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  • br Introduction Androgens have been shown to regulate

    2023-01-24


    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 research to date  functions.
    Pharmacological and genetic tools to assess neural AR function
    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 stimulatory feedback effect. Both male and female rodents respond to negative feedback, but only females respond to the positive feedback effect. The perinatal action of testosterone also triggers the adult expression of male-typical behavior (such as a preference for a receptive female, mounts and thrusts) and an inability to adopt the female posture (lordosis), which is triggered by male mounts (Phoenix et al., 1959, Baum et al., 1990). The pubertal testosterone increase also seems to be involved in the final maturation of neural structures underlying reproductive functions (Ahmed et al., 2008, De Lorme et al., 2012, De Lorme and Sisk, 2016, Schulz et al., 2004). During adulthood, testosterone acts transiently on cerebral areas by exerting an activational role on neuroendocrine functions and behavior.
    Cognition
    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 anxiety-like behavior (Edinger and Frye, 2006). In the Tfm rat model, Rizk et al. (2005) reported unchanged anxiety-state level assessed in the elevated-plus-maze and open field tests. In contrast, two other studies reported increased behavioral indices of anxiety in the open-field and elevated plus maze tests for Tfm rats compared to wild-type males and females (Hamson et al., 2014, Zuloaga et al., 2011). Mutant rats exhibited an increased corticosterone peak in response to mild stress, showing a chronic anxiety phenotype and dysregulated HPA axis (Zuloaga et al., 2011). An androgen-induced organization of the HPA axis through both AR and estrogen conversions was supported by data showing that postnatal treatment with flutamide or an aromatase inhibitor interfered with the adult HPA response to repeated stress (Bingham et al., 2011).