Review Brain and pineal 7a-hydroxypregnenolone stimulating locomotor activity: Identification, mode of action and regulation of biosynthesis Kazuyoshi Tsutsui a,⇑ , Shogo Haraguchi a , Yoshitaka Fukada b , Hubert Vaudry c a Laboratory of Integrative Brain Sciences, Department of Biology and Center for Medical Life Science, Waseda University, Tokyo 162-8480, Japan b Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan c Normandy University, INSERM U982, Institute for Biochemical Research and Innovation (IRIB), 76821 Mont-Saint-Aignan, France article info Article history: Available online 16 May 2013 Keywords: Neurosteroids 7a-Hydroxypregnenolone Cytochrome P450 7a Dopamine Melatonin Prolactin Corticosterone Brain Pineal gland Locomotion abstract Biologically active steroids synthesized in the central and peripheral nervous systems are termed neuros- teroids. However, the biosynthetic pathways leading to the formation of neurosteroids are still incom- pletely elucidated. 7a-Hydroxypregnenolone, a novel bioactive neurosteroid stimulating locomotor activity, has been recently identified in the brain of newts and quail. Subsequently, the mode of action and regulation of biosynthesis of 7a-hydroxypregnenolone have been determined. Moreover, recent studies on birds have demonstrated that the pineal gland, an endocrine organ located close to the brain, is an important site of production of neurosteroids de novo from cholesterol. 7a-Hydroxypregnenolone is a major pineal neurosteroid that stimulates locomotor activity in juvenile chickens, connecting light- induced gene expression with locomotion. This review summarizes the advances in our understanding of the identification, mode of action and regulation of biosynthesis of brain and pineal 7a-hydroxypregn- enolone, a potent stimulator of locomotor activity. Ó 2013 Elsevier Inc. All rights reserved. 1. Introduction Studies conducted over the past two decades have demon- strated that the central and peripheral nervous systems have the capacity of synthesizing steroids de novo from cholesterol, the so-called ‘‘neurosteroids’’ (for reviews, see Baulieu, 1997; Compag- none and Mellon, 2000; Do-Rego et al., 2009; Mellon and Vaudry, 2001; Tsutsui and Mellon, 2006; Tsutsui et al., 1999, 2000, 2003, 2006). The formation of neurosteroids in the brain was originally demonstrated in mammals by Baulieu and colleagues (Compag- none et al., 1995; Corpéchot et al., 1981, 1983; Jo et al., 1989; Lan- thier and Patwardhan, 1986; Mathur et al., 1993; Mellon and Deschepper, 1993; Robel and Baulieu, 1985; Robel et al., 1987). The brain of non-mammalian vertebrates also expresses several kinds of steroidogenic enzymes and produces a variety of neuros- teroids (for reviews, see Do-Rego et al., 2009; Mellon and Vaudry, 2001; Tsutsui and Mellon, 2006; Tsutsui et al., 1999, 2000, 2003, 2006). In the brain of birds, biosynthesis of neurosteroids has been reported both in galliform bird species such as the Japanese quail Coturnix japonica (Matsunaga et al., 2001, 2002; Tsutsui and Schlin- ger, 2001; Tsutsui and Yamazaki, 1995; Tsutsui et al., 1997, 1999, 2003; Ukena et al., 1999, 2001; Usui et al., 1995) and in passeri- form bird species such as the zebra finch Taeniopygia guttata (Fre- king et al., 2000; London and Schlinger, 2007; London et al., 2003, 2006, 2010; Schlinger et al., 1999; Soma et al., 2004; Tam and Sch- linger, 2007; Vanson et al., 1996). The formation of several neuros- teroids from cholesterol is now also well documented in various species of amphibians (Beaujean et al., 1999; Bruzzone et al., 2010; Do-Rego et al., 2007; Inai et al., 2003; Matsunaga et al., 2004; Mensah-Nyagan et al., 1994, 1996a,b, 1999; Takase et al., 1999, 2002, 2011) and fish (Brion et al., 2012; Diotel et al., 2011; Menuet et al., 2005; Sakamoto et al., 2001). Therefore, de novo syn- thesis of neurosteroids from cholesterol in the brain appears to be a conserved property across the vertebrate phylum (for reviews, see Baulieu, 1997; Compagnone and Mellon, 2000; Do-Rego et al., 2009; Mellon and Vaudry, 2001; Tsutsui and Mellon, 2006; Tsutsui et al., 1999, 2000, 2003, 2006). It appears, however, that the biosynthetic pathways leading to the formation of neurosteroids in vertebrates is still incompletely elucidated (for a review, see Tsutsui et al., 2006). In fact, using the Japanese red-bellied newt Cynops pyrrhogaster as a model, we recently found that the amphibian brain actively produces a previ- ously undescribed neurosteroid, 7a-hydroxypregnenolone through a-hydroxylation of pregnenolone at the 7-position (Matsunaga et al., 2004). In newt, 7a-hydroxypregnenolone acts on the brain as a novel neuromodulator to stimulate locomotor activity through 0091-3022/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yfrne.2013.05.002 ⇑ Corresponding author. Address: Laboratory of Integrative Brain Sciences, Department of Biology, Waseda University, Center for Medical Life Science of Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan. Fax: +81 3 3355 0316. E-mail address: k-tsutsui@waseda.jp (K. Tsutsui). Frontiers in Neuroendocrinology 34 (2013) 179–189 Contents lists available at SciVerse ScienceDirect Frontiers in Neuroendocrinology journal homepage: www.elsevier.com/locate/yfrne