Short-term testosterone manipulations do not affect cognition or motor function but differentially modulate emotions in young and older male rhesus monkeys
Introduction
Human cognitive aging is characterized by declines in working memory, executive function, long-term memory and speed of processing (Park and Schwartz, 2000). These declines are substantial, develop as early as the 30s and affect everyone (Salthouse, 2010). Deficits in fine motor function also develop with age (Seidler et al., 2010, Smith et al., 1999), and can lead to serious impairments in quality of life and activities of daily living (Desrosiers et al., 1999). In contrast to the age-related declines in cognitive and motor function, emotional regulation has consistently been shown to significantly improve with age in humans (Carstensen et al., 2003, Carstensen et al., 2011).
With the aging population growing at an unprecedented rate worldwide (Kinsella and Wan, 2009), it is imperative to design interventions that would lessen age-related declines in cognitive and motor function. Because both estrogens and androgens affect cognition and motor function (Hampson, 2002) and decline with age in men (Harman et al., 2001) and women (Burger, 1996), hormone replacement therapy (HRT) has long been considered as such an intervention. Most of the work on this issue has focused on women’s health and has provided inconsistent and still highly debated results regarding the potential benefits of HRT on cognitive aging (Maki and Henderson, 2012, Sherwin and Henry, 2008). Fewer data are available regarding the effects of testosterone (T) on cognition in older men, but they also show mixed results. Whereas positive effects of T have been reported for spatial and verbal memory (Cherrier et al., 2001), spatial ability (Janowsky et al., 1994) and working memory (Janowsky et al., 2000), other studies found detrimental effects of T on verbal memory (Maki et al., 2007) or no effect of T on cognition (Emmelot-Vonk et al., 2008, Young et al., 2010). With regards to motor function, very limited data are available, with one recent report finding no effect of T on sequential movement in young or older adults (Siegel et al., 2008). Finally, growing evidence indicates that T increases amygdala reactivity (van Wingen et al., 2011) and has a robust influence on socioemotional processing, at least in young adults (Bos et al., 2012, Eisenegger et al., 2011). Surprisingly little is known about the effects of T on emotions in older adults, although antidepressant effects have been noted (Zarrouf et al., 2009).
Well-controlled investigations in appropriate animal models are clearly needed to shed a new light on the association between T and brain functioning in males. Studies in male rats have shown that T affects brain regions important for cognitive function: T increases the number of dendritic spines in the CA1 field of the hippocampus (Leranth et al., 2003) as well as the prefrontal cortex (Hajszan et al., 2007). In addition, T has a myriad of neurotrophic and neuroprotective effects, which have been implicated in a decreased risk of developing Alzheimer’s disease (Pike et al., 2006, Pike et al., 2008).
Cognitive studies in male rats have generally found that T administration was able to restore memory impairments induced by gonadectomy in a wide range of working memory tasks such as the Morris water maze (Sandstrom et al., 2006, Spritzer et al., 2011), radial arm maze (Gibbs and Johnson, 2008, Spritzer et al., 2008), Y maze (Hawley et al., 2013) or delayed matching-to-position task (Gibbs, 2005). The effects of T are complex, however, and appear dose-, duration- and task-dependent (Spritzer et al., 2011). For example, Spritzer et al (2011) indicated that T differentially affected working memory and reference memory depending on the test used, the dose used and the timing of T administration. There is a paucity of data on the effects of T on cognition in aged male rodents. In one study, T administered to supraphysiological levels increased working memory in aged male rats (Bimonte-Nelson et al., 2003). An earlier study, however, failed to find any beneficial effects of T on spatial learning in aged male rats tested in the Morris water maze (Goudsmit et al., 1990). It has generally been found that the cognitive effects of T in male rodents are not mediated by sensorimotor effects (Kritzer et al., 2001).
Besides its cognitive effects, T has been shown to modulate the reactivity of the hypothalamic–pituitary–adrenal axis (Bingham et al., 2011, Handa et al., 1994) and to have anxiolytic effects in a number of studies in male rodents (Aikey et al., 2002, Bitran et al., 1993, Edinger and Frye, 2004, Fernandez-Guasti and Martinez-Mota, 2005, Toufexis et al., 2005), cattle (Boissy and Bouissou, 1994) and ewes (Bouissou and Vandenheede, 1996). However, whether the anxiolytic properties of T are maintained in aged animals is not known.
