The biology of fatherhood: A novel role for progesterone receptors in male physiology and behavior.

摘要

Progesterone receptors (PR) are ligand-inducible transcription factors that mediate the majority of the effects of progesterone on neuroendocrine functions. PR-mediated mechanisms in the regulation of male reproductive physiology and behavior are largely uncharacterized. Using mice that express a null mutation for PR, the effects of PR ablation on neuroendocrine mechanisms of male behavior and PR-mediated regulation of male endocrine systems were examined.; Male progesterone receptor knockout mice (PRKO) exhibit minor reproductive abnormalities including altered gonadotropin secretion and increased basal inhibin levels. In contrast, these males exhibit significant alterations in reproductive behaviors. We found that male PRKO mice exhibit no infanticidal behavior, little aggression towards young and significantly enhanced parental behaviors. In wild-type mice, blockade of PR induces a behavioral phenotype similar to that of PRKO males, while progesterone exacerbates aggressive tendencies toward infants. Aggressive behaviors directed towards adult males are unaffected by progesterone, PR antagonism, or PR gene deletion. Thus, PRs play a critical and specific role in modulating infant-directed behaviors in male mice.; We hypothesized that the mechanisms regulating paternal behavior are linked to those regulating other reproductive behaviors, specifically sexual behavior. Male PRKO mice exhibit altered sexual behaviors despite being fertile and exhibiting no gross testicular morphological differences. The differences in sexual behavior are independent of testosterone levels suggesting a PR-dependent regulation of sexual behavior in the male. We hypothesized that this increase in sexual behavior coupled with the increase in paternal behavior could be due to a differential stress response to novel environments. Basal anxiety levels in PRKO males, however, are higher than wild-type males indicating the PRKO behaviors are not a result of reduced anxiety and highlights a role for PR in the regulation anxiogenesis.; These studies establish for the first time that neuronal PRs play several key roles in the regulation of paternal behavior, aggression towards infants, sexual behavior and anxiogenesis in males. Although the molecular signaling pathways mediating these actions remain to be determined, these behavioral abnormalities in the absence of any significant alterations in hormone secretion or fertility, suggest PR is a neurochemical switch that can regulate a wide array of male behaviors.