Neurosteroid Biosynthesis and Function in the Brain of Domestic Birds

It is now established that the brain and other nervous systems have the capability of forming steroids de novo, the so-called “neurosteroids.” The pioneering discovery of Baulieu and his colleagues, using rodents, has opened the door to a new research field of “neurosteroids.” In contrast to mammalian vertebrates, little has been known regarding de novo neurosteroidogenesis in the brain of birds. We therefore investigated neurosteroid formation and metabolism in the brain of quail, a domestic bird. Our studies over the past two decades demonstrated that the quail brain possesses cytochrome P450 side-chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3β-HSD), 5β-reductase, cytochrome P450 17α-hydroxylase/c17,20-lyase (P45017α,lyase), 17β-HSD, etc., and produces pregnenolone, progesterone, 5β-dihydroprogesterone (5β-DHP), 3β, 5β-tetrahydroprogesterone (3β, 5β-THP), androstenedione, testosterone, and estradiol from cholesterol. Independently, Schlinger’s laboratory demonstrated that the brain of zebra finch, a songbird, also produces various neurosteroids. Thus, the formation and metabolism of neurosteroids from cholesterol is now known to occur in the brain of birds. In addition, we recently found that the quail brain expresses cytochrome P4507α and produces 7α- and 7β-hydroxypregnenolone, previously undescribed avian neurosteroids, from pregnenolone. This paper summarizes the advances made in our understanding of neurosteroid formation and metabolism in the brain of domestic birds. This paper also describes what are currently known about physiological changes in neurosteroid formation and biological functions of neurosteroids in the brain of domestic and other birds

Review: neuroestrogen regulation of socio-sexual behavior of males

It is thought that estrogen (neuroestrogen) synthesized by the action of aromatase in the brain from testosterone activates male socio-sexual behaviors, such as aggression and sexual behavior in birds. We recently found that gonadotropin-inhibitory hormone (GnIH), a hypothalamic neuropeptide, inhibits socio-sexual behaviors of male quail by directly activating aromatase and increasing neuroestrogen synthesis in the preoptic area (POA). The POA is thought to be the most critical site of aromatization and neuroestrogen action for the regulation of socio-sexual behavior of male birds. We concluded that GnIH inhibits socio-sexual behaviors of male quail by increasing neuroestrogen concentration beyond its optimal concentration in the brain for expression of socio-sexual behavior. On the other hand, it has been reported that dopamine and glutamate, which stimulate male socio-sexual behavior in birds and mammals, inhibit the activity of aromatase in the POA. Multiple studies also report that the activity of aromatase or neuroestrogen is negatively correlated with changes in male socio-sexual behavior in fish, birds, and mammals including humans. Here, we review previous studies that investigated the role of neuroestrogen in the regulation of male socio-sexual behavior and reconsider the hypothesis that neuroestrogen activates male socio-sexual behavior in vertebrates. It is considered that basal concentration of neuroestrogen is required for the maintenance of male socio-sexual behavior but higher concentration of neuroestrogen may inhibit male socio-sexual behavior

Biosynthesis, Mode of Action, and Functional Significance of Neurosteroids in the Purkinje Cell

The brain has traditionally been considered to be a target site of peripheral steroid hormones. In addition to this classical concept, we now know that the brain has the capacity to synthesize steroids de novo from cholesterol, the so-called “neurosteroids.” In the middle 1990s, the Purkinje cell, an important cerebellar neuron, was identified as a major site for neurosteroid formation in the brain of mammals and other vertebrates. This discovery has provided the opportunity to understand neuronal neurosteroidogenesis in the brain. In addition, biological actions of neurosteroids are becoming clear by the studies using the Purkinje cell, an excellent cellular model, which is known to play an important role in memory and learning processes. Based on the studies on mammals over the past decade, it is considered that the Purkinje cell actively synthesizes progesterone and estradiol from cholesterol during neonatal life, when cerebellar neuronal circuit formation occurs. Both progesterone and estradiol promote dendritic growth, spinogenesis, and synaptogenesis via each cognate nuclear receptor in the developing Purkinje cell. Such neurosteroid actions mediated by neurotrophic factors may contribute to the formation of cerebellar neuronal circuit during neonatal life. 3α,5α-Tetrahydroprogesterone (allopregnanolone), a progesterone metabolite, is also synthesized in the cerebellum and considered to act as a survival factor of Purkinje cells in the neonate. This review summarizes the current knowledge regarding the biosynthesis, mode of action, and functional significance of neurosteroids in the Purkinje cell during development in terms of synaptic formation of cerebellar neuronal networks