Male rhesus monkeys are particularly well suited for investigating the effects of T on cognition, motor function and emotions because they share many characteristics with humans, including in the organization of the brain and neuroendocrine systems (Sorwell and Urbanski, 2013). They exhibit age-related declines in cognition (Baxter, 2001, Herndon and Lacreuse, 2002, Herndon et al., 1997), fine motor function (Lacreuse et al., 2005, Zhang et al., 2000), and T levels (Sorwell and Urbanski, 2013) that closely resemble those observed in humans. In addition, rhesus monkeys are highly social primates that share a vast repertoire of socioemotional behaviors with humans (Kalin and Shelton, 2003). However, there is a paucity of data on age-related changes in socioemotional behaviors. In a longitudinal study spanning the ages of 6 to 20 years, Suomi et al. (1996) reported that older rhesus monkeys retained the temperamental characteristics that they exhibited in early adulthood, but that the distribution of specific activities (e.g., agonism) changed across time. In a related macaque species (M. fascicularis), Veenema et al. (1997) found in contrast that older females withdrew from social interactions and showed increased arousal (as shown by increased frequencies of yawning, scratching, and body shaking), perhaps due to the inability to deal with complex social interactions. Thus, it remains unclear how emotions change with age in macaques and what influence, if any, T may exert on this pattern.
The goal of the present study was to examine the effects of low and high T conditions on cognitive, motor and emotional behavior in aged male rhesus monkeys. We tested 10 aged males in a battery of tasks assessing these functions and compared the results to those of 6 younger male rhesus monkeys tested in the same paradigms in prior studies from our laboratory (Lacreuse et al., 2009, Lacreuse et al., 2010). Based on the literature referenced above, we predicted that T would improve selective aspects of cognition, would have little or no effect on motor function, and would bias emotional processing towards negative stimuli.
Section snippets
Subjects
Ten aged adult male rhesus monkeys (mean age = 19 years, range = 15–25 years) participated in the study. Their performance on a battery of cognitive, emotional and fine motor tasks was compared to that of 6 younger male rhesus monkeys (mean age = 5.8 years, range = 5–6 years), whose cognitive (Lacreuse et al., 2009) and emotional data (Lacreuse et al., 2010) have been published previously (see Table 1). Data on the older group were collected over 2009–2011. Data in the young monkeys were collected during
T levels
T levels for the 10 aged monkeys can be seen in Fig. 2. Due to the use of different RIA kits between the two age groups, we were not able to compare T levels between young and older monkeys. However, inspection of Fig. 2 does not show any obvious differences between the two groups. The ANOVA indicated a significant effect of Phase on T levels (F(3, 24) = 14.61, p < .001; η2 = 0.62) with no effect of Sequence (F(1,8) = 0.39, ns; η2 = 0.04) or Phase by Sequence interaction (F(3,24) = 0.76, η2 = 0.03). Planned
Discussion
In this study, 10 aged male rhesus monkeys were tested on a battery of cognitive, emotional and fine motor tasks at baseline and under high T and low T conditions induced by treatment with a GnRH agonist and add-back of T or oil vehicle. Their performance was compared to that of 6 young adult males previously tested in the same paradigm in our laboratory.
Acknowledgments
This research was supported in part by a research grant from the American Federation for Aging Research to Agnès Lacreuse, by NCRR Grant #RR11122 to Melinda A. Novak and by Grant #RR00168 to the New England Primate Research Center. We are grateful to Karen Stonemetz and Emily Kaplan for their help with data collection, Dr. Angela Carville for administering the treatments at the NEPRC and Dr. Sarah Partan for providing the video clips. We thank Dr. Jerrold Meyer for his assistance with the
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2017, Hormones and BehaviorCitation Excerpt :Comparable data are not available from non-human primates. Captive rhesus macaques that were given exogenous testosterone significantly increased their time spent watching video clips of fights between unfamiliar conspecifics, however, suggesting equivalent effects (Kelly et al. 2014, Lacreuse et al. 2010). Testosterone has the additional action, in a range of species, of reducing fear and anxiety in both social and non-social contexts.