| Popis: |
Sexual dysfunction affects approximately one third of men and 40% of women in the United States and world-wide. Unfortunately, existing treatments that target the periphery are not effective for all types of sexual dysfunction, and the involvement of the central nervous system in sexual behavior is not well-understood. Preclinical data has shown that central melanocortins and their receptors, particularly the melanocortin 4 receptor (MC4R), may play a role in sexual behavior in both male and female rodents. We found that six-month-old male MC4R null mice showed evidence of erectile dysfunction and an inability to ejaculate. Due to the high expression of MC4R in the paraventricular nucleus of the hypothalamus (PVN), we hypothesized that the PVN is a key site of melanocortin-mediated sexual behavior. Using Sim1 as a target for the PVN, we tested the sexual behavior of a tbMC4RSim1 transgenic mouse model in which MC4R was only expressed on Sim1 neurons. These mice did not have the sexual impairments seen in MC4RKO mice, implying that MC4R on Sim1 neurons is sufficient for erectile function and ejaculation. To reduce the confound of age-related obesity in MC4RKO mice, we also tested these mice at two-months of age. The younger MC4RKO mice had a different phenotype, with the only sexual deficit being delayed ejaculation. This was also recovered in tbMC4RSim1 mice. Furthermore, expressing MC4R only on oxytocin neurons similarly recovered the sexual impairment in MC4R null males. Finally, a metabolic profile indicated that the delayed ejaculation seen in MC4RKO mice at two months of age was independent of MC4R-mediated weight gain. Female MC4RKO mice had a decreased lordosis quotient at two months of age. Expression of MC4R only on Sim1 neurons or oxytocin neurons resulted in a lordosis quotient comparable to controls, despite a similar metabolic profile to MC4R null mice. This study implicates MC4R on Sim1 neurons, and more specifically oxytocin neurons, in the central neurocircuitry underlying sexual behavior in both male and female mice. |
