Abstract
Sexual dysfunction and cognitive deficits are markers of the aging process. Mammalian sirtuins (SIRT), encoded by sirt 1-7 genes, are known as aging molecules which are sensitive to serotonin (5-hydroxytryptamine, 5-HT). Whether the 5-HT system regulates SIRT in the preoptic area (POA), which could affect reproduction and cognition has not been examined. Therefore, this study was designed to examine the effects of citalopram (CIT, 10 mg/kg for 4 weeks), a potent selective-serotonin reuptake inhibitor and aging on SIRT expression in the POA of male mice using real-time PCR and immunocytochemistry. Age-related increases of sirt1, sirt4, sirt5, and sirt7 mRNA levels were observed in the POA of 52 weeks old mice. Furthermore, 4 weeks of chronic CIT treatment started at 8 weeks of age also increased sirt2 and sirt4 mRNA expression in the POA. Moreover, the number of SIRT4 immuno-reactive neurons increased with aging in the medial septum area (12 weeks = 1.00 ± 0.15 vs. 36 weeks = 1.68 ± 0.14 vs. 52 weeks = 1.54 ± 0.11, p < 0.05). In contrast, the number of sirt4-immunopositive cells did not show a statistically significant change with CIT treatment, suggesting that the increase in sirt4 mRNA levels may occur in cells in which sirt4 is already being expressed. Taken together, these studies suggest that CIT treatment and the process of aging utilize the serotonergic system to up-regulate SIRT4 in the POA as a common pathway to deregulate social cognitive and reproductive functions.
Highlights
Aging of the central nervous system deregulates homeostatic mechanisms responsible for sexual behavior (Davidson et al, 1983), feeding (Weindruch et al, 2001), sleep (Nakamura et al, 2011) and cognition (Barrientos et al, 2012)
Chronic Citalopram Treatment Mice were administered with CIT [10 mg/kg body weight (BW) in 50 μl, C7861, Sigma-Aldrich, Singapore; n = 15] or 50 μl vehicle daily at 9 a.m. by intraperitoneal (i.p) injections for 4 weeks beginning at 8 weeks of age until 12 weeks of age
SIRT4 Immunoreactive Analysis preoptic area (POA) sections were viewed using bright-field microscopy (Nikon Eclipse 50i) and images were captured in TIF format (Nikon, FIGURE 3 | Nicotinamide adenine dinucleotide (NAD) biosynthethic enzymes were not affected by chronic citalopram (CIT) treatment or aging
Summary
Aging of the central nervous system deregulates homeostatic mechanisms responsible for sexual behavior (Davidson et al, 1983), feeding (Weindruch et al, 2001), sleep (Nakamura et al, 2011) and cognition (Barrientos et al, 2012). To understand the mechanism of reproductive aging and cognitive loss, it is important to examine the serotonergic system in the POA during aging. The family of seven sirtuin (SIRT) proteins is involved in the aging mechanism, which may include reproductive aging (Duan, 2013). SIRT proteins are involved in energy balance, reproduction and in brain aging (Duan, 2013). Whether the 5-HT system regulates SIRT in the POA, which could affect the HPG axis, reproduction and cognition has not been examined. Treatment with citalopram (CIT), a potent selective-serotonin reuptake inhibitor, shows deficits in sexual behavior in adult mice (Soga et al, 2010) and sexual dysfunction in humans(Montejo et al, 2001), a condition that mimics aging, which has decreased 5-HT synthesis (Hussain and Mitra, 2000). This study was design to examine the effect of CIT and aging on sirt mRNA and SIRT expression in the POA of male mice using real-time PCR and immunocytochemistry respectively
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