Inflammation-induced preterm birth alters neuronal morphology in the mouse fetal brain

In the United States, approximately 12% of all live births are delivered preterm (Green et al., 2005). Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity in the United States. Specifically, PTB is a risk factor for adverse neurological outcome for ex-preterm children (Anderson and Doyle, 2003; Hack et al., 2005). It has long been believed that cerebral palsy is the primary neurological outcome of clinical interest. However, it is now known that ex-preterm children also are at a significant risk for a spectrum of cognitive and neurobehavioral disorders (Marlow et al., 2005; Wood et al., 2005; Costeloe, 2006; Limperopoulos et al., 2007; Lindstrom et al., 2009) including autism spectrum disorders (Brimacombe et al., 2007; Limperopoulos et al., 2008; Schendel and Bhasin, 2008). Current understanding of the pathogenesis of fetal brain injury in a PTB focuses mainly on specific structural findings of white matter damage (WMD) (Cai et al., 2000; Paintlia et al., 2004; Rousset et al., 2006). This current paradigm may be insufficient to explain the increasing prevalence of adverse cognitive and neurobehavioral outcomes in ex-preterm infants. While adverse neurological outcomes are increasingly prevalent in ex-preterm children, it remains unknown whether the process of parturition alone at an early gestational age or inflammatory pathways associated with preterm birth are mechanistically responsible for evoking injury in the fetal brain. Reports that maternal fever and/or inflammation of the placenta at the time of a PTB dramatically increase the risk for adverse neurological outcome in these infants (Dammann and Leviton, 1998; Dammann et al., 2002; Roze et al., 2008) strongly argue that activation of inflammatory pathways may mediate fetal brain injury in a preterm birth. Furthermore, increased levels of pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) in the amniotic fluid or cord blood are associated with future development of cerebral palsy in these preterm offspring (Duggan and Edwards, 2001; Yoon et al., 2003). Although the effect of preterm birth on the fetal brain has been investigated utilizing various animal models of inflammation (Bell and Hallenbeck, 2002; Debillon et al., 2003; Elovitz and Mrinalini, 2004; Wang et al., 2006, 2007), the outcomes of interest (e.g. WMD) was never compared to a non-infectious/inflammatory model of preterm birth. Furthermore, while the presence of WMD was investigated in these models, these previous studies did not address whether preterm birth evokes neuronal injury. For the current study, we hypothesize that exposure to inflammation in preterm parturition and not just the process of parturition causes a specific neuronal injury in the fetal brain that may result in long-term neuronal dysfunction that leads to cognitive, behavioral and motor abnormalities in ex-preterm children. These studies sought to assess whether preterm parturition promotes neuronal injury and to determine if these untoward effects were mediated by the process of parturition on a premature brain or whether activation of inflammatory cascade was required for the neuronal injury.