Abstract
Some hippocampally-influenced affective and/or cognitive processes decline with aging. The role of androgens in this process is of interest. Testosterone (T) is aromatized to estrogen, and reduced to dihydrotestosterone (DHT), which is converted to 5α-androstane, 3α, 17α-diol (3α-diol). To determine the extent to which some age-related decline in hippocampally-influenced behaviors may be due to androgens, we examined the effects of variation in androgen levels due to age, gonadectomy, and androgen replacement on cognitive (inhibitory avoidance, Morris water maze) and affective (defensive freezing, forced swim) behavior among young (4 months), middle-aged (13 months), and aged (24 months) male rats. Plasma and hippocampal levels of androgens were determined. In experiment 1, comparisons were made between 4-, 13-, and 24-month-old rats that were intact or gonadectomized (GDX) and administered a T-filled or empty silastic capsule. There was age-related decline in performance of the inhibitory avoidance, water maze, defensive freezing, and forced swim tasks, and hippocampal 3α-diol levels. Chronic, long-term (1–4 weeks) T-replacement reversed the effects of GDX in 4- and 13-month-old, but not 24-month-old, rats in the inhibitory avoidance task. Experiments 2 and 3 assessed whether acute subcutaneous T or 3α-diol, respectively, could reverse age-associated decline in performance. 3α-diol, but not T, compared to vehicle, improved performance in the inhibitory avoidance, water maze, forced swim, and defensive freezing tasks, irrespective of age. Thus, age is associated with a decrease in 3α-diol production and 3α-diol administration reinstates cognitive and affective performance of aged male rats.
Highlights
The hippocampus may be a target of androgens during aging
Androgen levels (Figure 6, Table 3) There was a main effect of age, but not 3α-diol administration or an interaction, such that 4-month-old rats had increased plasma T levels [F(2,30) = 4.05, p = 0.03] compared to 24-month-old rats (p = 0.02). 3α-diol administration did not alter plasma or hippocampal DHT
Our findings support the hypothesis that aged rats would have decreased plasma and hippocampal androgen levels, and that androgen regimen that increased plasma 3α-diol would enhance cognitive and affective behavior of rats with decreased steroid levels due to GDX or aging
Summary
The hippocampus may be a target of androgens during aging. Alzheimer’s Disease (AD), associated with profound loss of declarative memory, medial temporal lobe/hippocampus degeneration, and extensive accumulation of β-amyloid, is the most common form of dementia in the elderly, and is more prevalent in women, as compared to men (Light, 1991; Howieson et al, 1993). Persons with AD (Pike and Savage, 2008), those with lesions of the hippocampus (Rosenbaum et al, 2007), and/or androgen deprivation (Freedland et al, 2009), can all experience impairments in the processes by which information is consolidated or shifted to permanent storage compared to healthy, middle-aged counterparts. Age-associated increases in β-amyloid can be exacerbated by T deprivation in people (Almeida et al, 2004; Sunderland et al, 2004) and male mice (Rosario et al, 2006). Together, these findings suggest that androgens may play a role in age-related, hippocampally-influenced, cognitive behavior
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