Role of the androgen receptor in the central nervous system
Introduction
Androgens have been shown to regulate several neural functions ranging from reproduction to mood and cognitive abilities. This property starts as early as the perinatal period, which is characterized by prenatal and postnatal surges of gonadal testosterone, and continues through puberty and even adulthood. In the nervous system, the effects of testosterone are mediated either by androgen receptors (AR), or, after neural aromatization to 17β-estradiol, by estrogen receptors (ER) α and ERβ. Local synthesis of neuro-steroids has been reported in several cerebral regions such as the hippocampus, where they modulate hippocampal synaptic plasticity and healthy memory processes (Ooishi et al., 2012). AR and ER receptors are members of the nuclear receptor superfamily and act mainly through regulation of target genes at the transcriptional level, although several studies show rapid membrane and cytoplasmic changes. The present review focuses on studies in rodents that address the neural AR role in androgen-induced regulation of central nervous system (CNS) functions.
Section snippets
Pharmacological tools
To discriminate between the androgenic and estrogenic pathways in testosterone-mediated regulation of CNS functions, gonadectomy and supplementation with 5-α-dihydrotestosterone (DHT) are used. However, this non-aromatizable metabolite of testosterone does not exclusively activate AR. Indeed, it can be metabolized to 5α-androstan-3β, which binds ERs and triggers neural responses (Handa et al., 2008). Systemic or local treatments in specific CNS regions with AR-antagonists, such as flutamide and
Neuroendocrine functions and behavior related to reproduction
Perinatal testosterone permanently potentiates male (masculinization) and inhibits female (de-feminization) neuroanatomical and behavioral characteristics (Morris et al., 2004, Phoenix et al., 1959). These organizational effects of testosterone suppress the neuroanatomical characteristics required for sex steroids to induce the ovulatory surge of luteinizing hormone (LH) during adulthood (Corbier, 1985, Homma et al., 2009). Sex steroids regulate gonadotropin release through an inhibitory or
Cognition
Estrogen-mediated regulation of cognitive behavior and synaptic plasticity has been largely studied in rodents. In comparison, the neural function of AR has been investigated less thoroughly, although this receptor is expressed to a high level in brain structures that ensure underlying cognitive processes.
The hypothalamic-pituitary-adrenal (HPA) axis and anxiety-related behavior
Testosterone has been shown to modulate the HPA response to stress and attenuate anxiety-like behavior. In rats, supplementation or intra-hippocampal infusion of gonadectomized males with testosterone or DHT induced a lower anxiety-related behavior in the elevated-plus-maze, open field and defensive freezing tests (Edinger and Frye, 2004). Intra-hippocampal application of flutamide blocked DHT-induced effects, suggesting an implication of the hippocampal AR in an androgen-induced decrease of
Other brain functions
Recent reviews nicely summarize the role of expanded polyQ chain within the first exon of the AR in spinal and bulbar muscular atrophy and recent views on the development of this neurodegenerative disease (Giorgetti and Lieberman, 2016, Pennuto and Rinaldi, 2017). Otherwise, several studies documented the implication of androgens in neuroprotection. Pharmacological studies addressing the mechanisms underlying androgen-induced effects showed that pre-treatment of hippocampal neurons with
Conclusions and future directions
Information from in vitro and in vivo models is progressively allowing a more precise view of the neural role of AR in rodents. This helps to open and consider new perspectives in human studies since androgens are also suggested to modulate several brain functions related to reproduction, cognition, anxiety or neuroprotection in man. However, much remains to be discovered and many questions still need to be addressed. For instance, although the effects of androgens are widely studied in the
Acknowledgments
This work was supported by grants from the “Agence Nationale de la Recherche” ANR-09-CESA-006 program, the Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail (Anses, Project n° 2012-2-077) and the Interdisciplinary Program “Longévité et Vieillissement” of the CNRS.
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