Effects of Social Information on the Release and Expression of Gonadotropin-Inhibitory Hormone in Birds

The social environment changes circulating hormone levels and associated behavior in animals. Although social information is perceived by sensory systems in the brain, and peripheral reproductive hormonal levels are regulated mainly by the hypothalamus–pituitary–gonadal (HPG) axis, the neurochemical systems that convey social information to the HPG axis were not well-understood until the 2000s. In recent years, a growing body of evidence has demonstrated that a neuropeptide localized in the hypothalamus, gonadotropin-inhibitory hormone (GnIH), is responsive to social information. GnIH was first identified in the quail hypothalamo-hypophyseal system and named for its ability to inhibit gonadotropin secretion. Hypothalamic GnIH neurons have thus begun to be regarded as integrators, translating social information into changes in the levels of circulating gonadal hormones through the HPG axis. Here, we review current research investigating the responses of the GnIH neuronal systems to social status, offspring, and the presence/absence of conspecifics, and describe the neurochemical pathways linking visual perception of a potential mate to a rapid change in blood gonadotropin levels via the hypothalamus–pituitary axis in male birds

Comparative and Evolutionary Aspects of Gonadotropin-Inhibitory Hormone and FMRFamide-Like Peptide Systems

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that was found in the brain of Japanese quail when investigating the existence of RFamide peptides in birds. GnIH was named because it decreased gonadotropin release from cultured anterior pituitary, which was located in the hypothalamo-hypophysial system. GnIH and GnIH precursor gene related peptides have a characteristic C-terminal LPXRFamide (X = L or Q) motif that is conserved in jawed vertebrates. Orthologous peptides to GnIH are also named RFamide related peptide or LPXRFamide peptide from their structure. A G-protein coupled receptor GPR147 is the primary receptor for GnIH. Similarity-based clustering of neuropeptide precursors in metazoan species indicates that GnIH precursor of vertebrates is evolutionarily related to FMRFamide precursor of mollusk and nematode. FMRFamide peptide is the first RFamide peptide that was identified from the ganglia of the venus clam. In order to infer the evolutionary history of the GnIH-GnIH receptor system we investigate the structural similarities between GnIH and its receptor and well-studied nematode Caenorhabditis elegans (C. elegans) FMRFamide-like peptides (FLPs) and their receptors. We also compare the functions of FLPs of nematode with GnIH of chordates. A multiple sequence alignment and phylogenetic analyses of GnIH, neuropeptide FF (NPFF), a paralogous peptide of GnIH, and FLP precursors have shown that GnIH and NPFF precursors belong to different clades and some FLP precursors have structural similarities to either precursor. The peptide coding regions of FLP precursors in the same clade align well with those of GnIH or NPFF precursors. Alignment of GnIH (LPXRFa) peptides of chordates and FLPs of C. elegans grouped the peptides into five groups according to the last C-terminal amino acid sequences, which were MRFa, LRFa, VRFa, IRFa, and PQRFa. Phylogenetic analysis of receptors suggested that GPR147 has evolutionary relationships with FLP receptors, which regulate reproduction, aggression, locomotion, and feeding. GnIH and some FLPs mediate the effect of stress on reproduction and behavior, which may also be a conserved property of these peptide systems. Future studies are needed to investigate the mechanism of how neuropeptide precursor genes are mutated to evolve new neuropeptides and their inheritance

Neuropeptide FF/neuropeptide AF receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The Neuropeptide FF receptor family contains two subtypes, NPFF1 and NPFF2 (provisional nomenclature [10]), which exhibit high affinities for neuropeptide FF (NPFF, O15130) and RFamide related peptides (RFRP: precursor gene symbol NPVF, Q9HCQ7). NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus. NPFF2 is present in high density in the superficial layers of the mammalian spinal cord where it is involved in nociception and modulation of opioid functions

Neuropeptide FF/neuropeptide AF receptors in GtoPdb v.2023.1

The Neuropeptide FF receptor family contains two subtypes, NPFF1 and NPFF2 (provisional nomenclature [12]), which exhibit high affinities for neuropeptide FF (NPFF, O15130) and RFamide related peptides (RFRP: precursor gene symbol NPVF, Q9HCQ7). NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus. NPFF2 is present in high density in the superficial layers of the mammalian spinal cord where it is involved in nociception and modulation of opioid functions