ABSTRACT
Neonatal brain function was investigated in a prenatal BrdU-induced developmental disorder model, which has been reported to exhibit behavioral abnormalities such as locomotor hyperactivity, impaired learning and memory, and lower anxiety in offspring. After 1h home cage deprivation we observed an increase in the number of c-Fos (neuronal activity marker) immunoreactive cells in several brain regions of the olfactory and stress-related areas in normal neonates at 11 days. Next, pregnant rats were exposed to 50mg/kg of BrdU from gestation days 9-15, and their offspring at 11 days were home-cage deprived. Compared to vehicle control, the number of c-Fos immunoreactive cells in BrdU group was found to be decreased in the piriform cortex and locus coeruleus, which are known to play an important role in neonatal learning and memory. We also analyzed Pearson product-moment correlation coefficient of the number of c-Fos immunoreactive cells, focusing on the piriform cortex and locus coeruleus versus numerous other brain areas (11 areas including amygdala). Numerous significant correlations were observed in the vehicle control group, however, correlations of the locus coeruleus disappeared in the BrdU group. By observing c-Fos immunoreactivity after home cage deprivation our study uncovers abnormal brain functions as early as postnatal day 11 in this disorder model. Based on these results, we propose a new histological approach for functional characterization of developmental disorder models.
Subject(s)
Antimetabolites/toxicity , Brain/abnormalities , Developmental Disabilities/pathology , Prenatal Exposure Delayed Effects/physiopathology , Animals , Animals, Newborn , Brain/pathology , Bromodeoxyuridine/toxicity , Developmental Disabilities/etiology , Disease Models, Animal , Female , Gene Expression Regulation, Developmental/drug effects , Gene Expression Regulation, Developmental/physiology , Male , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Sprague-Dawley , Social IsolationABSTRACT
A longevity gene product, Sir2 (silent information regulator 2) is a NAD-dependent histone deacetylase involved in longevity in yeasts, worms and flies. The mammalian homolog of Sir2, SIRT1(sirtuin 1), has been shown to play important roles related to anti-aging effects (regulating apoptosis, stress tolerance, insulin resistance, and fat metabolism). Recently, SIRT1 expression has been demonstrated to occur at as early as embryonic day 10.5 in mice. SIRT1 during developing period may be involved in the mechanism of developmental origins of adult diseases, such as diabetes and cardiovascular disease. To investigate the contribution of SIRT1, it is important to reveal the distribution of this protein during development. In the present study, we demonstrated the distribution of immunoreactivity of SIRT1 in mouse organs during prenatal and neonatal development by staining a wide variety of serial sections. The SIRT1 immunoreactivity was strongly observed in the neuroepithelial layer, dorsal root ganglion, trigeminal ganglion, eyes, roots of whiskers, and internal organs, including the testis, liver, heart, kidney, and lung during the fetal period. Neurons which had finished migrating still showed relatively strong immunoreactivity. The immunoreactivity was completely absorbed by the blocking peptide in an absorption test. During the postnatal period, the immunoreactivities in most of these organs, except the heart and testis weakened, with the liver most dramatically affected. As SIRT1 expression was demonstrated in a wide variety of developing organs, further study to investigate prenatal factors which affect SIRT1 expression and its activity is important.
