Activational effects of estradiol and dihydrotestosterone on social recognition and the arginine-vasopressin immunoreactive system in male mice lacking a functional aromatase gene

Abstract

In rodents, parts of the arginine-vasopressin (AVP) neuronal system are sexually dimorphic with males having more AVP-immunoreactive cells/fibers than females. This neuropeptide neuronal system is highly sensitive to steroids and has been proposed to play an important role in the processing of olfactory cues critical to the establishment of a social memory. We demonstrate here that gonadally intact male aromatase knockout (ArKO) mice, which cannot aromatize androgens into estrogens due to a targeted mutation in the aromatase gene, showed severe deficits in social recognition as well as a reduced AVP-immunoreactivity in several brain regions. To determine whether this reduction is due to a lack of organizational or activational effects of estrogens, we assessed social recognition abilities and AVP-immunoreactivity in male ArKO and wild-type (WT) mice when treated with estradiol benzoate (EB) in association with dihydrotestosterone propionate (DHTP) in adulthood. Adult treatment with EB and DHTP restored social recognition abilities in castrated ArKO males since they showed normal female-oriented ultrasonic vocalizations and were able to recognize an unfamiliar female using a habituation-dishabituation paradigm. Furthermore, adult treatment also restored AVP-immunoreactivity in the lateral septum of ArKO males to levels observed in intact WT males. These results suggest that social recognition in adulthood and stimulation of AVP expression in the adult mouse forebrain depend predominantly on the estrogenic metabolite of testosterone. Furthermore, our results are in line with the idea that the organization of the AVP system may depend on androgen or sex chromosomes rather than estrogens.

Male risk taking, female odors, and the role of estrogen receptors

“…This is in agreement with the findings that non-copulating rats, while having similar testosterone levels as copulating rats, display reduced neuronal aromatase (Ar) activity and levels of ERα [131,132]. ArKO mice have a similar social and sexual phenotype as the ERαKO [128,133] further supporting the idea of aromatase and ERα dependent responses.…”

Insights into Rapid Modulation of Neuroplasticity by Brain Estrogens

“…Male aromatase KO mice display impairments in spatial reference memory (Martin et al, 2003), whereas severe deficits in social memory were seen in both gonadally intact and castrated male aromatase KO mice (Pierman et al, 2008). Interestingly, when gonadally intact or castrated male aromatase null mice were treated with estradiol benzoate, in association with dihydrotestosterone propionate, a recovery in social recognition was observed (Pierman et al, 2008). Collectively, these studies indicate that 17b-estradiol contributes to cognition in male rodents.…”

“…Several strains of aromatase KO mice have been produced (Fisher et al, 1998;Honda et al, 1998;Toda et al, 2001), resulting in mice that are estrogen deficient and hyperandrogenic. Male aromatase KO mice display impairments in spatial reference memory (Martin et al, 2003), whereas severe deficits in social memory were seen in both gonadally intact and castrated male aromatase KO mice (Pierman et al, 2008). Interestingly, when gonadally intact or castrated male aromatase null mice were treated with estradiol benzoate, in association with dihydrotestosterone propionate, a recovery in social recognition was observed (Pierman et al, 2008).…”

Oxytocin and social motivation

“…However, the most compelling evidence suggesting the HPG axis is crucial for maternal behavior comes from studies of mice that lack either aromatase (Ogawa et al, 1998; Spiteri et al, 2010a, 2010b) or estrogen receptor (ER) alpha (Pierman et al, 2008), which are discussed in the genetics section.…”

“…Concerning the HPG axis, gene knockout studies have found that mice lacking a key enzyme involved in estrogen synthesis, aromatase, display deficits in social recognition (essential for establishing the mother-infant bond) and AVP activation (Pierman et al, 2008). They also report that the exogenous administration of estrogen recovers social recognition and AVP activation.…”