**2.12 BDNF as another novel mechanism for individual differences in responses to androgens**

In addition to mechanisms of androgens in the brain and body through ERβ, the proposed project will investigate brain-derived neurotrophic factor (BDNF) as a target for these trophic actions. BDNF is a neurotrophin that is abundantly expressed in many central nervous system regions, most notably in regions of interest in the proposed studies for their involvement in cognitive, affective, and reproductive function (prefrontal cortex, hippocampus, and hypothalamus). BDNF is considered a marker of brain plasticity owing to its role in synaptic reorganization, neurogenesis, and dendritic branching and spine formation as well as cognitive and affective processes. Moreover, there is growing evidence for the role of gonadal hormones for regulating BDNF, namely, estradiol [23]. Less is known about the role of androgens for BDNF, but there is some evidence for sex differences, regimen, and region/cell-specific effects of androgens for BDNF. For instance, it has been argued that T produces tonic suppression of BDNF levels in mossy fibers of the hippocampus among adult male rats (but the opposite occurs with estradiol among female rats [24]. Indeed, among male rats that do not show GDX-induced decrements in cognitive performance, there is increased BDNF in mossy fibers of the hippocampus [25]. Enriched environment increases testosterone and BDNF levels in the grossly-dissected hippocampus of female, more so than male rats, compared to rats living under typical lab conditions [26]. However, among male mice, GDX decreased levels of BDNF in pyramidal neurons in the CA1 area, an effect prevented by T replacement [27]. Physiological dosing of T produced antidepressant effects that were mitigated when the BDNF target, extracellular signal-regulated kinase 2, is blocked [28]. We propose that some effects of T for BDNF may be related to its metabolite, 3α-diol. We have found that hippocampus levels of BDNF are reduced among mice with knockout of ERβ, coincident with lower 3α-diol levels (**Figure 8**). These findings indicate the role of androgens for BDNF is not linear, and there are gender, regimen, and target-specific effects (**Figure 10**).
