions of estrogens regulate birdsong in canaries (Serinus canaria). In the morning, male canaries sing within minutes after light onset. Birds were injected with fadrozole, a potent aromatase inhibitor, or vehicle within 2–5 minutes after lights on to implement a within-subjects experimental design. This single injection of fadrozole reduced the motivation to sing as well as song acoustic stereotypy, a measure of consistency over song renditions, on the same day. By the next day, however, all song measures that were affected had returned to baseline. This study indicates that estrogens also act in a rapid fashion to regulate two distinct features of song, a learned vocal behavior.

Blocking neuroestrogen synthesis modifies neural representations of learned song without altering vocal imitation accuracy in developing songbirds

“…In adult male zebra finches, long-term aromatase inhibition leads to suppressed courtship displays, including song production (Walters and Harding, 1988). More recent studies have found that neuroestrogen production also appears to acutely facilitate song production in adult zebra finches (Remage-Healey et al, 2009;Alward et al, 2016). Our data expand on this understanding that acute suppression of E2 production constrains singing to now include developing male songbirds.…”

“…Systemic administration: Birds in this experiment received an oral administration of either FAD or saline every other day for 20 days immediately following tutoring. Initially, we measured singing rates of systemically-treated animals before (<40 dph) and during the tutoring period (40 -60 dph) as global inhibition of estrogen synthesis in adult songbirds can reduce song production (Alward et al, 2016). Pre-tutoring, birds sang at comparable rates independent of the time of day or future treatment group (treatment: F(1, 13) = 2.466, p = 0.140; time of day: F(1, 13) = 1.797, p = 0.203; treatment * time of day: F(1, 13) = 0.719, p = 0.412; Fig.…”

“…Instead, we intentionally administered FAD immediately after the offset of tutoring to specifically target the post-training memory consolidation period as in studies on hippocampal E2 and memorization (Frick, 2015). Comparable systemic aromatase inhibition treatments in birds led to marked reductions in E2 and aromatase activity Remage-Healey et al, 2010;Rensel et al, 2013;Alward et al, 2016), and systemic injections lead to suppressed aromatase activity in NCM within 30 mins (Alward et al, 2016; but see Krentzel et al, in submission). Thus, if systemic FAD actively suppresses E2 synthesis >30 minutes after administration, and the putative post-training auditory memory consolidation period is <30 minutes, it is important to consider that the pharmacokinetics of oral FAD may not sufficiently target the period of immediate post-training auditory memory consolidation.…”

Estrogen and sex-dependent loss of the vocal learning system in female zebra finches

“…We were also surprised to see that chronic exemestane treatment in females caused some females to produce 1-2 repeated syllables in a song-like manner, even though they had atrophied song nuclei. Prior studies have shown that acute aromatase inhibition can suppress the rate of singing in zebra finches and canaries (Alward et al, 2016;Vahaba et al, 2019;Walters and Harding, 1988), but no changes in song learning acuity have been reported (Merten and Stocker-Buschina, 1995;Vahaba et al, 2019). Perhaps the more potent and longterm application of the estrogen inhibitor we used revealed an unknown involvement of estrogen in vocal learning.…”

“…Prior studies that have used fadrozole, a drug that inhibits aromatase from converting androgens to estrogens, did not reveal any impacts on male song development either behaviorally or anatomically (Merten and Stocker-Buschina, 1995;Wade and Arnold, 1994). However, fadrozole was later found to effect song behavior and aromatase activity only briefly within 30 minutes of injection; the effects were lost after 4 hours (Alward et al, 2016). It was also found that fadrozole can stabilize the aromatase protein, which is then followed by increased estrogen synthesis after drug clearance, causing a "rebound effect" (Harada and Hatano, 1998).…”