Testosterone (T) is an important hormone for various biological processes and is the principal androgen in men. There is growing evidence regarding the association between T concentrations and a number of behavioral measures including anxiety (Almeida et al., 2004; Amore et al., 2009; Wang et al., 1996, Wang et al., 2004), cognitive function (Moffat et al., 2002; Muller et al., 2005), and memory (Martin et al., 2007). Studies in both humans and rodents indicate that low T levels are associated with cognitive function deficits which are reversed upon T administration (Bimonte-Nelson et al., 2003; Cherrier et al., 2001; Daniel et al., 2003; Gibbs and Johnson, 2008; Spritzer et al., 2011). T has also been demonstrated to positively affect spatial and verbal memory in Alzheimer's disease (AD) patients (Cherrier et al., 2005; Postma et al., 2000). However, it appears that these effects are dose-dependent and respond in an inverted U pattern in which a moderate dose has a beneficial outcome while low or high dosages had no significant improvements in either humans (Cherrier et al., 2007) or rodents (Spritzer et al., 2011).

Brain derived neurotrophic factor (BDNF) expression declines during the aging process, and this decline has many implications on brain health and function including brain plasticity and cognitive function such as learning and memory (Hoffman et al., 2019; Rex et al., 2006; Tapia-Arancibia et al., 2008). An important intermediary of T's effect in the brain is BDNF. T concentrations in the frontal cortex during adolescence in different animals correlate with the expression of BDNF and its receptor, tropomyosin receptor kinase B (TrkB) (Hill et al., 2012; Purves-Tyson et al., 2015). The pro-proliferative effects of T are mediated by BDNF (Allen et al., 2015). Moreover, it has been reported that reduced gene expression of some BDNF transcripts in gonadectomized animals' frontal cortices can be reversed by testosterone replacement therapy (TRT) (Purves-Tyson et al., 2015).

The use of T as a therapeutic agent to treat hypogonadism, growth deficiencies, select blood disorders and various muscle wasting diseases has been well-established by the medical community (Bhasin et al., 2018; Hackett et al., 2017). However, there is a large segment of the young adult population (both competitive and non-competitive athletes) that self-administer anabolic-androgenic steroids (AAS) at supraphysiological doses to enhance physique or athletic performance (Hoffman et al., 2009). Investigations that have focused on T administration and its effects on young adults are limited. This is likely related to the fact that T administration in healthy, young individuals with an intact and functioning hypothalamic-pituitary-gonadal system is not recommended, and it's illegal to self-administer T without a medical prescription (Kanayama and Pope, 2018; Peltier and Pettijohn, 2018). Until 1990, when the Anabolic Steroid Control Act banned the use of AAS, its use was considered widespread among bodybuilders and strength/power athletes (Hoffman et al., 2009). Although testing in competitive athletes may have reduced its use in that specific community, it does appear that self-administration of AAS appears to be gaining popularity among tactical athletes (e.g., soldiers) (Johnson et al., 2007).

Many pathological conditions such as AD, Parkinson's disease and other neurodegenerative disorders are associated with elevated concentrations in biomarkers of inflammation and oxidative stress (Besga et al., 2017). As a normal consequence of aging in men, both circulating (Feldman et al., 2002; Gray et al., 1991) and brain (Rosario, 2004) concentrations of T exhibit gradual declines that become more robust as one ages (Gray et al., 1991). Oxidative stress and inflammation are thought to mediate a decrease in brain function as one ages (Chung et al., 2009; Wu et al., 2016). It has been suggested that reductions in T levels in the brain may be part of the pathogenesis associated with AD (Rosario, 2004). In addition, age-related loss of estrogen in women (Smith and Studd, 1992) and androgens (Malkin et al., 2004) in men are associated with an increased risk of inflammation. Estrogens and androgens are reported to have both anti-inflammatory actions and neuroprotective effects (Malkin et al., 2004). Moreover, these steroid hormones modulate AD risk factors (Uchoa et al., 2016). The relationship between T and AD becomes apparent at least ten years before clinical diagnosis, suggesting that low T contributes to, rather than results from, the disease process (Moffat et al., 2004). Androgens have also been noted to regulate the expression and function of inflammatory cytokines, including tumor necrosis factor–α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and C-reactive protein (CRP), and hence contribute to the attenuation of the inflammatory process (Traish et al., 2018).

Androgens are thought to have several additional neuroprotective effects. For instance, treatment with T as well as dihydrotestosterone (DHT) and estradiol, two major metabolites of T, have been reported to attenuate secondary dendritic atrophy induced by partial depletion of spinal motoneuron populations in rats (Cai et al., 2017). Animal experiments using exogenous T administration (in vitro and in vivo) revealed rapid and extensive dendritic growth, dendritic branching, creation of new synapses and increased synaptic size (Devoogd et al., 1985; Manolides and Baloyannis, 1984). T and other androgens can be converted into DHT or estrogen by the action of the enzymes 5-alpha reductase and aromatase, respectively. Some investigators have suggested that improved neurofunction following androgen administration may be mediated more by estrogens due to increased aromatase activity (Barreto et al., 2007). Others have demonstrated that androgens can also stimulate neuroprotection by their direct interaction with the androgen receptor (AR) (Lopez-Rodriguez et al., 2015).

In consideration of the potential role that T has on brain health, the purpose of this study was to examine the acute effect of a supraphysiological AAS regimen on behavior and brain inflammatory changes in healthy, young adult mice. In addition, the long-term effects of AAS use during young, adult years through the aging process were also explored.