3β-HSD activates DHEA in the songbird brain

Abstract

Dehydroepiandrosterone (DHEA) is an abundant circulating prohormone in humans, with a variety of reported actions on central and peripheral tissues. Despite its abundance, the functions of DHEA are relatively unknown because common animal models (laboratory rats and mice) have very low DHEA levels in the blood. Over the past decade, we have obtained considerable evidence from avian studies demonstrating that (1) DHEA is an important circulating prohormone in songbirds and (2) the enzyme 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD), responsible for converting DHEA into a more active androgen, is expressed at high levels in the songbird brain. Here, we first review biochemical and molecular studies demonstrating the widespread activity and expression of 3beta-HSD in the adult and developing songbird brain. Studies examining neural 3beta-HSD activity show effects of sex, stress, and season that are region-specific. Second, we review studies showing seasonal and stress-related changes in circulating DHEA in captive and wild songbird species. Third, we describe evidence that DHEA treatment can stimulate song behavior and the growth of neural circuits controlling song behavior. Importantly, brain 3beta-HSD and aromatase can work in concert to locally metabolize DHEA into active androgens and estrogens, which are critical for controlling behavior and robust adult neuroplasticity in songbirds. DHEA is likely secreted by the avian gonads and/or adrenals, as is the case in humans, but DHEA may also be synthesized de novo in the songbird brain from cholesterol or other precursors. Irrespective of its source, DHEA seems to be an important prohormone in songbirds, and 3beta-HSD is a key enzyme in the songbird brain.

The agonistic adrenal: melatonin elicits female aggression via regulation of adrenal androgens

“…during night time or in the 'timed' melatonin group) likely cause rapid increases in converting enzymes (e.g. 3b-hydroxysteroid dehydrogenase (HSD), 17b-HSD, aromatase) similar to what has been shown in songbirds [33,41], effectively converting prohormones to biologically active androgens, or oestrogens [7]. These data suggest that circulating melatonin likely triggers changes in aggression via metabolism of circulating DHEA to androgens and oestrogens that, in turn, act on target tissues (e.g.…”

“…Further, these findings demonstrate a key role of melatonin in regulating both peripheral androgens and aggression in females; this is the first finding of a direct action of melatonin on adrenal DHEA release. This peripheral mechanism provides an alternative to the previously described actions of gonadal steroids acting on the brain to regulate behaviour [17,18], and described actions of DHEA regulating aggression [7,16,33,41]. From a comparative perspective, this seasonal mechanism may also regulate aggression in other vertebrate species, including frogs, lizards, mammals and snakes, where melatonin also facilitates seasonal changes ( [20][21][22][23]; reviewed in [7]).…”

A Quantification of the Injury‐Induced Changes in Central Aromatase, Oestrogenic Milieu and Steroid Receptor Expression in the Zebra Finch

“…Interestingly, TSPO was more highly expressed in females than males following injury, perhaps suggesting a compensation for lower levels of testosterone in the female brain. Furthermore, the formation of E 2 from the substrate dehydroepiandrosterone has been documented in the songbird brain (41)(42)(43). The precise mechanism of injury-induced changes in aromatase in the female finch are currently being studied intensely in our laboratory.…”

Comparative aspects of neurosteroidogenesis: From fish to mammals

“…The presence of a bioactive form of 3b-HSD has also been documented in the brain of birds (Ukena et al, 1999b;Matsunaga et al, 2004;Schlinger et al, 2008), amphibians (Mensah-Nyagan et al, 1994;Takase et al, 1999;Inai et al, 2003) and fish (Sakamoto et al, 2001b;Diotel et al, 2011).…”

“…The 3b-HSD gene is also expressed in the peripheral nervous system (PNS) of rodents, particularly in dorsal root ganglions and the sciatic nerve (Guennoun et al, 1997;Robert et al, 2001). 3b-HSD-expressing cells have been visualized in the brain of quail (Ukena et al, 1999b;Matsunaga et al, 2001) and zebra finch (London et al, 2006;Schlinger et al, 2008). In amphibians, the distribution of 3b-HSD immunoreactivity has been described in the CNS of R. esculenta (Mensah-Nyagan et al, 1994;Do Rego et al, 1998Bruzzone et al, 2010) and C. pyrrhogaster (Inai et al, 2003).…”