Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis

Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13100-5. doi: 10.1073/pnas.1210023109. Epub 2012 Jul 17.

Abstract

Mild exercise activates hippocampal neurons through the glutamatergic pathway and also promotes adult hippocampal neurogenesis (AHN). We hypothesized that such exercise could enhance local androgen synthesis and cause AHN because hippocampal steroid synthesis is facilitated by activated neurons via N-methyl-D-aspartate receptors. Here we addressed this question using a mild-intense treadmill running model that has been shown to be a potent AHN stimulator. A mass-spectrometric analysis demonstrated that hippocampal dihydrotestosterone increased significantly, whereas testosterone levels did not increase significantly after 2 wk of treadmill running in both orchidectomized (ORX) and sham castrated (Sham) male rats. Furthermore, analysis of mRNA expression for the two isoforms of 5α-reductases (srd5a1, srd5a2) and for androgen receptor (AR) revealed that both increased in the hippocampus after exercise, even in ORX rats. All rats were injected twice with 5'-bromo-2'deoxyuridine (50 mg/kg body weight, i.p.) on the day before training. Mild exercise significantly increased AHN in both ORX and Sham rats. Moreover, the increase of doublecortin or 5'-bromo-2'deoxyuridine/NeuN-positive cells in ORX rats was blocked by s.c. flutamide, an AR antagonist. It was also found that application of an estrogen receptor antagonist, tamoxifen, did not suppress exercise-induced AHN. These results support the hypothesis that, in male animals, mild exercise enhances hippocampal synthesis of dihydrotestosterone and increases AHN via androgenenic mediation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / metabolism
  • Age Factors
  • Animals
  • Bromodeoxyuridine
  • Dihydrotestosterone / metabolism*
  • Hippocampus / cytology*
  • Hippocampus / metabolism
  • Male
  • Mass Spectrometry
  • Membrane Proteins / metabolism
  • Motor Activity / physiology*
  • Neurogenesis / physiology*
  • Neurons / metabolism*
  • Orchiectomy
  • Rats
  • Receptors, Androgen / metabolism
  • Tamoxifen

Substances

  • Membrane Proteins
  • Receptors, Androgen
  • Dihydrotestosterone
  • Tamoxifen
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
  • Srd5a1 protein, rat
  • Srd5a2 protein, rat
  • Bromodeoxyuridine