Control of cell number in the bed nucleus of the stria terminalis of mice: role of testosterone metabolites and estrogen receptor subtypes.
BACKGROUND
The bed nucleus of the stria terminalis (BNST) exhibits several sex differences that may be related to male sexual behavior and gender identity. In mice and rats, sex differences in the principal nucleus of the BNST (BNSTp) are due to sexually dimorphic cell death during perinatal life. Although testosterone treatment of newborn female rats increases BNSTp cell number, the relevant hormone metabolite(s) are not known, and the effect of testosterone on the development of BNSTp cell number in mice has not been examined.


OBJECTIVE
To identify the sex hormone metabolites and receptors controlling cell number, volume, and cell size in the BNSTp of mice.


METHODS
In the first experiment, C57BL/6J male mice were injected on the day of birth with peanut oil; females were injected with testosterone propionate (TP), estradiol benzoate (EB), dihydrotestosterone propionate (DHTP), or oil alone, and the BNSTp of all animals was examined in adulthood. In the second experiment, to compare effects of EB to the effects of estrogen receptor subtype specific agonists, newborn female mice were injected with EB, propyl-pyrazole-triol (PPT, a selective estrogen receptor alpha [ERalpha] agonist), or diarylpropionitrile (DPN, a selective estrogen receptor beta [ERbeta] agonist).


METHODS
Nuclear volume measurements and stereological cell counts in the BNSTp in adulthood.


RESULTS
TP treatment of newborn females completely masculinized both BNSTp volume and cell number. EB masculinized neuron number, whereas DHTP had no effect on volume or cell number. In the second experiment, EB again fully masculinized neuron number in the BNSTp and in this study also masculinized BNSTp volume. PPT and DPN each significantly increased cell number, but neither completely mimicked the effects of EB.


CONCLUSIONS
We conclude that estrogenic metabolites of testosterone control sexually dimorphic cell survival in the BNSTp and that activation of both ERalpha and ERbeta may be required for complete masculinization of this brain region.
Hisasue
Shin-ichi
S
Department of Psychology and Center for Neuroendocrine Studies, University of Massachusetts, Amherst, MA, USA. hisasue@sapmed.ac.jp
Seney
Marianne L
ML
Immerman
Eleanor
E
Forger
Nancy G
NG
D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D048429:Cell Size / Q000187:drug effects; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000187:drug effects* / Q000502:physiology*; D005260:Female; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology*; D010636:Phenols; D011422:Propionates / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D012686:Septal Nuclei / Q000166:cytology*; D012733:Sex Differentiation / Q000187:drug effects* / Q000502:physiology*; D043343:Testosterone Propionate / Q000494:pharmacology*
C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009570:Nitriles; D010636:Phenols; D011422:Propionates; D011720:Pyrazoles; D013196:Dihydrotestosterone; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; C074283:estradiol 3-benzoate; D004958:Estradiol; C030445:dihydrotestosterone propionate; D043343:Testosterone Propionate