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The reward system in healthy ageing and its modulation by gonadal steroid hormones: multimodal neuroimaging studies (fMRI/PET)

Final Report Summary - AGING_HORMONE (The reward system in healthy ageing and its modulation by gonadal steroid hormones: multimodal neuroimaging studies (fMRI/PET))

With the increasing lifespan expectancy in modern societies, successful aging becomes a challenging socioeconomic problem. Sex steroids are known to influence not only sexual and reproductive behaviour, but also to shape cognitive functions. Aging is accompanied by gonadal steroid function decline, which may, in part, be responsible for age-related cognitive impairment. Achieving an understanding of how key brain circuits, such as the reward system and the neural networks involved in decision making, known to be modulated by aging, change with variations of gonadal steroids levels is an integral part of rising to this crucial public health issue.

The goals of this research project were to investigate the effects of gonadal steroid hormones on reward processing and decision making in older women and healthy young men. We performed four different event-related functional magnetic resonance imaging (fMRI) experiments: two studies in early post-menopausal women scanned twice, after placebo and after Hormonal Treatment (17Beta estradiol+progesterone), and two studies in young men (2 groups of subjects: placebo/testosterone treatment). The first two experiments investigated how HT modulates the reward system and cognitive flexibility in healthy early post-menopausal women using a counterbalanced, double-blind, randomised, placebo-controlled design. In two fMRI experiments in young men, we studied the effects of testosterone or placebo injection on brain activity related to reward processing and social decision making:
(a) processing of primary (erotic stimuli) and secondary (monetary) rewards;
(b) social interaction during a modified behavioural economics paradigm testing inequity aversion, retaliation behaviour after unfair offers and prosocial behaviour after generous offers. Estradiol levels were measured in women and testosterone levels were measured in men after taking blood samples.

The results in early post-menopausal women indicate a neurofunctional modulation of the reward system and cognitive control by HT and may establish a neurobiological foundation for understanding the beneficial influences that HT may exert on brain activity related to reward processing and cognitive control. These findings have important clinical implication because oestrogen therapy may decrease cognitive decline in aging women if it is initiated around the time of menopause but not if it is administered decades later.

In men, the results showed that testosterone differentially modulates anticipatory and reception-related reward processing. These findings indicate that testosterone modulates mesolimbic dopaminergic pathways involved in incentive motivation and reward processing. Moreover, the role of testosterone in human social behaviour and neural functioning support both social status seeking and pro-social behaviour. Indeed, subjects administered with testosterone tended to punish more unfair offers and to reward more generous offers than subjects under placebo, suggesting that the effects of this steroid hormone depend on the social situation, promoting both retaliation / status-seeking and altruistic behaviours.

Together, these results provide evidence of a neurofunctional modulation of the reward system and of decision making mechanisms by gonadal steroid hormones in humans and establish a neurobiological foundation for understanding the impact of gonadal steroid hormones on vulnerability to drug abuse, neuropsychiatric diseases with differential expression across males and females, and hormonally mediated mood disorders. The ground-breaking character of this research is to combine endocrinology and functional brain imaging in healthy men and women. It allowed us to disentangle the effect of aging and hormonal changes, often intermingle during the aging process, by revealing how hormonal treatments influence the brain systems involved in reward processing and decision making.