ABSTRACT
Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder, learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2'-deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neurons in the medial prefrontal cortex (medial PFC) was reduced, implying glutamatergic dysregulation. Mice with PNE exhibited behavioral impairments in attentional function and behavioral flexibility in adulthood, and the deficits were ameliorated by microinjection of D-cycloserine into the PFC. Collectively, our findings suggest that PNE affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring.
Subject(s)
Neurogenesis/physiology , Neurons/physiology , Nicotine/toxicity , Nicotinic Agonists/toxicity , Prefrontal Cortex/growth & development , Prenatal Exposure Delayed Effects , Animals , Cell Cycle/drug effects , Cell Cycle/physiology , Cell Movement/drug effects , Cell Movement/physiology , Cognition Disorders/drug therapy , Cognition Disorders/etiology , Cognition Disorders/pathology , Cognition Disorders/physiopathology , Disease Models, Animal , Female , Glutamic Acid/metabolism , Male , Mice, Inbred C57BL , Neural Stem Cells/drug effects , Neural Stem Cells/pathology , Neural Stem Cells/physiology , Neurogenesis/drug effects , Neurons/drug effects , Neurons/pathology , Prefrontal Cortex/drug effects , Prefrontal Cortex/pathology , Prefrontal Cortex/physiopathology , Pregnancy , Random Allocation , gamma-Aminobutyric Acid/metabolismABSTRACT
PURPOSE: To clarify the progression of zone I retinopathy of prematurity (ROP) and elucidate the most suitable time and method of treatment. DESIGN: Interventional case series. METHODS: Forty-six eyes of 23 zone I ROP infants were studied at a single institution. Birth weight ranged from 448 to 954 g, and gestational age ranged from 22 to 26 weeks. Fundus examination was started at 29 or 30 weeks postmenstrual age and was performed once or more per week. The first treatment was performed using laser photocoagulation or cryotherapy when zone I ROP progressed to the following criteria. Treatment criteria A included 35 eyes of 18 cases of zone I any stage ROP with plus disease (Early Treatment for Retinopathy of Prematurity [ETROP] type 1), criteria B included five eyes of three cases of zone I stage 3 ROP with or without plus disease (ETROP type 1), criteria C included six eyes of four cases of stage 1 or stage 2 ROP without plus disease; the demarcation lines belonged, in large part, within the zone I area. RESULTS: Hazy media such as corneal opacity, miotic pupil, tunica vasculosa lentis, and hazy vitreous persisted until approximately 32 weeks postmenstrual age. The mean period between stage 1 and stage 3 mild was one week, that between stage 1 and stage 3 moderate was 1.7 weeks, and that between stage 1 and stage 3 severe was 1.3 weeks. The period between stage 1 and the first treatment was zero to 20 days, and 60.9% of all the cases were treated within 10 days after stage 1. Six of 46 eyes had unfavorable outcomes. Surgical results of our treatment were comparable or better than those of other reports. CONCLUSIONS: Immediate treatment was required when zone I ROP was diagnosed behind persistent hazy media.
