To date perturbations in gene network regulation has also

To date, perturbations in gene network regulation has also been recognized as a key component of the pathogenesis of neurological disorders (Narayanan et al., 2014; Zhang et al., 2013). We identified the impact of TBI on the organization of select networks of genes under regulatory control of key driver genes, which may be responsible for the cascade of cellular events involved in the TBI pathology. We found that TBI affects hippocampal and leukocyte gene networks orchestrated by key driver genes associated with the extracellular matrix (e.g., Fmod, Dcn, Pcolce, collagens), transcription factors (e.g., Tcf7l2, Cebpd), and other functions discussed below (e.g., Anxa2, Ogn). These master genes are located at the center of gene subnetworks surrounded by TBI signature genes, and are likely key regulatory points of these networks. The extracellular matrix genes Fmod and Pcolce have been recently experimentally validated as key regulators of cognitive and metabolic functions (Meng et al., 2016). Tcf7l2 and Cebpd are key transcription factors involved in metabolic processes, diabetes and fat differentiation. The key driver Anxa2 (annexin A2) has been associated with Erismodegib tumor formation (Zhai et al., 2011) and the long-term neurological outcomes of focal embolic stroke (Wang et al., 2014). In turn, the fact that Ogn (osteoglycin) is reduced in the amygdala of animals exposed to stress (Jung et al., 2012), suggests that this gene can be an important link between TBI and psychiatric-like disorders such as anxiety and depression (Max, 2014). The fact that TBI-affected genes are tightly connected through key drivers in gene regulatory networks constructed from completely independent studies supports their functional relatedness and their synchronized actions. The identification of key regulatory genes of the entire network spectrum affected by TBI provides a framework for understanding the integrated actions of multiple pathways on the TBI pathology, and offers plausible key interventional targets (Kasarskis et al., 2011; Yang et al., 2012; Schadt et al., 2009). Although an increasing body of information indicates that TBI is a risk factor for a range of neurological disorders such as CTE, PTSD, AD (Levin and Diaz-Arrastia, 2015; Rabinowitz and Levin, 2014), mechanisms involved remain elusive. In our rodent model, we found that the signature genes Cldn4, Cldn5, Klhdc8a, Lrg1, and Lrrc10b are correlated with the latency time in the Barnes maze. Claudins 4 and 5 belong to a family of genes whose protein products are components of tight junctions and regulate permeability of molecules to the intercellular space. Claudin-5 is a tight junction protein that connects endothelial cells, and is considered important for maintaining permeability of molecules within the extracellular space (Doherty et al., 2016). Therefore, it is possible that genes like Claudins could play a role in the regulation of the BBB, which is a prevalent aspect in the TBI pathology. In turn, the claudin gene CLDN1 has been associated with working memory in human GWAS (Table 1). The actions of klhdc8a, Lrrc10b, and Lrg1 in the brain are poorly understood. However, it has been described that the expression of klhdc8a is elevated in human glioblastomas (Mukasa et al., 2010), and that Lrg1 is associated with regulation of stress (Stankiewicz et al., 2015) and recollection of contextual fear memories (Barnes et al., 2012). Although none of these genes have been studied in the context of TBI, some of their known functions overlap with physiological manifestations of the TBI pathology. By integrating our rodent findings with human GWAS, we found significant overlap between the rodent TBI genes and candidate genes in human GWAS for several neurodegenerative diseases such as AD, cognitive disorders, PTSD and other neuropsychiatric disorders. In particular, we found 16 hippocampal genes including APOE, which are known to provide genetic predisposition to AD (Lupton et al., 2016), and 9 leukocyte genes that overlapped with AD genes. Additionally, four hippocampal genes and one leukocyte gene have known association with human PTSD. Further, we found 14 hippocampal and 5 leukocyte genes are associated with major depressive disorders in humans. These findings provide important genomic leads to elucidate how the TBI pathology can escalate to neurological/psychiatric disorders, and suggest specific interventional targets.