Developing fetus in maternal womb can be exposed to environmental stress, and this may lead to the development of long-lasting neurological and behavioral changes. Uncontrolled Inflammation encountered in utero and its effects on behaviors of offspring have been modeled in rodents and subsequently coined as maternal immune activation (MIA). However, it is still unknown how the immune activation, which takes place in pregnant dams, is translated into neurological and behavioral changes in offspring. Using both genetic mutants lacking a particular subset of pro-inflammatory immune cells and blocking antibodies targeting their activities, we have recently found that pro-inflammatory T helper cells (Th17 cells) expressing intereukin-17a (IL-17a) in mothers induce MIA-dependent behavioral changes and abnormal cortical phenotypes in offspring. We also observed that the receptor for IL-17a (IL-17Ra) is expressed in the fetal brain and its expression is increased in the cortical plate upon MIA. These observations taken together suggest an exciting hypothesis that uncontrolled activation of IL-17Ra expressed in fetal brain induces abnormal cortical patches and these structural abnormalities eventually lead to the MIA- associated behavioral phenotypes. Thus, in this application, we propose 1) to determine if cortical abnormalities could predict behavioral phenotypes in MIA offspring, 2) to characterize cortical abnormalities in adult MIA offspring, and 3) functionally determine if the cortical phenotype is the underlying cause of the MIA behavioral abnormalities.
Maternal inflammation influences fetal brain development by inducing pathological cortical phenotype accompanied by behavioral abnormalities. However, underling mechanisms both at immunological and neurological levels are not well understood. We propose to take genetic, neural anatomical and functional approaches to characterize critical cytokines and their receptors as well as affected brain regions for their roles in mediating maternal immune activation-dependent phenotypes observed in affected offspring.! !
|Shin Yim, Yeong; Park, Ashley; Berrios, Janet et al. (2017) Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature 549:482-487|
|Kim, Sangdoo; Kim, Hyunju; Yim, Yeong Shin et al. (2017) Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549:528-532|