Androgens Increase Survival of Adult-Born Neurons in the Dentate Gyrus by an Androgen Receptor-Dependent Mechanism in Male Rats

• Published in: Endocrinology (Philadelphia) 2013-09, Vol.154 (9), p.3294-3304
• Main Authors: Hamson, D. K, Wainwright, S. R, Taylor, J. R, Jones, B. A, Watson, N. V, Galea, L. A. M
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Androgen Antagonists - toxicity; Androgen receptors; Androgen-Insensitivity Syndrome - chemically induced; Androgen-Insensitivity Syndrome - drug therapy; Androgen-Insensitivity Syndrome - metabolism; Androgens; Androgens - chemistry; Androgens - metabolism; Androgens - pharmacology; Androgens - therapeutic use; Animals; Biological and medical sciences; Biomarkers - metabolism; Brain; Castration - adverse effects; Cell proliferation; Cell survival; Cell Survival - drug effects; Dentate gyrus; Dentate Gyrus - cytology; Dentate Gyrus - drug effects; Dentate Gyrus - metabolism; Dentate Gyrus - pathology; Dihydrotestosterone; Doublecortin protein; Drug Resistance; Experiments; Flutamide; Fundamental and applied biological sciences. Psychology; Hippocampus; Hormone Replacement Therapy; Male; Males; Microtubule-Associated Proteins - metabolism; Mutant Proteins - agonists; Mutant Proteins - antagonists & inhibitors; Mutant Proteins - metabolism; Mutation; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurodegenerative diseases; Neurogenesis; Neurogenesis - drug effects; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuropeptides - metabolism; Neuroprotective Agents - antagonists & inhibitors; Neuroprotective Agents - metabolism; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Rats; Rats, Sprague-Dawley; Receptors; Receptors, Androgen - chemistry; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Sex hormones; Signal Transduction - drug effects; Survival; Testes; Testosterone; Testosterone Propionate - antagonists & inhibitors; Testosterone Propionate - pharmacology; Testosterone Propionate - therapeutic use; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2013-1129

Gonadal steroids are potent regulators of adult neurogenesis. We previously reported that androgens, such as testosterone (T) and dihydrotestosterone (DHT), but not estradiol, increased the survival of new neurons in the dentate gyrus of the male rat. These results suggest androgens regulate hippocampal neurogenesis via the androgen receptor (AR). To test this supposition, we examined the role of ARs in hippocampal neurogenesis using 2 different approaches. In experiment 1, we examined neurogenesis in male rats insensitive to androgens due to a naturally occurring mutation in the gene encoding the AR (termed testicular feminization mutation) compared with wild-type males. In experiment 2, we injected the AR antagonist, flutamide, into castrated male rats and compared neurogenesis levels in the dentate gyrus of DHT and oil-treated controls. In experiment 1, chronic T increased hippocampal neurogenesis in wild-type males but not in androgen-insensitive testicular feminization mutation males. In experiment 2, DHT increased hippocampal neurogenesis via cell survival, an effect that was blocked by concurrent treatment with flutamide. DHT, however, did not affect cell proliferation. Interestingly, cells expressing doublecortin, a marker of immature neurons, did not colabel with ARs in the dentate gyrus, but ARs were robustly expressed in other regions of the hippocampus. Together these studies provide complementary evidence that androgens regulate adult neurogenesis in the hippocampus via the AR but at a site other than the dentate gyrus. Understanding where in the brain androgens act to increase the survival of new neurons in the adult brain may have implications for neurodegenerative disorders.