, 2004 and Modulators Clarke et al., 2013). However, similar changes were not observed following restraint of conventionally housed mice suggesting that the absence of the early microbiota influences stress responsivity into adulthood. Further, monoassociation with Bifidobacterium infantis, a bacterium commonly isolated from the neonate gut, partially rescued the HPA stress activation, and gnotobiotic mice reconstituted with normal specific pathogen-free microbiota exhibited decreased anxiety-like behaviors ( Sudo et al., 2004, Clarke et al., 2013 and Nishino et al., 2013). Further evidence

of the role of microbiota in shaping stress pathway regulation comes from the study Z-VAD-FMK molecular weight of serotonergic dysregulation, a common feature ZD1839 molecular weight in sex-specific affective disorders (Ressler and Nemeroff, 2000 and Goel and Bale, 2010). Consistent with previous reports of sex differences in serotonergic neurocircuitry and established sex differences in the HPA axis stress response (Goel and Bale, 2010), hippocampal serotonin and 5-HIAA, the main metabolite of serotonin, concentrations were higher in conventionally colonized (CC) female mice than in males (Clarke et al., 2013). Interestingly, serotonin and 5-HIAA levels remain unchanged in GF females relative to CC females, while concentrations of these monoamines

and metabolites were increased to female-typical levels in GF male mice (Clarke et al., 2013), suggesting potential dysmasculinization of hippocampal serotonergic neurocircuitry in GF males. Consistent with previous work on early life stress and sex-specific dysregulation of neuroplasticity (Mueller and

Bale, 2008), BDNF expression was decreased in the hippocampus of GF male, but not GF female mice (Clarke et al., 2013). While bacterial colonization of GF males during the post-weaning period did not rescue hippocampal serotonergic alterations, this treatment successfully rescued altered anxiety-like behaviors observed in male GF mice (Clarke et al., 2013). This demonstration of the absence of a normal gut microbiota exhibiting consequences on neurodevelopment and adult behavior in males but not females introduces the possibility that the microbiome may also contribute to a larger extent to sex differences in the susceptibility to disease. Of great importance to stress Endonuclease pathway regulation, a direct interaction between gonadal hormones and microbial exposure in mediating sex-specific disease risk has been recently illustrated (Markle et al., 2013 and Yurkovetskiy et al., 2013). The incidence of autoimmune disorders such as type 1 diabetes (T1D) displays a strong female bias, with nearly twice as many females affected as males (Pozzilli et al., 1993). Similar sex-specific susceptibility is observed in the non-obese diabetes (NOD) mouse model where female NOD mice exhibit increased incidence of T1D pathogenesis relative to NOD males (Pozzilli et al., 1993).