TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors.

Testosterone regulates dimorphic sexual behaviors in all vertebrates. However, the molecular mechanism underlying these behaviors remains unclear. Here, we report that a newly identified rapid testosterone signaling receptor, Transient Receptor Potential Melastatin 8 (TRPM8), regulates dimorphic sexual and social behaviors in mice. We found that, along with higher steroid levels in the circulation, TRPM8-/- male mice exhibit increased mounting frequency indiscriminate of sex, delayed sexual satiety, and increased aggression compared to wild-type controls, while TRPM8-/- females display an increased olfaction-exploratory behavior. Furthermore, neuronal responses to acute testosterone application onto the amygdala were attenuated in TRPM8-/- males but remained unchanged in females. Moreover, activation of dopaminergic neurons in the ventral tegmental area following mating was impaired in TRPM8-/- males. Together, these results demonstrate that TRPM8 regulates dimorphic sexual and social behaviors, and potentially constitutes a signalosome for mediation of sex-reward mechanism in males. Thus, deficiency of TRPM8 might lead to a delayed sexual satiety phenomenon.

Perinatal High-Fat Diet and Bisphenol A: Effects on Behavior and Gene Expression in the Medial Prefrontal Cortex.

Both high-fat diets (HFD) and bisphenol A (BPA), an environmental endocrine disruptor, are prevalent in industrialized societies. Previous studies have detected separate effects of BPA and HFD; however, none have assessed possible interactive effects. Here, pregnant dams consumed 0, 40, or 400 µg BPA/kg/day and were fed either a control (CON; 15.8% kcal fat) or HFD (45% kcal fat) from gestational day 2 through parturition. The pups were individually dosed with BPA from postnatal days (P) 1-10, while the dams continued to consume one of the two diets. Maternal behavior increased with the HFD while the offspring's periadolescent social play decreased with BPA, but no interactive effects were observed. Neither HFD nor BPA exposure changed performance on a social recognition task, and only BPA had an effect on the elevated plus maze. BPA increased several cytokines in the medial prefrontal cortex (mPFC) of P10 males but not females. Expression of several genes related to hormone synthesis and receptors, inflammation, oxidative stress, and apoptosis in the mPFC on P10 and P90 were altered due to BPA and/or HFD exposure with rare interactive effects. BPA resulted in an increase in the gene expression of Esr1 in the mPFC of females on both P10 and P90. Epigenetic analysis on P90 did not show a change in methylation or in the levels of pre-mRNA or microRNA. Thus, perinatal BPA and HFD have separate effects but rarely interact.

Long-term effects of adolescent exposure to bisphenol A on neuron and glia number in the rat prefrontal cortex: Differences between the sexes and cell type.

Bisphenol A (BPA), an endocrine disruptor used in a variety of consumer products, has been found to alter the number of neurons in multiple brain areas in rats following exposure in perinatal development. Both the number of neurons and glia also change in the medial prefrontal cortex (mPFC) during adolescence, and this process is known to be influenced by gonadal hormones which could be altered by BPA. In the current study, we examined Long-Evans male and female rats that were administered BPA (0, 4, 40, or 400µg/kg/day) during adolescent development (postnatal days 27-46). In adulthood (postnatal day 150), the number of neurons and glia in the mPFC were stereologically assessed in methylene blue/azure II stained sections. There were no changes in the number of neurons, but there was a significant dose by sex interaction in number of glia in the mPFC. Pairwise comparisons between controls and each dose showed a significant increase in the number of glia between 0 and 40µg/kg/day in females, and a significant decrease in the number of glia between 0 and 4µg/kg/day in males. In order to determine the type of glial cells that were changing in these groups in response to adolescent BPA administration, adjacent sections were labelled with S100ß (astrocytes) and IBA-1 (microglia) in the mPFC of the groups that differed. The number of microglia was significantly higher in females exposed to 40µg/kg/day than controls and lower in males exposed to 4µg/kg/day than controls. There were no significant effects of adolescent exposure to BPA on the number of astrocytes in male or females. Thus, adolescent exposure to BPA produced long-term alterations in the number of microglia in the mPFC of rats, the functional implications of which need to be explored.

Gonadectomy before puberty increases the number of neurons and glia in the medial prefrontal cortex of female, but not male, rats.

The human prefrontal cortex, important for executive functions, loses gray matter throughout the adolescent period. In rats, our laboratory demonstrated that a loss of neurons between adolescence and adulthood partially underlies the loss of volume, and this loss is greater in females than males. Here, we examine whether being deprived of gonadal hormones before puberty through adulthood influences the number of neurons in the medial prefrontal cortex (mPFC). Prior to puberty, the testes or ovaries were removed in male and female rats. In adulthood, the number of neurons and glia in the mPFC were quantified using unbiased stereology, and the volume of the frontal white matter was measured. Prepubertal ovariectomy resulted in a higher number of neurons and glia and a larger volume of white matter compared to sham control littermates. Castrated males were not different from sham males on any measure. Thus ovarian hormones secreted after puberty influence the cellular composition of the medial prefrontal cortex.