Developmental alterations in CNS stress-related gene expression following postnatal immune activation

Abstract

Early-life adversity is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and increased susceptibility to later-life psychopathology. Specifically, there is mounting evidence suggesting that the immune system plays an important role in central nervous system (CNS) development and in the programing of behavior. The current study investigated how early-life immune challenge affects the development of CNS stress neurocircuitry by examining the gene expression profile of corticotropin-releasing hormone (CRH), CRH receptors, and the major corticosteroid receptors within the limbic-hypothalamic circuit of the developing rodent brain. Mice were administered a 0.05 mg/kg lipopolysaccharide (LPS) injection on postnatal day (P) 3 and 5 and gene expression was assessed using in situ hybridization from P14 to P28. Target genes investigated were CRH, CRH receptor-1 (CRHR1), CRH receptor-2, the mineralocorticoid receptor, and the glucocorticoid receptor (GR). Early LPS challenge resulted in a transient decrease in CRHR1 mRNA expression in the cornuammonis 1 (CA1) and CA3 regions of the hippocampus that were accompanied by increased hippocampal GR mRNA expression in the CA1 region between P14 and P21. This was followed by increased hypothalamic CRH expression in LPS-mice on P28. Our current findings suggest that early-life LPS challenge impacts the developmental trajectory of CNS stress neurocircuitry. These results lend insight into the molecular basis for the later development of stress-related behaviors as previously described in early immune challenge rodents.