Estrogen receptor alpha is required in GABAergic, but not glutamatergic, neurons to masculinize behavior

Horm Behav. 2017 Sep:95:3-12. doi: 10.1016/j.yhbeh.2017.07.001. Epub 2017 Jul 20.

Abstract

Masculinization of the altricial rodent brain is driven by estrogen signaling during a perinatal critical period. Genetic deletion of estrogen receptor alpha (Esr1/ERα) results in altered hypothalamic-pituitary-gonadal (HPG) axis signaling and a dramatic reduction of male sexual and territorial behaviors. However, the role of ERα in masculinizing distinct classes of neurons remains unexplored. We deleted ERα in excitatory or inhibitory neurons using either a Vglut2 or Vgat driver and assessed male behaviors. We find that Vglut2-Cre;Esr1lox/lox mutant males lack ERα in the ventrolateral region of the ventromedial hypothalamus (VMHvl) and posterior ventral portion of the medial amygdala (MePV). These mutants recapitulate the increased serum testosterone levels seen with constitutive ERα deletion, but have none of the behavioral deficits. In contrast, Vgat-Cre;Esr1lox/lox males with substantial ERα deletion in inhibitory neurons, including those of the principal nucleus of the bed nucleus of the stria terminalis (BNSTpr), posterior dorsal MeA (MePD), and medial preoptic area (MPOA) have normal testosterone levels, but display alterations in mating and territorial behaviors. These mutants also show dysmasculinized expression of androgen receptor (AR) and estrogen receptor beta (Esr2). Our results demonstrate that ERα masculinizes GABAergic neurons that gate the display of male-typical behaviors.

MeSH terms

  • Aggression / physiology
  • Animals
  • Brain / metabolism
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor alpha / physiology*
  • Estrogens / metabolism
  • Female
  • GABAergic Neurons / metabolism*
  • Glutamic Acid / metabolism*
  • Hypothalamus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / metabolism*
  • Sexual Behavior, Animal / physiology*
  • Territoriality
  • Virilism / genetics*
  • Virilism / metabolism

Substances

  • Estrogen Receptor alpha
  • Estrogens
  • Glutamic Acid