The Impact Of Androgens On Hippocampal Dependent Function

The normal function of the mammalian central nervous system (CNS) is largely dependent on structural plasticity. This plasticity can be modulated by a variety of environmental and endogenous factors. Changes in dendrite morphological may be associated with altered region-specific function and behaviour. The hippocampus is a highly plastic structure responsible for a diverse range of functions including memory consolidation (Lee et al. , 2014) and emotional processing (Vertes 2006). The hippocampus is particularly sensitive to stress (Diamond et al. , 1996) and gonadal steroid hormones (Galea et al. , 2013), indicating glucocorticoids and androgens can modulate hippocampal-dependent function and may contribute to the etiology of neurological conditions associated with this area. Much of the work surrounding the effects of gonadal steroid hormones on hippocampal morphology and function focuses on estrogens, with less emphasis placed on androgens.

This is surprising given the significant decline in circulating androgens seen in ageing men (Feldman et al. , 2002). Although the results of studies investigating the cognitive effects of testosterone supplementation are mixed, there is some evidence showing androgens improve hippocampal dependent function such as spatial memory (Cherrier et al. , 2001). Meanwhile, androgen ablation therapy used to treat hormone-sensitive prostate cancer is associated with impairments in spatial memory (Jenkins et al. , 2005). Further, low levels of androgens have been associated with increased risk of Alzheimer’s disease (Moffat et al. , 2004) and depression (Almeida et al. , 2004), while others report no changes in hippocampal-related function (Maggio et al. , 2012). Reflective of human studies, androgens exert variable effects on hippocampal function in animal models as well. Some demonstrate positive effects of androgens on spatial memory (Daniel et al. , 2003; Khalil et al. , 2005) and depressive and anxiety like behaviour (Frye et al. , 2010; Aikey et al. , 2002) while others report no effects on hippocampal-dependent function (Vaughan et al. , 2007). Discrepancies in the data may be task-dependent, but there is sufficient evidence to support the idea that androgen deprivation is associated with negative outcomes involving hippocampal function.

Further, the time spent in a state of androgen deprivation also appears to influence the degree of cognitive decline. Males undergoing greater than one year of androgen deprivation therapy are at a greater risk for developing Alzheimer’s Disease (AD) compared to those undergoing short-term therapy (Nead et al. , 2016; Jhan et al. , 2017). These findings may in part be explained by changes at the cellular level. A reduction in spine synapses is noted following gonadectomy (GDX) of adult male rats (Leranth et al. , 2003; MacLusky et al. , 2006). Treatment with either testosterone or non-aromatizable DHT recovers hippocampal spine synapses to levels of SHAM operated controls (Leranth et al. , 2003). These findings highlight involvement of the AR. Furthermore; a reduction in the survival, but not proliferation, of newborn cells in the dentate gyrus (DG) has been reported in male rats following GDX (Spritzer and Galea 2007). Cell survival is rescued upon treating GDX animals with either testosterone or DHT indicating that these effects are also due to AR-mediated effects and not through aromatization to estrogen (Spritzer and Galea 2007). Androgens have also been shown to alter ascending cholinergic input from basal forebrain structures like the medial septum band of brocca (MSDB) (Kovacs et al. , 2003) and the burst-firing of dopaminergeic afferents arising from the ventral tegmental area (VTA) projecting towards the mPFC (Locklear et al. , 2017).

Together, these findings implicate androgens as key regulators of hippocampal plasticity. In contrast to the trophic effects of androgen on the male brain, androgens have also been shown to suppress excitability and growth of the mossy fiber pathway, a major excitatory pathway within the hippocampus. GDX of male rats results in increased arborization of CA3 pyramidal neurons and growth of mossy fiber input into these same neurons (Mendell et al. , 2017). Other changes after GDX include enhancements in long-term potentiation (LTP) and neurotrophic peptide expression in the mossy fiber pathway, which may be involved in the mechanisms underlying the structural changes (Skucas et al. , 2013). It has been proposed that these changes may represent compensatory responses to declines in androgen-mediated neuroplasticity, and highlight the mixed effects of androgens on hippocampal morphology and function (Skucas et al. , 2013).