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

Abstract

Masculinization of the rodent brain is driven by estrogen signaling during a perinatal critical period. Genetic deletion of estrogen receptor alpha (Esr1/ER) results in altered hypothalamic-pituitary-gonadal (HPG) axis signaling and a dramatic reduction of male sexual and territorial behaviors. However, the requirement of ER function in masculinizing distinct classes of neurons, and if these populations mediate components of male-typical behavior, remains unexplored. We deleted ER 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 ERa 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 ER deletion, but have none of the behavioral deficits. In contrast, Vgat-Cre;Esr1lox/lox males with substantial ER 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 demasculinized expression of androgen receptor (AR) and estrogen receptor beta (Esr2). Our results demonstrate that ER masculinizes GABAergic neurons that gate the display of male-typical behaviors.