Acetylcholine (ACh) release in the hippocampus increases during learning or exploration, exhibiting a sex-specific 24-h release profile. We examined the activational effect of gonadal steroid hormones on the ACh levels. Gonadectomy severely attenuated the ACh levels and severely reduced the correlation with spontaneous behaviors. The testosterone replacement in gonadectomized males or estradiol replacement in gonadectomized females successfully restored the ACh levels and the correlation. However, estradiol-priming in gonadectomized males could not restore the ACh levels, and testosterone replacement in gonadectomized females failed to raise ACh levels to those seen in testosterone-primed gonadectomized males, revealing a sex-specific activational effect. Moreover, neonatal testosterone or estradiol treatment not only increased the ACh levels but also altered them to resemble male-specific ACh release properties without affecting behavioral levels. We conclude that the activational effects of gonadal steroids maintaining the ACh levels are sex-specific, and that neonatal sexual differentiation of cholinergic system may suggest sex-specific clinical strategies for Alzheimer’s disease. (The Journal of Neuroscience, 29:3808-3815, 2009)
Figure Gonadal steroids maintain the sex-specific ACh release in the hippocampus. The testosterone (T) replacement in gonadectomized males or estradiol (E) replacement in gonadectomized females successfully restored the ACh levels and the correlation with spontaneous behaviors. Moreover, neonatal activation of estrogen receptors masculinizes the sex-specific action of gonadal steroids.
*Department of Physiology, Yokohama City University Graduate School of Medicine
