Conditional Inactivation of Androgen Receptor Gene in the Nervous System: Effects on Male Behavioral and Neuroendocrine Responses

Abstract

Testosterone (T) profoundly influences central sexual differentiation and functions. In the brain, T signals either directly through androgen receptor (AR) or indirectly through estrogen receptor (ER) following aromatization into E2 (17-␤-estradiol).As T, through AR, also controls peripheral male sexual differentiation, the relative contribution of central AR in T-mediated regulation of behavioral and neuroendocrine responses still remains unclear. To address this question, we generated, by using Cre-loxP technology, mice selectively lacking AR expression in the nervous system. The mutant male urogenital tract was normally developed, and mice were able to produce offspring. Nonetheless, sexual motivation and performance as well as aggressive behaviors were affected. Only a low percentage of males displayed a complete sexual behavior and offensive attacks. The latency to show masculine behaviors was increased and copulation length prolonged. Erectile activity during mating was also altered. These alterations occurred despite increased levels of T and its metabolites, and an unaffected number of ER␣-immunoreactive cells. Olfactory preference and neuronal activation, mapped by Fos immunoreactivity, following exposure to estrus female-soiled bedding were also normal. At comparable T levels, greater differences in masculine behaviors were observed between gonadectomized control and mutant males. AR invalidation in the nervous system also disrupted the somatotropic axis since mutant males exhibited growth retardation and decreased serum levels of insulin-like growth factor I. Our findings show that central AR is required in T-induced regulation of male-typical behaviors and gonadotrope and somatotropic axes. This genetic model offers a unique opportunity in the understanding of AR's role in cerebral functions of T.

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

“…In previous studies, AR immunoreactivity has been mainly localized to neurons and reactive microglia and to subpopulations of astrocytes and oligodendrocytes (30,33). In our conditional AR NesCre mice, the AR was selectively inactivated in neurons, astrocytes, and oligodendrocytes, whereas microglial cells were spared (19). Thus, the effect of testosterone observed here does not involve microglial AR.…”

“…Transgenic AR NesCre mice, displaying selective ablation of the AR in neurons, astrocytes, and oligodendrocytes, but with microglial cells being spared (19), were castrated and received a testosteronefilled s.c. Silastic implant during 4 wk following lysolecithin-induced demyelination. As in AR Tfm mice and in contrast to uncastrated wild-type animals, testosterone therapy failed to restore astrocytes and MBP-immunoreactive myelin within the lesion.…”

“…We used the Nestin-Cre mouse strain for two major reasons. First, the high efficiency of the Cre-mediated recombination, which is well characterized for this strain, results in almost complete ablation of the floxed genes in neurons and macroglial cells (15,19,34). Then, this choice allowed us to analyze the role of testosterone without any preconceived idea about its neural targets.…”

Neuromolecular responses to social challenge: Common mechanisms across mouse, stickleback fish, and honey bee

“…Animals were killed after an additional 15 min (mouse) or 25 min (honey bee and stickleback). These slight variations in timelines were required to keep mouse and stickleback experiments consistent with previously published protocols (8,43,67,68). The protocol for honey bee was novel, so we followed the stickleback timeline because expression differences for IEGs and other socially responsive genes are generally best detected 30 min poststimulus (69,70).…”

Androgen receptor gene sequence and basal cortisol concentrations predict men's hormonal responses to potential mates

“…As a result, men with shorter CAG repeats appear to convert the same concentrations of androgen into larger physiological effects than do men with longer repeats (Campbell et al 2007;Zitzmann & Nieschlag 2007), which may explain why shorter repeats have in some studies been associated with the risk of prostate cancer (Casella et al 2001), enhanced spermatogenesis (von Eckardstein et al 2001) and incidence of violent behaviour (Rajender et al 2008). Importantly, the limbic -hypothalamic circuit that regulates responses to potential mates contains the highest density of AR of any brain region (Pfaff 1981), and blockade of AR in this pathway reduces or eliminates sexual responses to females (Harding & McGinnis 2004;Raskin et al 2009). In addition, sexual satiety that eliminates behavioural and hormonal responses to females (Bronson & Desjardins 1982;Bonilla-Jaime et al 2006) is associated with dramatic drops in AR density in this pathway (Fernandez-Guasti et al 2003;Romano-Torres et al 2007), and subsequent recovery of sexual responses over time is correlated with restoration of AR levels (Romano-Torres et al 2007).…”